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Immunomodulatory Effects of Withania Somnifera on Azoxymethane Induced Experimental Colon Cancer in Mice

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Abstract

The efficacy of Withania somnifera on immunomodulation was tested in experimental azoxymethane induced colon cancer in mice. Azoxymethane is a potential carcinogen to induce the colon cancer in Swiss albino mice. Azoxymethane 15 mg/kg body weight was injected intraperitoneally once a week for 28 days. The colon cancer was confirmed by the appearance of aberrant crypt foci (ACF) in the colons of the experimental mice. The progression in colon tumor development was correlated with the appearance of the histological biomarker and ACF. Azoxymethane induced colon cancer animals were treated with 400 mg/kg body weight of W. somnifera extract once a week for four weeks orally. After the experimental period, the animals were sacrificed and analyzed for immunocompetent cells, immune complexes and immunoglobulins. W. somnifera significantly altered the level of leucocytes, lymphocytes, neutrophils, immune complexes and immunoglobulins (Ig) A, G and M. The azoxymethane induced colon cancer and immune dysfunction was better controlled by W. somnifera. These results suggested that the immunomodulatory effects of W. somnifera could be useful in the treatment of colon cancer.

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... It has been used as an herbal tonic and healthy food to treat various diseases and human ailments (Gurav & Gurav, 2014. Ashwagandha is reported to possess multiple pharmacological activities including immune booster, hepatoprotective, anxiolytic, antidepressant, nootropic, antiinflammatory, antioxidant, anti-stress, anticonvulsant, antitumor, anti-genotoxic, and immunomodulatory properties (Gurav et al., 2020;Muralikrishnan et al., 2010). Additionally, a previous report suggests the anti-viral property of W. somnifera (Cai et al., 2015). ...
... Previously, W. somnifera has been identified as an immune system booster (Muralikrishnan et al., 2010). Further, it is also used to manage multiple infectious and non-infectious diseases (Cai et al., 2015;Palliyaguru et al., 2016;Udayakumar et al., 2009). ...
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Traditionally, Withania somnifera is widely used as an immune booster, anti-viral, and for multiple medicinal purposes. The present study investigated the withanolides as an immune booster and anti-viral agents against the coronavirus-19. Withanolides from Withania somnifera were retrieved from the open-source database, their targets were predicted using DIGEP-Pred, and the protein-protein interaction was evaluated. The drug-likeness score and intestinal absorptivity of each compound were also predicted. The network of compounds, proteins, and modulated pathways was constructed using Cytoscape, and docking was performed using autodock4.0, and selected protein-ligand complexes were subjected to 100 ns Molecular Dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-GBSA method. Withanolide_Q was predicted to modulate the highest number of proteins, showed human intestinal absorption, and was predicted for the highest drug-likeness score. Similarly, combined network interaction identified Withanolide_Q to target the highest number of proteins; RAC1 was majorly targeted, and fluid shear stress and atherosclerosis associated pathway were chiefly regulated. Similarly, Withanolide_D and Withanolide_G were predicted to have a better binding affinity with PLpro, Withanolide_M with 3CLpro, and Withanolide_M with spike protein based on binding energy and number of hydrogen bond interactions. MD studies suggested Withanoside_I with the highest binding free energy (ΔGbind-31.56 kcal/mol) as the most promising inhibitor. Among multiple withanolides from W. somnifera, Withanolide_D, Withanolide_G, Withanolide_M, and Withanolide_Q were predicted as the lead hits based on drug-likeness score, modulated proteins, and docking score to boost the immune system and inhibit the COVID-19 infection, which could primarily act against COVID-19. • Highlights • Withanolides are immunity boosters. • Withanolides are a group of bio-actives with potential anti-viral properties. • Withanolide_G, Withanolide_I, and Withanolide_M from Withania somnifera showed the highest binding affinity with PLpro, 3CLpro, and spike protein, respectively. • Withanolides from Withania somnifera holds promising anti-viral efficacy against COVID-19. Communicated by Vsevolod Makeev
... Skin tumor multiplicity was also decreased upon feeding of mice with WRE-supplemented diets (Padmavathi et al. 2005). Muralikrishnan et al. (2010) provided evidence for constraint of azoxymethane-induced colon cancer and immune dysfunction in mice by oral administration of 400 mg WS extract/kg once every week for 4 weeks. Chemopreventive effect of WRE against estrogen receptor-positive breast cancer was examined using N-methyl-N-nitrosourea-rat model (Khazal et al. 2013). ...
... Administration of WS could reduce leucopenia, enhance bone marrow cellularity and normalize the ratio of normochromatic to polychromatic erythrocytes in mice treated with sub-lethal dose of gamma radiation (Kuttan 1996). Extract of WS showed immunomodulatory effects on azoxymethane-induced colon cancer in Swiss albino mice when treated with the plant extract at 400 mg/kg body weight once a week for 4 weeks (Muralikrishnan et al. 2010). WA and Withanolide E (WE) exhibited specific immunosuppressive effect on human B and T lymphocytes and on mice thymocytes. ...
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Withania somnifera (WS) plant has been used for centuries to cure or treat various disorders in the Ayurvedic medicine. Research over the years has indicated that withanolides are the primary bioactive constituents in WS. Scientific evidence for anticancer effects of WS root extract (WRE) is quite strong, and is derived from both in vitro cellular experiments and in vivo studies in rodent models of cancer. This article reviews scientific evidence supporting anticancer effects of WRE and its primary withanolide (withaferin A). The primary focus of the present article is on: (a) phytochemistry of WS, (b) withanolide biosynthesis, (c) pharmacokinet-ics, (d) in vivo evidence for anticancer activity of WRE and its primary bioactive component withaferin A (WA), and (e) effect of WA and WRE on cancer stem cell population and/or epithelial-mesenchymal transition. Unpublished results from our own laboratory are presented to demonstrate that WA is the most likely primary anticancer agent in WRE standardized for WA content (sWRE). The mechanisms underlying anticancer effects of WRE and WA have been reviewed extensively by us and others, and therefore are not elaborated in this article.
... Based on the above concept, we attempted to investigate Withania somnifera as an immune system booster in COVID-19 infection and its binding a nity to three reported targets i.e. 3CLpro, PLpro, and spike protein in COVID-19 infection. Withania somnifera is itself is an anti-viral agent [7] and also recorded as the immune booster [8] in the ayurvedic medicine and multiple scienti c literatures. Further, it composes withanolides as major components that are popular in increasing the immune system [9], are anti-viral [10], and act as anti-in ammatory [11]. ...
... Withania somnifera has been identi ed as an immune system booster [8] and it is used in the management of multiple infectious and non-infectious diseases [7,25,26]. Hence, an attempt was made to identify the possible role of this agent against COVID-19 management. ...
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Aim: The present study aimed to investigate the withanolides as an immune system booster and anti-viral agents against the coronavirus. Materials and Methods: Reported withanolides from Withinana somnifera were retrieved from the open-source database i.e. ChEBI, PCIDB and Dr. Duke's Phytochemical and Ethnobotanical Databases. Their protein-based targets were predicted using DigepPred and the protein-protein interaction was evaluated using STRING. Similarly, the drug-likeness score of individual compounds was predicted using MolSoft and intestinal absorptivity was predicted using the boiled-egg model. The network among the compounds, proteins, and modulated pathways was constructed using Cytoscape and the docking was performed using autodock4.0. Results: Withanoloid Q was predicted to modulate the highest number of proteins, showed positive human intestinal absorption and had the highest druglikeness score. Similarly, combined network interaction identified withanolide Q to target the highest number of proteins; RAC1 was majorly modulated and regulating Fluid shear stress and atherosclerosis as a majorly regulated pathway. Similarly, Withanolide D and Withanolide G were predicted to have the better binding affinity with PLpro, Withanolide M with 3clpro, and Withanolide M with spike protein based on binding energy and number of hydrogen bond interactions. Conclusion: Among the multiple withanolides from Withania somnifera, withanolide-D, -G, -M, and -Q were predicted as a lead hit based on druglikeness score, modulated proteins, and docking score to boost immune system and inhibit the COVID infection.
... Administration of WS could reduce leucopenia, enhance bone marrow cellularity and normalize the ratio of normochromatic to polychromatic erythrocytes in mice treated with sub-lethal dose of gamma radiation (Kuttan 1996). Extract of WS showed immunomodulatory effects on azoxymethane-induced colon cancer in Swiss albino mice when treated with the plant extract at 400 mg/kg body weight once a week for 4 weeks (Muralikrishnan et al. 2010). WA and Withanolide E (WE) exhibited specific immunosuppressive effect on human B and T lymphocytes and on mice thymocytes. ...
... ).Muralikrishnan et al. (2010) provided evidence for constraint of azoxymethane-induced colon cancer and immune dysfunction in mice by oral administration of 400 mg WS extract/kg once every week for 4 weeks. Chemopreventive effect of WRE against estrogen receptor-positive breast cancer was examined using N-methyl-N-nitrosourea-rat model(Khazal et al. 2013). ...
... Withania somnifera is an Ayurvedic medicinal plant whose root and leaves extracts have been used for its antioxidant and restorative properties as well as to reduce cancer growth a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 [2,6,15]. W. somnifera extracts have been found to be effective in treating several types of cancer including skin, leukaemia, breast, colon and pancreas [15][16][17][18][19][20][21]. ...
... Withania somnifera is an Ayurvedic medicinal plant whose root and leaves extracts have been used for its antioxidant and restorative properties as well as to reduce cancer growth a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 [2,6,15]. W. somnifera extracts have been found to be effective in treating several types of cancer including skin, leukaemia, breast, colon and pancreas [15][16][17][18][19][20][21]. However, the mechanisms of action have yet to be fully elucidated, but indications of involvement in mitochondrial membrane permeability have been reported in several studies [1,[21][22][23]. ...
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Withania somnifera extracts are known for their anti-cancerous, anti-inflammatory and antioxidative properties. One of their mechanisms of actions is to modulate mitochondrial function through increasing oxidative stress. Recently ‘priming’ has been suggested as a potential mechanism for enhancing cancer cell death. In this study we demonstrate that ‘priming’, in HT-29 colon cells, with W. somnifera root extract increased the potency of the chemotherapeutic agent cisplatin. We have also showed the W. somnifera root extract enhanced mitochondrial dysfunction and that the underlying mechanism of ‘priming’ was selectively through increased ROS. Moreover, we showed that this effect was not seen in non-cancerous cells.
... Withania somnifera components are found to be effective against several types of cancers. It has been observed that Withania somnifera extract can inhibit activities of key TCA cycle enzymes like isocitrate dehydrogenase, malate dehydrogenase in colon cancer bearing animals [5]. 1-oxo-5beta, 6beta-epoxy-witha-2-enolide isolated from the roots of Withania somnifera, is effective against ultraviolet radiation induced skin carcinoma in rats [6]. ...
... Withania somnifera is well identified for its various biological activities such as adaptogenic/anti-stress, immunomodulatory, anti-ageing, anti-fatigue, antioxidant, antiparkinsonism, antiulcerogenic and anti-tumors/adenomas properties [4,[16][17][18][19][20][21][22][23][24][25][26]. A number of studies have been carried out to assess the efficiency of Withania somnifera in prevention and treatment of diverse kinds of cancer of colon [5], lung [7], blood [8], breast [11], renal [12], prostate [11], pancreatic [10] and mouse skin [6]. Most of the skin cancer studies have been carried out on the mouse model and there is no report about the effect of Withania somnifera on human malignant melanoma cells, A375. ...
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In Ayurveda, Withania somnifera is commonly known as Ashwagandha, its roots are specifically used in medicinal and clinical applications. It possesses numerous therapeutic actions which include anti-inflammatory, sedative, hypnotic and narcotic. Extracts from this plant have been reported for its anticancer properties. In this study we evaluated for the first time, the cytotoxic effect of Withania root extract on human malignant melanoma A375 cells. The crude extract of Withania was tested for cytotoxicity against A375 cells by MTT assay. Cell morphology of treated A375 cells was visualized through phase contrast as well as fluorescence microscopy. Agarose gel electrophoresis was used to check DNA fragmentation of the crude extract treated cells. Crude extract of Withania root has the potency to reduce viable cell count in dose as well as time dependent manner. Morphological change of the A375 cells was also observed in treated groups in comparison to untreated or vehicle treated control. Apoptotic body and nuclear blebbing were observed in DAPI stained treated cells under fluorescence microscope. A ladder of fragmented DNA was noticed in treated cells. Thus it might be said that the crude water extract of Withania somnifera has potent cytotoxic effect on human malignant melanoma A375 cells.
... Colon cancer ranks third globally incidence wise and ranks second in mortality cases among the various cancers [1,111]. In Swiss albino mice, it was observed that ethanolic extracts of WS evinced immunoregulatory tendencies in azoxymethane-induced colon cancer [129]. Withaferin A has also demonstrated anticancer activity against colon cancer by targeting and downregulating Notch-1 signaling via targets such as Hey-1 and Hes-1 and concurrently suppressing crosstalk between Notch-1 and Akt/mTOR pathways. ...
Article
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Chemotherapy is one of the prime treatment options for cancer. However, the key issues with traditional chemotherapy are recurrence of cancer, development of resistance to chemotherapeutic agents, affordability, late-stage detection, serious health consequences, and inaccessibility. Hence, there is an urgent need to find innovative and cost-effective therapies that can target multiple gene products with minimal adverse reactions. Natural phytochemicals originating from plants constitute a significant proportion of the possible therapeutic agents. In this article, we reviewed the advances and the potential of Withania somnifera (WS) as an anticancer and immunomodulatory molecule. Several preclinical studies have shown the potential of WS to prevent or slow the progression of cancer originating from various organs such as the liver, cervix, breast, brain, colon, skin, lung, and prostate. WS extracts act via various pathways and provide optimum effectiveness against drug resistance in cancer. However, stability, bioavailability, and target specificity are major obstacles in combination therapy and have limited their application. The novel nanotechnology approaches enable solubility, stability, absorption, protection from premature degradation in the body, and increased circulation time and invariably results in a high differential uptake efficiency in the phytochemical’s target cells. The present review primarily emphasizes the insights of WS source, chemistry, and the molecular pathways involved in tumor regression, as well as developments achieved in the delivery of WS for cancer therapy using nanotechnology. This review substantiates WS as a potential immunomodulatory, anticancer, and chemopreventive agent and highlights its potential use in cancer treatment.
... The authors concluded that methanolic extract of W. somnifera root has antiproliferative activity due to increase production of ROS and reduced function of mitochondria. W. somnifera was evaluated in a mouse model of AOM-induced colon cancer by Muralikrishnan et al. (2010). Four-week treatment of W. somnifera extract was reported to better regulate the immune dysfunction and colon cancer and it was found that the immunomodulatory effect was beneficial in the treatment of colon cancer. ...
Article
Background : Ayurveda is a highly recognized, well-documented, and well-accepted traditional medicine system. This system utilizes many natural products in various forms for therapeutic purposes. Thousands of plants mentioned in the Ayurvedic system are useful in disease mitigation and health preservation. One potential plant of the Ayurvedic system is “Ashwagandha” [Withania somnifera (L.) Dunal], commonly regarded as Indian Ginseng. It possesses various therapeutic activities, such as neuroprotective, hypoglycemic, hepatoprotective, antiarthritic, and anticancer effects. Purpose : Here we present a comprehensive insight on the anticancer effects of W. somnifera and mechanistic attributes of its bioactive phytocompounds. This review also provides an updated information on the clinical studies pertaining to cancer, safety evaluation and opportunities for chemical modifications of withanolides, a group of specialized phytochemicals of W. somnifera. Methods : The present study was performed in accordance with the guidelines of the Preferred Reporting Items for Systemic Reviews and Meta-Analysis. Various scientific databases, such as PubMed, Science Direct, Scopus, Google Scholar, were explored for related studies published up to May 2021. Results : An updated review on the anticancer potential and mechanisms of action of the major bioactive components of W. somnifera, including withanolides, withaferin A and withanone, is presented. Comprehensive information on clinical attributes of W. somnifera and its active components are presented with the structure-activity relationship (SAR) and toxicity evaluation. Conclusion : The outcome of the work clearly indicates that W. somnifera has a significant potential for cancer therapy. The SAR revealed that various withanolides in general and withaferin A in particular have binding energies against various proteins and tremendous potential to serve as the lead for new chemical entities. Nevertheless, additional studies, particularly well-designed clinical trials are required before therapeutic application of withanolides for cancer treatment.
... Animals were treated with 400 mg/kg of W. somnifera extract once a week for four weeks orally. W. somnifera significantly altered the level of leucocytes, lymphocytes, neutrophils, immune complexes and immunoglobulins (Ig) A, G and M. (Muralikrishnan, 2010) [19] . ...
Research
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Coronavirus disease 2019 (COVID-19) has been increasing and has a widespread prevalence hence it is receiving extensive attention for its incidence. COVID-19 infection is known to affect individuals with weak immunity more severely. Immune functions are requisite for shielding the body against attack by pathogens, and thus play an essential role in the maintenance of health. Therefore, the ingestion of foods with immune-modulating activities is considered an efficient way to prevent immune functions from declining and reduce the risk of infection or cancer. The present review describes Ashwagandha (W. somnifera) immunomodulatory effects, activity against microbes and infection, general health benefits
... Following W. somnifera supplement, hens susceptible to ovarian cancer displayed a significant reduction in tumor development associated with increased NK cell population [85]. Similarly, oral administration of W. somnifera extract (400 mg/kg body weight) once a week for four weeks treating azoxymethane-induced colon cancer in Swiss albino mice increased the number and functional activity of immune cells [89]. NMITLI 101R, a chemotype of W. somnifera, generated humoral and cellular immune responses in Balb/c mice as measured by a high number of antibody-producing cells. ...
Article
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Medicinal plants serve as a lead source of bioactive compounds and have been an integral part of day-to-day life in treating various disease conditions since ancient times. Withaferin A (WFA), a bioactive ingredient of Withania somnifera, has been used for health and medicinal purposes for its adaptogenic, anti-inflammatory, and anticancer properties long before the published literature came into existence. Nearly 25% of pharmaceutical drugs are derived from medicinal plants, classified as dietary supplements. The bioactive compounds in these supplements may serve as chemotherapeutic substances competent to inhibit or reverse the process of carcinogenesis. The role of WFA is appreciated to polarize tumor-suppressive Th1-type immune response inducing natural killer cell activity and may provide an opportunity to manipulate the tumor microenvironment at an early stage to inhibit tumor progression. This article signifies the cumulative information about the role of WFA in modulating antitumor immunity and its potential in targeting prostate cancer.
... Withania somnifera Dunal (commonly known as Ashwagandha or Indian ginseng) is used in many indigenous systems of medicine, primarily Ayurveda in India [3,4] for the treatment of a number of diseases. This herb is found to be effective in the treatment of carbohydrate and lipid metabolism dysregulation [5] , anxiety [6] , enhancement of immune modulation [7] , prevention of neurodegenerative diseases [8] and cancer [9] . WSE prevents the acquisition and expression of morphine-elicited conditioned place preference, possibly through a GABAB receptor-mediated mechanism [10] . ...
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Objective: To investigate the effect of withania somnifera extract (WSE) on nicotine mediated reinforcement effect and withdrawal symptoms which attributed for the addiction liabilities of nicotine. Methods: In Swiss albino mice nicotine mediated locomotor sensitization and anxiogenic effects of chronic and acute nicotine treatment respectively was tested per se or in combination with WSE. In addition, nicotine withdrawal induced anxiety-like behavior was also studied. Locomotor sensitization was tested by employing open field test (OFT), while symptoms of anxiety were evaluated by subjecting mice to elevated plus maze (EPM). Results: Daily treatment with nicotine (subcutaneous) for 7 days showed gradual increase in the locomotor activity in OFT as compared to saline group indicating the development of locomotor sensitization. Following 3 days of drug free period, nicotine challenge on day 11 also showed rise in locomotor activity depicting expression of sensitization. WSE pretreatment inhibited the nicotine induced development and expression of locomotor sensitization. WSE+nicotine treated group showed decreased ambulations as compared to per se nicotine group on day 1-7 and day 8 (P<0.05). In EPM, acute nicotine treated mice spend more time in open arms as compared to saline indicating the anxiolytic behavior. WSE pretreatment reversed this anxiolytic effect. Nicotine withdrawal mice showed significant increase in the number of entries in arm and total time spend in closed arm indicating anxiety-like behavior. WSE treatment in nicotine withdrawal mice inhibited the nicotine withdrawal induced increased number of entries and time spend in closed arms. Conclusion: These results indicated that WSE may serve an effective herbal medicine in arresting nicotine mediated reinforcement and withdrawal signs.
... Cancer is a hyper-proliferative disorder, which led to restrained propagation, apoptosis dysregulation, and cell cycle. The extracted solutions of W. somnifera were found to be operative inhibitors for TCA cycle enzymes i.e. isocitrate dehydrogenase, malate dehydrogenase in colon cancer-bearing animals [3]. Withanolide steroidal lactones and Withaferin A (Figure 1) isolated from plant roots were reported to be potent anticancer for skin carcinoma in rats [4]. ...
Article
Withania somnifera L. is a medicinal herb related to Solanaceae family, known as ashwagandha. The aqueous extract of W. somnifera was utilized for the green synthesis of zinc nanoparticles to investigated their antioxidant and anticancer potentials. The synthesized zinc nanoparticle solution of W. somnifera extract was characterized by phytochemical analysis, Transmission Electron Microscope (TEM), and zeta potential. The results revealed reduced values of the phytochemical constitutes, large surface area, and high stability of the nanoparticles. The antioxidant activity of the extracted W. somnifera and its zinc nanoparticles was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH•) assay, in which the original extract has the more antioxidant capacity with IC50= 0.701 mg/mL, along with potent results for both samples relative to ascorbic acid. The extracted W. somnifera, its zinc nanoparticles, and zinc sulfate solution were in vitro assessed as anticancer agents on well-known six human tumor, and a normal cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The results demonstrated that the synthesized zinc nanoparticles of the W. somnifera extract shown the most potent cytotoxicity with IC50= 19.17 µg/mL on HeLa cell line. The synthesized nano-zinc solution of the W. somnifera aqueous extract performed to be proficient as a potent anticancer characteristic than the plant extract with developed biological potency.
... General studies with various W. somnifera extracts have reported their ability to inhibit enzymes essential for the cell's TCA cycle such as malate dehydrogenase and isocitrate dehydrogenase in test animals with induced colon cancer (65). Myeloid cells are known to regulate tumor progression. ...
Article
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Cancer is a leading cause of mortality worldwide, the conventional chemotherapeutic drugs have been known for their toxicity and numerous side effects. A new approach to treat cancer involves phytochemical drugs. In the present review, anti-cancer activity of a class of steroidal lactones called withanolides obtained from Withania somnifera (L.) Dunal is discussed. The commonly studied bioactive compounds namely withaferin-A, withanoside IV, withanoside VI and withanolide-A among others obtained from methanolic and chloroform extract of the leaves and various alcoholic, aqueous and chloroform extract of roots have shown inhibition to various human cancer cell lines including skin, breast, colon, prostate, liver, ovary, cervical and lung. Prominent mechanisms of action include induction of apoptosis by NOS upregulation, ROS production and NBS2 or COX-2 inhibition; cytotoxicity by humoral and cell mediated immune response, activation of p53 and pRB and inhibition of various viral oncoproteins; cell cycle arrest by Cdc2 facilitated mitotic catastrophe, cyclin-D1 down-regulation and inhibition of transcription factors. Cancers are also controlled by inhibition of angiogenesis and metastasis of the tumor cells. In addition to anti-tumorogenic properties, W. somnifera also holds properties that make it a potential adjuvant in integrated cancer therapeutics and in enhancing the effectiveness of ongoing radiation therapy.
... General studies with various W. somnifera extracts have reported their ability to inhibit enzymes essential for the cell's TCA cycle such as malate dehydrogenase and isocitrate dehydrogenase in test animals with induced colon cancer (65). Myeloid cells are known to regulate tumor progression. ...
Article
Full-text available
Cancer is a leading cause of mortality worldwide, the conventional chemotherapeutic drugs have been known for their toxicity and numerous side effects. A new approach to treat cancer involves phytochemical drugs. In the present review, anti-cancer activity of a class of steroidal lactones called withanolides obtained from Withania somnifera (L.) Dunal is discussed. The commonly studied bioactive compounds namely withaferin-A, withanoside IV, withanoside VI and withanolide-A among others obtained from methanolic and chloroform extract of the leaves and various alcoholic, aqueous and chloroform extract of roots have shown inhibition to various human cancer cell lines including skin, breast, colon, prostate, liver, ovary, cervical and lung. Prominent mechanisms of action include induction of apoptosis by NOS upregulation, ROS production and NBS2 or COX-2 inhibition; cytotoxicity by humoral and cell mediated immune response, activation of p53 and pRB and inhibition of various viral oncoproteins; cell cycle arrest by Cdc2 facilitated mitotic catastrophe, cyclin-D1 down-regulation and inhibition of transcription factors. Cancers are also controlled by inhibition of angiogenesis and metastasis of the tumor cells. In addition to anti-tumorogenic properties, W. somnifera also holds properties that make it a potential adjuvant in integrated cancer therapeutics and in enhancing the effectiveness of ongoing radiation therapy.
... The cancerous mice were administrated with 400 mg/kg body weight of the extract once a week (4 weeks) and were noticed with significant increase in immunocompetent cells. In another study, Muralikrishnan et al. (2010b) evaluated the effect of withania extracts on tricarboxylic acid (TCA) cycle enzymes [isocitrate dehydrogenase (ICDH), succinate dehydrogenase (SDH), malate dehydrogenase (MDH) and α-keto glutarate dehydrogenase (α-KDGH)] and electron transport chain (ETC) of mice colon cancer. Extract treatment lead to great modifications of these enzymes and ETC complex and all were retained to their optimum activity and prevented carcinogenesis. ...
Article
Ethnopharmacological relevance. Withania somnifera, commonly known as Ashwagandha, is an important medicinal herb belonging to family Solanaceae. It is widely used in folkloric and Ayurvedic medicines since antiquity. Traditionally, the plant is highly practiced throughout the globe as immunomodulator, anti-inflammatory, anti-stress, anti-parkinson, anti-alzheimer, cardio protective, neural and physical health enhancer, neurodefensive, anti-diabetic, aphrodisiac, memory boosting etc. The plant is also effective in combating various cancer and related problems of colon, mammary, lung, prostate, skin, blood, liver and kidney. Aim of this review. The present review represents the critical assessment of the literature available on the anticancerous role of W. somnifera. The present study throws light on its diverse chemical compounds and the possible mechanisms of action involved. This review also suggests further research strategies to harness the therapeutic potential of this plant. Materials and methods. The present review is the outcome of a systematic search of scientific literature about ‘Withania somnifera and its role in cancer prevention’. The scientific databases viz. Google Scholar, Science Direct, Pubmed and Web of Science were searched from 2001 to 2019. Textbooks, magazines and newspapers were also consulted. This review summarizes all the published literature about its therapeutic potential for the treatment of different types of cancers. Results. W. somnifera has been widely used in traditional and ayurvedic medicines for treatment of numerous problems related to health and vitality. The plant is a reservoir of diverse phytoconstituents like alkaloids, steroids, flavonoids, phenolics, nitrogen containing compounds and trace elements. Withanolides are the major alkaloids which renders its anticancer potential due to its highly oxygenated nature. The plant is highly effective in combating various types of cancers viz. colon, mammary, lung, prostate, skin, blood, liver and kidney. Previous studies depict that this plant is more effective against breast cancer followed by colon, lung, prostate and blood cancer. Furthermore, from different clinical studies it has been observed that the active constituents of the plant like withaferin-A, withanolide-D have least toxic effects. Conclusion. The present review confirms the various medicinal values of W. somnifera without any significant side effects. Withaferin-A (WA) and Withanolides are its most promising anticancer compounds that play a major role in apoptosis induction. Keeping in mind the anticancerous potential of this plant, it is suggested that this plant may further be investigated and more clinical studies can be performed.
... Cuscuta reflexa (Giant dodder) in cell lines [5], Swiss albino mice [6], human red blood cells [7] and human cancer cell lines [8]. Ashwagandha or Indian ginseng Withania somnifera has immunomodulatory and anti-cancer effects [9][10][11][12][13][14]. Glycyrrhiza glabra (Liquorice) expresses promising antimicrobial, cytotoxic and anti-cancer effects [15,16]. ...
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UNANI MEDICINE AND CANCER Christer Sundqvist. Prepublished article, 2020 Petrafoundation, Helsinki, Finland https://www.petrafoundation.com/en/foundation Unani medicine is an alternative medical system originating in ancient Greece almost 2500 years back. It is now practiced primarily in India. Herbal remedies, dietary practices and alternative therapies characterize Unani medicine. Let us study what it can offer for a cancer patient.
...  In a study, Withania Somnifera (WS) showed significant alteration in levels of Leucocytes, Lymphocytes, Neutrophils, Immune complexes and Immunoglobulin levels and also considerable reduction in polyethylene glycol (PEG) indices in azoxymethane induced colon cancer of swiss albino mice 25 ...
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Cancer is one of the fastest growing diseases, with an estimated worldwide incidence of 10 million new cases per year. Mortality is high, with >7 million deaths per year. In the last two decades, great advances have been made in cancer therapy; however, the success rates still remain unsatisfactory. Current conventional anticancer therapies are associated with adverse effects, drug resistance, and cancer recurrence. In Unani system of medicine, Cancer is known as Sartān, an Arabic word which means "crab". In the classical Unani literature, Sartān (Cancer) has been mentioned with great description, causes, origin, expansion, metastasis and all of clinical presentations. Renowned physicians like Buqrat, Jalinoos, Razi, Ibn Sina, Tabri and Jurjani gave the details of Sartān and its management. Through this paper, an attempt has been made to highlight the strength of Unani medicine in Sartān.
... showed the immunostimulatory effect of WS ethanolic extract in mice models of colon cancer. The comparative results showed significant increase in immunocompetent cells and immune complexes followed by normalized antibody titer in WS treated mice (Muralikrishnan et al., 2010b). ...
Article
Ethnopharmacological relevance Withania somnifera (L.) Dunal (WS) is one of the most-studied Rasayana botanicals used in Ayurveda practice for its immunomodulatory, anti-aging, adaptogenic, and rejuvenating effects. The botanical is being used for various clinical indications, including cancer. Several studies exploring molecular mechanisms of WS suggest its possible role in improving clinical outcomes in cancer management. Therefore, research on WS may offer new insights in rational development of therapeutic adjuvants for cancer. Aim of this review The review aims at providing a detailed analysis of in silico, in vitro, in vivo and clinical studies related to WS and cancer. It suggests possible role of WS in regulating molecular mechanisms associated with carcinogenesis. The review discusses potential of WS in cancer management in terms of cancer prevention, anti-cancer activity, and enhancing efficacy of cancer therapeutics. Material and methods The present narrative review offers a critical analysis of published literature on WS studies in cancer. The reported studies were analysed in the context of pathophysiology of cancer, commonly referred as ‘cancer hallmarks’. The review attempts to bridge Ayurveda knowledge with biological insights into molecular mechanisms of cancer. Results The critical analysis suggests an anti-cancer potential of WS with a key role in cancer prevention. The possible mechanisms for these effects are associated with the modulation of apoptotic, proliferative, and metastatic markers in cancer. WS can attenuate inflammatory responses and enzymes involved in invasion and metastatic progression of cancer. The properties of WS are likely to be mediated through withanolides, which may activate tumor suppressor proteins to restrict proliferation of cancer cells, regulate the genomic instability, and energy metabolism of cancer cells. The reported studies indicate the need for deeper understanding of molecular mechanisms of WS in inhibiting angiogenesis and promoting immunosurveillance. Additionally, WS can augment efficacy and safety of cancer therapeutics. Conclusion The experimentally-supported evidence of immunomodulatory, anti-cancer, adaptogenic, and regenerative attributes of WS suggest its therapeutic adjuvant potential in cancer management. The adjuvant properties of withanolides can modulate multidrug resistance and reverse chemotherapy-induced myelosuppression. These mechanisms need to be further explored in systematically designed translational and clinical studies that will pave the way for integration of WS as a therapeutic adjuvant in cancer management.
... The alcoholic extract of WS (400 mg/kg b.wt) along with paclitaxel (33 mg/kg b.wt) provided stabilization of membrane-bound ATPase enzymes levels and decreased lipid peroxidation against benzo(a)pyrene-induced lung cancer in male Swiss albino mice (Senthilnathan et al. 2006). Other in vivo studies have shown that alcoholic extract of WS root could also be useful in the treatment of colon and brain or glioblastoma multiforme (GBM) cancers (Chang et al. 2016;Muralikrishnan et al. 2010). However, no evidence suggests that WS exerts similar effect in humans. ...
Conference Paper
The purpose of this review is to introduce the readers about the pharmacological and chemical aspects of the genus Withania. Present review has a brief description about almost all the pharmacological and chemical studies made on the six different species of this genus and tells about the future prospectus of these plants in the field of drug discovery and health care. It also provides key information about the structure activity relationship in withanolides which are the major bioactive constituents of these plants.
... ( Muralikrishanan et al., 2010)  ANTI INFLAMMATORY: ...
Article
Background - Soo-ul-Qinya (Anaemia) is a major public health problem in India. According to the World Health Organization (WHO), there are two billion people with anaemia in the world and half of the anaemia is due to iron deficiency. Unani system of medicine has a treasure of single and compound formulations for the treatment of anaemia. The compound drug (Sharbat-e-Faulad) is one of widely prescribed medicine for the treatment of Soo-ul-Qiniya (Anaemia) in Unani medicine. Material and Methods- Present open labelled, multi-centric, single arm validation was conducted to evaluate the safety and efficacy of Unani pharmacopeial drug Sharbat-e-Faulad in So-ul-qinya. Patients with Hb% in the range of 8-12 mg% in males and 8-10 mg % in female are included in the study. Sharbat- e- Faulad were given in the dose of 12 ml twice a day for the period of 12 weeks. Clinical as well haematological parameters were assesses before and after the treatment to evaluate the safety and efficacy of the drug. Results– there is significant improvement in the Hb% of the patients treated with Unani formulation. Also, improvement in the sign and symptoms associated with Sū’ al-Qinya (Anaemia) are recorded. Conclusion- Unani compound formulation Sharbat-e-Faulad has
... A number of compounds are isolated from it; several alkaloids such as withsomine, withaferinA, phytosterol, reducing sugars, glycosides, flavonoids and saponins are the most common which are responsible for its extensive use. Further studies are required to isolate other biological active constituents responsible for its therapeutic use and also to validate the traditional knowledge of Asgand [28][29][30][31] . ...
Article
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Withania somnifera Dunal. is a well known Indian medicinal plant widely used in the treatment of many clinical conditions in India. It is an important drug commonly known as Asgand which has been used either single or in combination with other drugs in Unani as well as Ayurvedic system of medicine for centuries. Withania somnifera holds a place in Ayurveda similar to that of ginseng has in Chinese medicine. Asgand is commonly known as Indian ginseng or Indian winter cherry. It has been described by Dioscorides (78 AD) in his book “Kitab-ul-Hashaish”. The objective of this paper is to review the literature regarding Withania somnifera Dunal. The search was carried out through Unani classical books via library, ethno botanical literature, journals and electronic search. Asgand consists of the roots of Withania somnifera which has various therapeutic actions such as female disorders, cough, rheumatism and dropsy and as a sedative in case of senile debility. Chemical analysis of Asgand shows that it contains several alkaloids such as withsomine, withaferinA, withanolide A and withanolide D and various other constituents. Research studies have shown that it possesses anti-inflamma¬tory, anti-oxidative, antimicrobial, anti-anxiety, aphrodisiac, immunomodulation, anti-diabettic, anti-ulcer, anticancer, central nervous system depressant and hepatoprotective activities. An extensive review of ancient literature of Unani medicine revealed that the drug having numerous therapeutic action such as Muhallile warm (anti-inflammatory), Moallide mani (semen producer), Musakkin (sedative), Muqawwie aam (General tonic) and Muqawwie Bah (aphrodisiac). Keeping in view the medicinal properties of Withania somnifera Dunal (Asgand), an attempt has been made in this review paper to explore various dimensions of the drug including botanical, chemical and pharmacological studies of plant besides its traditional uses in Unani Medicine.
... W. somnifera has been reported to show anti-cancer activity both in vitro and in vivo in various studies. Muralikrishnan et al. (1996) reported that W. somnifera was able to normalise the count of immune cells and immunoglobins in an experimental colon cancer model induced by Azoxymethane in mice (Muralikrishnan et al. 2010). Several studies reported that root extract of W. somnifera suppressed stomach and skin cancer and tumour development in mice (Singh et al. 1984;Chandra et al. 2012;Kuttan 1996). ...
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Withania somnifera is wonder shrub used traditionally as a folk medicine for several remedies in the Indian subcontinent. During last few decades numerous scientific studies have shown the potential therapeutic prospects of this herb and of its various constituents in different disease models. Several classes of compounds including withanolides, sitoindosides and other useful alkaloids have been isolated from this plant with promising medicinal value. It has been demonstrated that different parts of plant including roots, leaves and fruits exhibit unique biological activities that actually are manifested to the presence and the abundance of specific constituent/s in the respective parts of the plant. It was also established that same plant grown at different locations under varied environmental conditions influences the synthesis of the individual constituents in different parts of the plant, hence their biological activities. Studies conducted in cellular and murine models have shown that extracts made of roots bear immune activating properties, whereas leaf extracts showed anticancer activities. It has been observed that root and leaf extracts of plant characterised with about a dozen markers displayed that root extracts demonstrated Th1 specific immunomodulatory and anti-inflamatory activities, whereas leaf extracts showed anticancer properties, respectively. It was further explored that anti-cancer potential of leaf extracts was mainly due to Withaferin A, a potent cytotoxic withanoloid, existing in abundance and a major constituent in the leaves of the plant. Similarly, anti-inflammatory and Th1 immune skewing properties of the root extract was conferred to the higher amount of Withanolide A, present in the roots of the plant along with other constituents. Meanwhile several studies have deciphered the role of individual constituents in various biological activities with extensive mechanism of action discussed in this review. This review while summarises the potential medicinal benefits of the W.somnifera, it also emphasizes that marketed product of the plant extracts for human consumption should scientifically validated for bioactive constitutents.
... Root extract of W. somnifera was shown in a large number of publications to inhibit cancer cells and tu- mor growth including lymphoma, colon cancer and skin carcinogenesis in mice (e.g., [57][58][59]). W. somnif- era extract had a clear immunomodulatory effect, since it significantly altered the levels of leucocytes, lym- phocytes, neutrophils, immune complexes and immu- noglobulins (Ig) A, G and M in the Azoxymethane in- duced colon cancer model in animals [60]. It was also shown, in combination with paclitaxel, to effectively treat benzo(a) pyrene-induced lung cancer in mice, by reducing reactive oxygen species damage and suppress- ing cell proliferation (indicated by the levels of glyco- proteins) [61]. ...
Article
Background The Mediterranean basin is one of the richest biodiversity areas in the world, and the use of medicinal plants for treating cancer in this area has been documented for generations in different cultures. Objective To present and discuss the findings related to medicinal plants with confirmed data on active compounds and/or clear mode of action. Methods We undertook a structured search of bibliography of peer-reviewed research literature using key words and a focused review question. Papers with sufficient quality were reviewed, their findings presented and integrated into a coherent, state of the art document on wild plants of the Middle East with anti-cancer activity. Results 121 papers were included in the review, among them 10 define herbal medicine, 3 describe the status of cancer worldwide, 18 discuss biodiversity, chemodiversity, ethnopharmacological survey and conservation of medicinal plants, 12 describe well known natural products from plants used to treat cancer and 78 papers describe specific compounds and mode of action in different wild plants from the middle east, traditionally used to treat cancer. Conclusions Confirmed data on active compounds and/or clear mode of action exist for several wild plants traditionally used in herbal medicine to treat cancer. Yet, medicinal plants were mainly gathered from the wild, resulting in some of the commonly used herbs becoming endangered species. Also, in many cases, the activity and biochemical profile of plants harvested over different time spans and ecosystems may vary. Rational cultivation may ensure optimized yield with a uniform high quality of products.
... Genetic studies might point to the different genotypic variations that might explain why these elderly patients have the capacity to mount a full blown immunological response to infections. Further research on immunity will probably help in finding ways and means by which immunomodulation might help the elderly in the prevention of infections 14 . In developing a preventive strategy to preserve or increase the immunity of the elderly all the above points will need to be taken into consideration. ...
Article
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The elderly are at increased risk of developing Streptococcus gallolyticus endocarditis. The infection is easily controlled by antibiotics but a valvular replacement may be needed for gross valvular dysfunction. Some patients may have associated colonic or hepatic lesions needing surgical intervention that increase morbidity, mortality and costs. We describe a 71-year-old patient with Streptococcus gallolyticus endocarditis and discuss the differences of response between the strong and the frail elderly.
... Studies have revealed that extracts of Withania somnifera have controlling effect on azoxymethane induced colon cancer and im-mune dysfunction [28]. reported that extract of Withania somnifera decreased the activities of some key enzymes of Kreb s cycle, such as succinate dehydrogenase, alphaketoglutarate dehydrogenase, isocitrate dehydrogenase and malate dehydrogenase, which in turn starve the cancer cells in validated colon cancer bearing experimental animal models [29]. ...
Article
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Withania somnifera is an important medicinal herb that has been widely used for the treatment of different clinical conditions. The overall medicinal properties of Withania somnifera make it a viable therapeutic agent for addressing anxiety, cancer, microbial infection, immunomodulation, and neurodegenerative disorders. Biochemical constituents of Withania somnifera like withanolideA, withanolide D, withaferin A and withaniamides play an important role in its pharmacological properties. Proteins like Withania somnifera glycoprotein and withania lectin like-protein possess potent therapeutic properties like antimicrobial, anti-snake venom poison and antimicrobial. In this review, we have tried to present different pharmacological properties associated with different extract preparations, phytochemical constituents and protein component of Withania somnifera. Future insights in this direction have also been highlighted.
... Withania somnifera Dunal (commonly known as Ashwagandha or Indian ginseng) is used in many indigenous systems of medicine, primarily Ayurveda in India (Kulkarni and Dhir, 2008), for the treatment of a number of diseases, including carbohydrate and lipid metabolism dysregulation (Shukla et al., 2012), anxiety (Sarris et al., 2013), enhancement of immune modulation (Muralikrishnan et al., 2010), prevention of neurodegenerative diseases (Ames et al., 1993; Mishra et al., 2000; Ahmad et al., 2005) and cancer (Singh et al., 2011). W. somnifera extract (WSE) has also been shown to be a potent enhancer of cellular antioxidant mechanisms (Parihar et al., 2004), to have a significant free radical scavenging activity in various disease models (Bhattacharya et al., 2001; Davis and Kuttan, 2001) and to be effective in a mouse model of obsessive–compulsive disorder (Kaurav et al., 2012). ...
... The increase in antibody titre on Stresomix supplementation was because of its constituent herbs viz. Magnifera indica [11], Ocimum sanctum [12,13], Withania somnifera [14] and Phyllanthus emblica [15] possess antistress and immuno modulatory activities. ...
Chapter
Immunomodulators are biomolecules that are recognized for their characteristics to stimulate or suppress the adaptive or innate immunity. These agents modify the immune response by either enhancing (immunostimulators) or suppressing (immunosuppressants) the expression of inflammatory mediators such as cytokines and chemokines that activate immune cells. Withania somnifera (WS) is an ancient ayurvedic herb popularly known as “Ashwagandha” in India in Sanskrit and “winter cherry” outside India in English that has been used in indigenous medicines for over 3500 years or more, owing to its inexhaustible therapeutic value. Studies have shown a wide range of therapeutic applications associated with WS such as antibacterial, anti-inflammatory, antioxidant, anti-stress, antitumor, and anxiolytic, along with its protective role in numerous other ailments like cardiovascular, epilepsy, arthritis, diabetes, and depression. WS has also been recognized for its neuroprotective role in a number of degenerative conditions like Parkinson’s, Huntington’s, and most importantly Alzheimer’s disease. In today’s global scenario, the problem of infertility in males and disturbed sexual behavior in females is commonly observed. Withania has been shown to cure disorders related to reproductive system across countries with acceptable results. Currently, there is a drastic universal demand for development of herbal therapies effective for these ailments to minimize the side effects arising from chemotherapies. An overview of introduction and immunomodulatory role of Withania somnifera will be presented here with special focus on the mechanistic insights into the therapeutic effect of WS in treating Alzheimer’s and infertility problem. This chapter will also describe the latest attempts in biotechnological production of withanolides.
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Conveyance of pathogens between organisms causes communicable diseases. On the other hand, a non-communicable disease (NCD) was always thought to have no causative transmissible infective agents. Today, this clear distinction is increasingly getting blurred and NCDs are found to be associated with some transmissible components. The human microbiota carries a congregation of microbes, the majority and the most widely studied being bacteria in the gut. The adult human gut harbors ginormous inhabitant microbes, and the microbiome accommodates 150-fold more genes than the host genome. Microbial communities share a mutually beneficial relationship with the host, especially with respect to host physiology including digestion, immune responses, and metabolism. This review delineates the connection between environmental factors such as infections leading to gut dysbiosis and NCDs and explores the evidence regarding possible causal link between them. We also discuss the evidence regarding the value of appropriate therapeutic immunomodulatory nutritional interventions to reduce the development of such diseases. We behold such immunomodulatory effects have the potential to influence in various NCDs and restore homeostasis. We believe that the beginning of the era of microbiota-oriented personalized treatment modalities is not far away.
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Background : Colorectal cancer is among the most common malignancy and the third prime cause of cancer-associated mortalities. Long-term inflammation of the colon can promote carcinogenesis by facilitating oxidative stress which enhances deoxyribonucleic acid damage resulting in the tumor initiation step. The existing chemotherapeutic options are often associated with adverse reactions and emergence of drug resistance. The carefully selected plants are cited to demonstrate anticancer properties as has been revealed in this review. Of significance, these plant species are widely available, especially in Africa Objective The major goal was to present an updated comprehensive review of herbal plants used to treat colon cancer around the world. More specifically, the goal of this study was to analyse a group of selected plant species with proven efficacy, safety, and pharmacological effects on colon cancer models for further research. Methods A systematic search of relevant literature was performed considering all the articles published until November 2021 through searching six library databases and a web search engine, Google scholar. It was created using MeSH terms and free text describing plant species and colorectal cancer. For subsequent investigation, all articles describing the use of medicinal plants to treat colorectal cancer and/or their pharmacological evaluation were maintained. The plant species investigated in this research for their pharmacotherapeutic effects were: Withania somnifera, Zingiber officinale, Moringa oleifera, Azadirachta indica and Aloe barbadensis. Results The search yielded a total of 4803 papers published between the year 2000-2021 for further analysis. A total of 4726 articles (reports, reviews, and less relevant research papers) were excluded as they did not meet the inclusion criteria. A cumulative sum of 77 articles including research papers and reviews detailing in vivo and in vitro experiments of the specific plants of interest, with demonstrated activity met the inclusion criteria, and have been discussed in the present review. Conclusion The pharmacological activities of the selected plant species have been demonstrated to inhibit cyclooxygenase 2, inhibit immunomodulation, suppress angiogenesis, inhibit proliferation, induce apoptosis, and reduction of oxidative stress with sufficient anti-colorectal cancer effects. These essential mechanisms make them befitting alternative options to synthetic chemotherapeutic options. In vivo studies are however encouraged in Moringa oleifera that has a significant gap identified through our search. In addition, more research is encouraged to document sufficient dose levels enough to elicit anti-colorectal cancer effects among the reviewed plants.
Chapter
Natural products are unique sources for drug discovery and exhibit diverse biological activities. The immunomodulatory properties of natural agents have gained great interest during the past decades. Natural immunomodulators can contribute to the management of various diseases including cancer, because they provide great efficacy and safety profiles. In order to illustrate the potential of natural immunomodulators in traditional medicine application, we exemplarily focus on the anticancer potentials of two medicinal plants and one medicinal fungus regarding their phytochemical constituents and bioactivity properties. In this context, the importance and possibility of plant/fungus-based agents as cancer preventives and/or chemotherapeutics through their immunomodulatory characteristics were highlighted.
Article
During tumor initiation and progression, the complicated role of immune cells in the tumor immune microenvironment remains a concern. Myeloid-derived suppressor cells (MDSCs) are a group of immune cells that originate from the bone marrow and have immunosuppressive potency in various diseases, including cancer. In recent years, the key role of cancer stemness has received increasing attention in cancer development and therapy. Several studies have demonstrated the important regulatory relationship between MDSCs and cancer stem cells (CSCs). However, there is still no clear understanding regarding the complex interacting regulation of tumor malignancy, and current research progress is limited. In this review, we summarize the complicated role of MDSCs in the modulation of cancer stemness, evaluate the mechanism of the relationship between CSCs and MDSCs, and discuss potential strategies for eradicating CSCs with respect to MDSCs.
Article
Background Among gastrointestinal cancers, colon cancer is the fourth leading cause of death in the world, accounting for about 8% of all cancer deaths. Early detection of colon cancer can play an important role in survival in recent years. Although chemotherapy drugs prevent cells from proliferating in certain tissues of the body and induce apoptosis in tumor cells, one of the problems is that treatments for advanced stages of colon cancer have detrimental effects on the patient the American Society of Clinical Oncology (ASCO) proposed natural or synthetic substances that can prevent the recurrence of cancer or slow down the progression of cancer as preventative substances with chemical mechanisms. Resveratrol and quercetin are the natural compounds that has biological effects in the prevention and treatment of cancer. Therefore, the purpose of current study was evaluated the effect of quercetin and resveratrol in colon cancer rats. Materials and Methods Fifty-five male Sprague dawley rats were randomly assigned to healthy group, control group, resveratrol group, quercetin group and combination of resveratrol and quercetin treated group. At the fourth week animals received azoxymethane (AOM) (15 mg/kg) subcutaneous as a carcinogenic agent weekly for two consecutive weeks except for healthy group. The resveratrol (8 mg/kg) and quercetin (10 mg/kg) intervention done from two weeks before carcinogenesis induction until week 19 via oral gavage. The effect of resveratrol and quercetin was investigated on apoptosis by M30 antibody, cell proliferation by AgNOR staining, histopathological and histomorphological examination of AOM-induced colon cancer in rats model. Other findings were measured by using a beta-catenin count under a microscope. Result The highest frequency and highest percentage of nuclear polymorphism scores are observed in the control group, resveratrol, quercetin, and resveratrol + quercetin, respectively. In mucosal stratification the highest frequency and severity of low anomalies are related to resveratrol+ quercetin group and the highest frequency and severity of anomalies are related to control group. Also, in loss of nuclear polarity the highest frequency and low severity of anomalies are related to quercetin group and the highest frequency and severity is related to the control group. In goblet cells the highest frequency and lowest severity of anomalies are related to resveratrol + quercetin group and the highest frequency and severity of anomalies are related to control group. The highest frequency and lowest rate of crypt anomalies is related to resveratrol + quercetin group and the highest frequency and rate of crypt anomaly is related to control group. The highest and lowest mean of M30 expression are in healthy and control group, respectively. The highest and lowest mean of AgNOR are related to control and healthy groups, respectively. Beta-catenin proteins expression was lower in the combination of resveratrol and quercetin group in versus to others group. Conclusion Intervention of resveratrol and quercetin supplements together can be promising as a therapeutic strategy in future studies for colon cancer.
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For centuries, traditional medicines of Ayurveda have been in use to manage infectious and non-infectious diseases. The key embodiment of traditional medicines is the holistic system of approach in the management of human diseases. SARS-CoV-2 (COVID-19) infection is an ongoing pandemic, which has emerged as the major health threat worldwide and is causing significant stress, morbidity and mortality. Studies from the individuals with SARS-CoV-2 infection has shown significant immune dysregulation and cytokine overproduction. Neutrophilia and neutrophil to lymphocyte ratio has been correlated to poor outcome due to the disease. Neutrophils, component of innate immune system, upon stimulation expel DNA along with histones and granular proteins to form extracellular traps (NETs). Although, these DNA lattices possess beneficial activity in trapping and eliminating pathogens, NETs may also cause adverse effects by inducing immunothrombosis and tissue damage in diseases including Type 2 Diabetes and atherosclerosis. Tissues of SARS-CoV-2 infected subjects showed microthrombi with neutrophil-platelet infiltration and serum showed elevated NETs components, suggesting large involvement and uncontrolled activation of neutrophils leading to pathogenesis and associated organ damage. Hence, traditional Ayurvedic herbs exhibiting anti-inflammatory and antioxidant properties may act in a manner that might prove beneficial in targeting over-functioning of neutrophils and there by promoting normal immune homeostasis. In the present manuscript, we have reviewed and discussed pathological importance of NETs formation in SARS-CoV-2 infections and discuss how various Ayurvedic herbs can be explored to modulate neutrophil function and inhibit NETs formation in the context of a) anti-microbial activity to enhance neutrophil function, b) immunomodulatory effects to maintain neutrophil mediated immune homeostasis and c) to inhibit NETs mediated thrombosis.
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Plants belonging to Withania genus are well-known medicinal plants and are commonly used as herbal medicine in the Ayurvedic health system. These plants belong to the family Solanaceae and comprise of 23 known species distributed in North Africa, the Middle East, Asia, the Mediterranean, and the Canary Islands. However, only six species, namely, Withania somnifera (L.) Dunal, Withania coagulans (Stocks) Dunal, Withania adpressa Coss, Withania aristata (Aiton) Pauquy, Withania frutescens (L.) Pauquy, and Withania obtusifolia Täckh, are extensively investigated with regard to their pharmacological properties and bioactive constituents. Therefore, in this chapter, the traditional uses of the six Withania species and the pharmacological validations of the plants and plant-derived constituents are discussed. Applications of the bioactive constituents in drug discovery are explained by discussing the semisynthetic modifications and structure-activity relationships.
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This review provides an overview on the active phytochemical constituents of medicinal plants that are traditionally used to manage cancer in Ethiopia. A total of 119 articles published between 1968 and 2020 have been reviewed, using scientific search engines such as ScienceDirect, PubMed, and Google Scholar. Twenty-seven medicinal plant species that belong to eighteen families are documented along with their botanical sources, potential active constituents, and in vitro and in vivo activities against various cancer cells. The review is compiled and discusses the potential anticancer, antiproliferative, and cytotoxic agents based on the types of secondary metabolites, such as terpenoids, phenolic compounds, alkaloids, steroids, and lignans. Among the anticancer secondary metabolites reported in this review, only few have been isolated from plants that are originated and collected in Ethiopia, and the majority of compounds are reported from plants belonging to different areas of the world. Thus, based on the available bioactivity reports, extensive and more elaborate ethnopharmacology-based bioassay-guided studies have to be conducted on selected traditionally claimed Ethiopian anticancer plants, which inherited from a unique and diverse landscape, with the aim of opening a way forward to conduct anticancer drug discovery program.
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Increasing herbal formulations have been used to treat several diseases including cancer. W. somnifera (Ashwagandha) is one such plant the extracts of which have been tested against a number of ailments including cancer, which remains as one of the most dreadful diseases on the globe. The ever-increasing number of cancer related mortality demands the development of novel chemopreventive agents with minimum side effects. Different compounds isolated from various parts of the plant like root, stem, and leaves have been reported to display significant anti-cancerous and immunomodulating properties and thus can be used alone or in combination with other chemotherapeutic drugs for cancer treatment. Through this review, we highlight the importance of W. somnifera in countering the potential oncogenic signaling mediators that are modulated by active constituents of W. somnifera in a variety of cancer types. Further, we hope that active constituents of W. somnifera will be tested in clinical trials so that they can be used as an important adjuvant in the near future for the effective treatment of cancer.
Article
Withania somnifera, commonly known as "Ashwagandha" or "Indian ginseng" is an essential therapeutic plant of Indian subcontinent regions. It is regularly used, alone or in combination with other plants for the treatment of various illnesses in Indian Systems of Medicine over the period of 3,000 years. Ashwagandha (W. somnifera) belongs to the genus Withania and family Solanaceae. It comprises a broad spectrum of phytochemicals having wide range of biological effects. W. somnifera has demonstrated various biological actions such as anti-cancer, anti-inflammatory, anti-diabetic, anti-microbial, anti-arthritic, anti-stress/adaptogenic, neuro-protective, cardio-protective, hepato-protective, immunomodulatory properties. Furthermore, W. somnifera has revealed the capability to decrease reactive oxygen species and inflammation, modulation of mitochondrial function, apoptosis regulation and improve endothelial function. Withaferin-A is an important phytoconstituents of W. somnifera belonging to the category of withanolides been used in the traditional system of medicine for the treatment of various disorders. In this review, we have summarized the active phytoconstituents, pharmacologic activities (preclinical and clinical), mechanisms of action, potential beneficial applications, marketed formulations and safety and toxicity profile of W. somnifera.
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Chapter
Withania somnifera (Ashwagandha), the member of Solanaceae family is recognized to be one of the most significant therapeutically known herbs in the traditional Indian system of medicine, the Ayurveda. In specific, its root is reported to be applied in the treatment of nervous exhaustion, insomnia, skin problems, and coughing. Scientific studies carried out in accordance to the modern system of medicine have shown that the plant extracts possess antimicrobial, anti-inflammatory, antioxidant, antiulcer, analgesic, anti-stress, wound healing, hepatoprotective, cardioprotective, antidiabetic, and immunomodulatory effects. In addition, studies have shown that withaferin A, the principal phytochemical of Ashwagandha, exhibits activity against inflammation, apoptosis, invasiveness, and angiogenic effects in various cancer progression conditions. In this chapter, an attempt is made to summarize the antineoplastic effects of Ashwagandha and its principal phytochemical, withaferin A, in various cultured neoplastic cell lines and the mechanisms involved.
Chapter
Withania somnifera (WS) plant has been used for centuries to cure or treat various disorders in the Ayurvedic medicine. Research over the years has indicated that withanolides are the primary bioactive constituents in WS. Scientific evidence for anticancer effects of WS root extract (WRE) is quite strong, and is derived from both in vitro cellular experiments and in vivo studies in rodent models of cancer. This article reviews scientific evidence supporting anticancer effects of WRE and its primary withanolide (withaferin A). The primary focus of the present article is on: (a) phytochemistry of WS, (b) withanolide biosynthesis, (c) pharmacokinetics, (d) in vivo evidence for anticancer activity of WRE and its primary bioactive component withaferin A (WA), and (e) effect of WA and WRE on cancer stem cell population and/or epithelial-mesenchymal transition. Unpublished results from our own laboratory are presented to demonstrate that WA is the most likely primary anticancer agent in WRE standardized for WA content (sWRE). The mechanisms underlying anticancer effects of WRE and WA have been reviewed extensively by us and others, and therefore are not elaborated in this article.
Chapter
Withania somnifera is universally known as Ashwagandha in Ayurveda. Different parts of the Withania are used in medicinal and clinical applications. It possesses a lot of therapeutic action. Among them anticancer activity of Withania is the most interesting subject to research with. Recently in various studies Withania somnifera extract, different metabolites derived from Withania are found to show potent anticancer efficacy against various cancers including pancreatic, breast, lung, cervical, skin etc. The mostly studied Withaferin A (WA), a withanolide purified from Withania somnifera is an important bioactive molecule. WA showed promising inhibitory activity against various cancer cells in vitro and in vivo. WA induces apoptosis in cancer cells by stimulating pro-apoptotic proteins and inhibiting anti-apoptotic proteins. The mechanisms of action of WA in cancer cells are extensively studied all over the world. Withania somnifera could be use full medicinal herb as a potent chemotherapeutic agent in diverse clinical circumstances.
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Cancer is a significant global healthcare problem with an estimated worldwide incidence of 10 million new cases per year and morbidity is high with > 7 millions death per year. Among that breast cancer is a major public health challenge is often associated with high morbidity. The goal of carcinoma treatment is first to eradicate the cancer. In last two decades the treatment options for cancer are advances but those therapies have its own hazards. But now the world turned to an alternative system to defeat the situation by utilization of herbs. The Unani eminent physicians like Ibn Sina and Al Razi claimed most type of cancers and its treatment based on the herbs, which are can be correlated with cytotoxicity, antioxidant, immune modulators and apoptosis actions and these herbs are safest and easily available. Therefore the aim of this review is to embracive information about Sartan e Sadi (Breast Cancer) in Unani system of medicine to validate our eminent Unani physicians' claims.
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Tumor immunotherapy has come to the fore fuelled by impressive clinical responses to checkpoint inhibitor antibodies in a range of adult malignancies and by the success of chimeric antigen receptor T cells targeting adult and pediatric B-cell malignancies. Clearly, if appropriately fine-tuned, the immune system has the capability to seek out and destroy cancer. Studies in pediatric solid cancers so far have not shown the therapeutic potential checkpoint inhibitors described in adult cancers and this may reflect fewer tumor-associated antigens or different immune evasion mechanisms. One potential approach to overcome these limitations will be to combine interventions to undermine immune evasion mechanisms with engineered T-cell adoptive transfer.
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Cancer is a major health problem in both developed and developing countries. Cancer is the second leading cause of death after cardiovascular disease. Due to high death rate associated with cancer and serious side effects of chemotherapy and radiation therapy, many cancer patients seek alternative and/or complementary methods of treatment. India, which are being used traditionally for the prevention and treatment of cancer. However, only few medicinal plants have attracted the interest of scientists to investigate the remedy for neoplasm (tumor or cancer). Hence, an attempt has been made to review some medicinal plants used to prove scientific validation for the prevention and treatment of cancer. This article considers 82 medicinal plants belonging to 46 families and information on the Botanical name, family name, parts used, experimental model and mechanism of action were presented. This article provides basic handful information for researchers who are interested to work on medicinal plants for innovation of active biological compounds that to work on cancer as a principle mechanism.
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Aberrant crypt foci (ACF) are grossly invisible putative premalignant lesions in the colon. As dysplasia is considered an important precursor of colon carcinoma, we wanted to determine the presence and severity of dysplasia in human ACF. Fifty ACF from 28 patients were embedded in paraffin, cut serially, and stained with hematoxylin and eosin. Multiple slides from each ACF were evaluated for dysplasia according to a defined set of criteria. Of 50 ACF, 3 (6%) contained focal areas with severe dysplasia, ie, carcinoma in situ, 4 (8%) contained focal areas with moderate dysplasia, and 20 (40%) contained focal areas with mild dysplasia. Twenty-three ACF (46%) contained no detectable dysplasia. In 15 of 27 ACF with dysplasia, less than 50% (eg, 4 of 28, 10 of 54, and 10 of 30 sections) of the sections cut and evaluated from each ACF demonstrated dysplasia. The presence of dysplasia in a large proportion of ACF supports the hypothesis that they may be precarcinomatous.
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Aberrant crypt foci (ACF), putative preneoplastic lesions, are early morphological changes induced by the colon carcinogen azoxymethane (AOM). Although inbred mice differ markedly in their susceptibility to AOM carcinogenesis, we have previously shown that ACF develop in both resistant and sensitive mouse strains after AOM treatment. The purpose of this study was to examine the sequential development and identify the morphological characteristics of ACF induced by AOM in the distal colon of sensitive and resistant mice. A/J (highly susceptible), SWR/J (relatively susceptible) and AKR/J (resistant) mice were treated with 10 mg/kg AOM or saline i.p. once a week for 6 weeks and were killed at 1, 2, 4, 6, 9 and 24 weeks after the last injection. The distal colons were stained with methylene blue and the numbers of ACF and tumors determined. Tumors were present as early as 4 weeks after AOM exposure in SWR/J and A/J mice and increased in frequency throughout the study in both strains. No tumors developed in the AKR/J mice. ACF, however, formed in all strains of mice. The greatest difference between susceptible and resistant strains was in the number of large ACF that developed at later time points. Furthermore, morphometric analysis revealed that A/J mice had the highest percentage of dysplastic ACF, followed by SWR/J mice. These data indicate that the difference in cancer risk from AOM may be due to the lack of progression of smaller ACF in the resistant mice and to the development of dysplasia in a higher percentage of ACF from susceptible strains.
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The Significant role of immunoglobulin (Ig) through the feeding of colostrum to provide protection to the new born from various infections at neonatal stage is a well established fact (Me Ewan et al., 1970; Perryaman, 1982). The present study was taken up to asses the probable reason for early mortality with special reference to (Hypogammaglobulinemic) condition by Glutaraldehyde Coagulation Test (GCT) in neonatal kids.
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In order to study a possible immunomodulatory effect of the royal jelly (RJ) secreted by mandibular and hypopharingeal glands of the worker honeybee (Apis mellifera Linne.) we have used a well established rodent model. The CBA mice were given s.c. 0.1 ml of RJ, 7 days before, or immediately after, the immunization with sheep red blood cells (SRBC). The Y59 rats received i.m. 0.4 ml or i.v. 0.025 ml of RJ once or twice at 7 day intervals. Serum levels of total proteins and immunoglobulins in the rats that received RJ once or twice within a 2-week-period were significantly lower (P ≤ 0.05) as compared with the nontreated animals. In mice which were immunized with 4 x 108 of SRBC 7 days after the application of RJ the number of plaque forming splenocytes was significantly higher (P ≤ 0.05) than that in the controls. Both the weight of inguinal lymph node and the number of peripheral blood lymphocytes were increased (P ≤ 0.05) in RJ-treated mice 3 or 5 days after the immunization, respectively. Neutrophils were decreased (P ≤ 0.05) in the mice that were killed 5 or 10 days after the RJ treatment. Overall these results indicate that RJ exhibited immunomodulatory properties by stimulating antibody production and immunocompetent cell proliferation in mice or depressing humoral immune functions in rats. Both phenomena, though species-related in this model, could probably be reversed by changing the dose or the route of RJ application.
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Leukopenia and immunity impairment usually occur during cancer therapy. Citronellol, an oil soluble compound derived from the geranium, has anticancer and antiinflammatory properties, as well as promoting wound healing. Ganoderma lucidum, Codonopsis pilosula and Angelicae sinensis are traditional Chinese herbs, all of which have proven immunomodulatory functions in laboratory-based research. This randomized, double-blind, placebo-controlled study examined whether the Chinese medicinal herb complex (CCMH; a mixture of citronellol and extracts of G. lucidum, C. pilosula and A. sinensis) improves the immune cell counts of cancer patients receiving chemotherapy and/or radiotherapy. A total of 105 cancer patients receiving chemotherapy or radiotherapy were enrolled. The quantities of immune cells in the blood of the subjects were determined before and after 6 weeks of cancer treatment, with either CCMH or a placebo. CCMH significantly reduced the depletion of leukocytes (14.2% compared with 28.2%) and neutrophils (11.0% compared with 29.1%). Analysis of the lymphocyte phenotype revealed that the patients receiving the placebo had reduced CD4 lymphocytes and natural killer (NK) cells than the CCMH-treated patients. Treatment with CCMH for patients receiving chemotherapy and/or radiotherapy may improve their immune function, improving their ability to fight off the cancer, as well as any secondary infections that could compromise their treatment and their health.
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To investigate the immunomodulatory effects of ASMq, a herbal preparation used in Traditional Uighur Medicine, on the combined stress mice. The combined stress was induced on mice by application of the electric-foot shock in a cold-dry environment and three different doses of ASMq were orally administered to the animals for 14 days. The effect of ASMq on the immune apparatus weight index, lymphocytes proliferation, serum levels of the cytokines, immunoglobulins, hemolysin and NK cells as well as the phagocytic activity of the macrophages were evaluated. Oral administration of ASMq was found to increase the thymus and spleen indices, lymphocytes proliferation induced by Con A and LPS, the percentage of CD4(+) in thymus, spleen and peripheral blood and restore the CD4(+)/CD8(+) ratio. The serum concentrations of INF-beta, IL-2, IL-6, IgG, NK cells and hemolysin were also increased. The macrophage phagocytic activity was also enhanced.
Article
Serum IgE concentrations were determined and IgE turnover studies were performed in control individuals as well as in patients with several disease states. Patients with common variable hypogammaglobulinemia, thymoma and hypogammaglobulinemia, ataxia telangiectasia, and selective IgA deficiency had significantly decreased mean serum IgE concentrations. In turnover studies, this was found to be due to decreased IgE synthesis. In spite of these depressed mean values, some patients with common variable hypogammaglobulinemia had normal serum IgE concentrations and synthetic rates. Patients with the Wiskott-Aldrich syndrome had a significantly elevated mean serum IgE concentration. In one of four patients studied with the turnover technique, a strikingly high IgE concentration was present and was associated with an elevated IgE synthetic rate. Three other patients had both normal serum IgE concentrations and synthetic rates. Patients with chronic lymphocytic leukemia had significantly decreased mean serum concentrations and synthetic rates for IgE. The depressed IgE synthesis was associated with a significantly prolonged IgE half-life. Patients with Hodgkin's disease had significantly increased serum IgE concentrations. One of three patients studied had a high serum IgE concentration and synthetic rate of IgE. The two other patients had normal serum IgE concentrations associated with normal synthetic rates. Finally patients with protein-losing enteropathy or familial hypercatabolic hypoproteinemia had normal IgE concentrations associated with normal IgE metabolic parameters. In these cases, the disorder in the catabolic rate was not severe enough to affect the total amount of circulating IgE because IgE normally has a very high fractional catabolic rate. In general, IgE levels in a variety of disease states were correlated with IgE synthetic rates and abnormalities in the catabolic rate of IgE in disease did not exert an important effect on IgE concentration.
Article
CF-1 female adult mice were given weekly sc injections of 20 mg symmetrical 1,2-dimethylhydrazine (DMH)-2HCl/kg body weight and killed at various intervals after commencement of the injection. [3H]thymidine (TdR) was given before the animals were killed. The histogenesis of colon neoplasms was investigated by means of autoradiographs prepared from sections of Epon-embedded descending colon, which were stained with periodic acid-Schiff reaction and iron hematoxylin. By 9 weeks after initiation of DMH treatment, the distal 5 cm of the colon became enlarged, the mucosa thickened, and the crypts were elongated and hyperplastic. In the hyperplastic crypts, the number of proliferating cells increased, but the distribution of these cells followed a previously discussed slow cut-off model of Cairnie et al. as for the normal crypts. Differentiation and transformation of epithelial cells occurred, but somewhat aberrantly. Hyperplasia of the crypts occurred diffusely, but neoplastic lesions that began to appear by 9 weeks after the intiial treatment were isolated. An isolated crypt from which a neoplasm developed was first repopulated by what appeared to be altered, undifferentiated "stem" cells. These cells did not differentiate, continued to divide, and eventually upon migration accumulated in the upper part of the crypts, where an earliest identifiable neoplastic lesion was observed. Once such a lesion was formed, it expanded in various directions, depending on the local environments, and formed a polypoid or discoid lesion. The biologic behavior of the neoplasm seemed to be determined by the downward progression of its leading edge. When it penetrated the muscularis mucosae, the neoplasm became highly invasive. In the murine model, the invasive adenocarcinomas were observed by 26 weeks after commencement of DMH treatment.
Article
In the present study a methodological approach is taken which quantitates aberrant dysplastic crypts in the unsectioned murine colon. C57BL/6J or CF1 female mice (7-8 weeks old) were injected (i.p.) with azoxymethane (5 mg/kg body wt./week) for 4 weeks. Their colons were excised, cut open on the median axis and fixed flat in buffered formalin. Unsectioned colons were stained with methylene blue. The mucosal side was examined under a light microscope. The aberrant crypts, which are larger and have a thicker epithelial lining, were easily visualized using X 4 or X 10 objectives. CF1 mice, which are more sensitive to developing colon tumors, had a higher number of aberrant crypts/colon than their less sensitive counterparts, C57BL/6J mice (5.0 +/- 0.7 vs. 2.4 +/- 0.7). The usefulness of this observation as a possible measure of neoplastic events is discussed in the animal and human situation.
Article
Patients with tumors of the brain underwent complex immunological examination. Anticerebral antibodies were discovered and the IgM and IgG levels were found to be diminished. Reduction of the T lymphocyte content was paralleled by the compensatory increase of the B lymphocyte level in the blood. It is shown that according to the findings of some allergic tests, neurosensitization develops; the tests employed were the leukocyte injury, leukocyte agglomeration, and leukocyte migration inhibition. The immune disorders and the autoimmune shifts correlate with the stage of the organism compensation, the degree of tumor malignancy, and the efficacy of the operation.
Article
The diagnosis of chronic granulomatous disease (CGD) has depended on special laboratory techniques not easily carried out in most laboratories. A simple, rapid, histochemical micromethod is described in which granulocytes are separated from a single drop of blood by their propensity to stick to glass and are exposed to nitro-blue tetrazolium (NBT) with the use of readily available equipment. A large percentage of normal granulocytes exposed to NBT become distinctive, degenerate cells diffusely laden with blue formazan precipitate ("formazan cells"), whereas granulocytes from patients with CGD form no such cells. This method has permitted us to spot affected patients at a glance and makes possible the screening of all patients with unexplained recurrent infection.
Article
The human liver probably removes circulating polymeric IgA by two routes: (1) secretory component-mediated endocytic transport of polymeric IgA from portal tract blood vessels into bile across biliary epithelial cells and (2) uptake with possible catabolism by hepatocytes and/or sinusoidal phagocytic cells by uncharacterized receptor(s). Failure of either clearance mechanism due to liver disease results in elevated serum polymeric IgA levels. In patients with cholestasis, the raised serum polymeric IgA concentration is due to reflux of biliary secretory immunoglobulin into the blood.
Article
Carcinogen-induced primary intestinal adenocarcinomas serve as a useful animal model for human colonic adenocarcinomas. Although striking similarities between this model and the human disease state exist, there are also troublesome discrepancies-a major one being the reported lack of an adenoma-carcinoma sequence in the experimental model. However, the original morphologic descriptions of these experimental neoplasms predated the development of presently accepted morphologic criteria that have been used to describe the adenoma-carcinoma sequence in humans. Therefore, the authors reevaluated the structural evolution of dimethylhydrazine-induced rat intestinal neoplasms, using the same criteria that were recently applied to evaluate human colonic adenocarcinomas. Such an approach shows that many dimethylhydrazine-induced intestinal adenocarcinomas have peripheral foci of adenomatous epithelium associated with them. In addition, the frequency of this association correlates inversely (P less than .001) with the depth of invasion. These findings are comparable to those which, in humans, have been used as evidence supporting the adenoma-carcinoma sequence. Thus, when assessed with equivalent criteria, dimethylhydrazine-induced intestinal adenocarcinomas appear to be similar, not dissimilar, to human colonic adenocarcinomas in their structural evolution. These data suggest that, at least in part, dimethylhydrazine-induced intestinal adenocarcinomas arise in foci of preexisting adenomatous epithelium.
Article
Eight-week-old mice of 3 sublines of strain C57BL/6 were given s.c. injections of 1,2-dimethylhydrazine (DMH), once weekly for 10 weeks. The highest incidence (85%) of colorectal tumors occurred in C57BL/6N mice. Colorectal tumors occurred in 43% of C57BL/6J mice, while only 3 (10%) C57BL/6Ha mice developed these tumors. Possible factors responsible for the differential susceptibility of 3 sublines of C57BL/6 mice to the induction of colorectal tumors by DMH are discussed.
Article
One hallmark of malignant potential is dysplasia, the disruption of normal morphology. While it is generally recognized that cancer is the result of a series of genetic changes, the relationship of these alterations and their timing to the advent of dysplasia remains obscure. To address this issue, 54 small benign colorectal lesions of various malignant potential were analyzed for APC and K-RAS mutations, two alterations which have been implicated in the early stages of colorectal tumorigenesis. APC mutations were closely associated with dysplasia. In contrast, K-RAS mutations were found to be remarkably common in small nondysplastic lesions which apparently have a limited potential to progress to larger tumors. These results provide evidence that the nature and order of genetic changes can have a specific impact on both tumor morphology (e.g., dysplasia) and the likelihood of tumor progression.
Article
A mutation in c-K-ras (KRAS2) has long been implicated as one of the important early events in the development of a large proportion of human colon cancers. Aberrant crypt foci, putative preneoplastic lesions identified microscopically in wholemounts of colons, have been shown to occur with high frequency in the colons of animals treated with colon carcinogens and in the grossly normal mucosas of patients with colon cancer. In this study, we asked whether the mutational activation of K-ras occurs in the aberrant crypt foci of human colon. Grossly normal colonic mucosas were obtained from seven patients during surgery and were provided to us by the Western Division of the Cooperative Human Tissue Network located at Case Western Reserve University. A total of 42 samples, consisting of aberrant crypt foci and similarly sized normal crypt areas, were microdissected from the grossly normal colonic mucosas. The DNA region containing codon 12 of K-ras was amplified by polymerase chain reaction and analyzed for mutations by dot-blot hybridization with specific oligonucleotide probes complementary to normal or mutant sequences. Mutations in codon 12 of K-ras were found in 11 (73%) of 15 aberrant crypt foci but not in any of 27 morphologically normal crypt areas from the same patients. The observed high frequency of K-ras mutations in these microscopically identifiable lesions makes mutation in K-ras the earliest identified gene-mutational event in human colon tumorigenesis, establishes that it often occurs prior to the development of polyps, and is consistent with the hypothesis that aberrant crypt foci are the earliest identified precursors of human colon cancer. Further analysis of aberrant crypt foci may identify yet unknown early genetic events that precede human colon cancer.
Article
The immunomodulatory activity of an Indian Ayurvedic medicinal preparation, Ashwagandna (Withania somnifera (L. Dunal)) was studied in mice with myelosuppression induced by one or more of the following three compounds: cyclophosphamide, azathioprin, or prednisolone. The assessment of immunomodulatory activity was carried out by hematological and serological tests. A significant modulation of immune reactivity was observed in all the three animal models used. Ashwagandha prevented myelosuppression in mice treated with all three immunosuppressive drugs tested. A significant increase in hemoglobin concentration (P < 0.01), red blood cell count (P < 0.01), white blood cell count (P < 0.05), platelet count (P < 0.01), and body weight (P < 0.05) was observed in Ashwagandha-treated mice as compared with untreated (control) mice. We also report an immunostimulatory activity: treatment with Ashwagandha was accompanied by significant increases in hemolytic antibody responses towards human erythrocytes.
Article
Azoxymethane (AOM) is an organotropic colon carcinogen that is commonly used to induce colon tumors in rodents. Unlike its parent compound, 1,2-dimethylhydrazine (DMH), a tumor susceptibility phenotype in inbred mice with respect to AOM has not been established. Thus, this study was undertaken to determine whether genetic susceptibility extends to this carcinogen. SWR/J, A/J (both susceptible to DMH carcinogenesis) and AKR/J (resistant) mice were treated with 10 mg/kg AOM i.p. once a week for 8 weeks. Twenty-five weeks after the initial injection, tumor yield was determined. With a single exception, only SWR/J and A/J mice developed tumors, with a distribution that was limited to the distal colon (16.3+/-1.1 and 36.4+/-2.4. respectively). The formation of aberrant crypt foci (ACF), putative preneoplastic lesions, was also assessed in whole-mount colons using Methylene Blue staining. Consistent with tumor multiplicity, the total number of ACF was highest in A/J mice, followed by SWR/J mice. In addition, A/J mice had a significantly greater number of large ACF (five or more crypts per foci) than the other strains. Despite the absence of colon tumors, however, AKR/J mice did develop a significant number of ACF. This finding suggests that ACF in resistant mice are persistent but do not progress to tumors.
Article
A differential susceptibility phenotype to the organotropic colon carcinogen azoxymethane (AOM) has been described in mice. The following studies were undertaken to test the hypothesis that intraspecific susceptibility can be accounted for by the specific complement of genetic alterations acquired by precancerous colon lesions referred to as aberrant crypt foci (ACF). As an initial approach to this question, mutations in codons 12 and 13 of the Ki-ras proto-oncogene were assessed in ACF, normal-appearing AOM-treated colonic epithelium, and tumors from A/J and SWR/J (susceptible) as well as AKR/J (resistant) mice. Four-week-old male mice were injected intraperitonealy, with AOM once a week for a total of 6 wk and killed 4 and 24 wk after the last injection. DNA was isolated from microdissected tissue, and polymerase chain reaction (PCR)-amplified products of Ki-ras exon 1 (codons 12 and 13) were directly sequenced from microdissected tissues. At 4 wk after AOM exposure, there was no significant difference in the frequency of Ki-ras activation (20-33%) between the three strains. Ki-ras mRNA expression was also evaluated by reverse transcription (RT)-PCR analysis and was comparably reduced (40-50%) in all three strains at the 4 wk time point. However, Ki-ras expression returned to normal by 24 wk after treatment. Finally, to gain further insight into the molecular pathogenesis underlying this experimental tumor model, analysis of the adenomatous polyposis coli (APC) protein within the colonic epithelium was undertaken by using an immunohistochemical approach. Although the APC protein was lost to a varying extent in tumors from A/J and SWR/J mice, the full-length form of the protein was still present in precancerous ACF isolated from each of the three strains, regardless of the degree of dysplasia of the lesion. A further molecular genetic analyses of ACF will be required to gain a more complete understanding of the molecular basis of tumor susceptibility phenotype in this murine model.
Article
The beta-catenin gene is frequently mutated at codons 33, 41 and 45 of the glycogen synthase kinase-3beta phosphorylation motif in human colon cancers in patients without APC mutations. Frequent mutations at codons 32 and 34, as well as 33 and 41, have been detected in rat colon tumors induced by azoxymethane (AOM), with the second G of CTGGA sequences being considered as a mutational hot-spot. In the present study, exon 3 of the beta-catenin gene in mouse colon tumors induced by AOM was amplified by PCR and mutations were detected by the single strand conformation polymorphism method, restriction enzyme fragment length polymorphism and direct sequencing. All 10 colon tumors tested were found to have beta-catenin mutations, four in codon 34, three in codon 33, two in codon 41 and one in codon 37, nine being G:C-->A:T transitions. However, no mutations were found in codon 32 of the mouse beta-catenin gene. On immmunostaining, beta-catenin was observed in the cytoplasm and nucleus of the tumor cells. The cytoplasmic staining was homogeneous, while both homogeneous and heterogeneous patterns were noted for the nuclei. Highly frequent mutations of the beta-catenin gene in AOM-induced mouse colon tumors suggest that consequent alterations in the stability and localization of the protein may play an important role in this colon carcinogenesis model.
Article
The current experimental work deals with the chemopreventive studies of a hydroalcoholic extract of Withania somnifera roots, against 20-methylcholanthrene induced fibrosarcoma tumours in Swiss albino mice. A single subcutaneous injection of 200 microg 20-methylcholanthrene in 0.1 mL of dimethylsulphoxide into the thigh region of mice produced a high incidence (96%) of tumours. Oral treatment of animals with 400 mg/kg body weight of Withania somnifera extract (one week before injecting 20-methylcholanthrene and continued until 15 weeks thereafter) significantly reduced the tumour incidence, tumour volume and enhanced the survival of the mice, compared with 20-methylcholanthrene injected mice. The tumour incidence was also delayed in the treatment group when compared with 20-methylcholanthrene injected mice. Liver biochemical parameters revealed a significant modulation of reduced glutathione, lipid peroxides, glutathione-S-transferase, catalase and superoxide dismutase in extract treated mice compared with 20-methylcholanthrene injected mice. The mechanism of chemopreventive activity of Withania somnifera extract may be due to its antioxidant and detoxifying properties.
Article
Mangifera indica Linn, a plant widely used in the traditional medicinal systems of India, has been reported to possess antiviral, antibacterial and anti-inflammatory activities. In the present study, the alcoholic extract of stem bark of Mangifera indica Linn (Extract I containing mangiferin 2.6%), has been investigated for its effect on cell mediated and humoral components of the immune system in mice. Administration of test extract I produced increase in humoral antibody (HA) titre and delayed type hypersensitivity (DTH) in mice. It is concluded that test extract I is a promising drug with immunostimulant properties.
Article
Immune dysfunction has been found to be associated with diabetes mellitus. Tungstate treatment restored the number and function of immune cells as well as the immunoglobulin level in STZ diabetic rats. This indicated the immunomodulatory effect of tungstate in diabetics and would be effective in inhibiting diabetic-induced alterations.
Article
Azoxymethane (AOM) is a colon carcinogen that is used to study the pathogenesis of sporadic colorectal cancer. We have evaluated differential susceptibility to AOM in inbred mice used as progenitors of recombinant/transgenic lines. In experiment 1, male FVB/N, 129/SvJ, C57Bl/6J mice were treated i.p. with 10 mg/kg AOM once per week for 4 weeks and sacrificed after 20 weeks. Only AOM-treated FVB/N mice developed tumors (3.6 tumors/mouse) in distal colon. In experiment 2, A/J, AKR/J, Balb/CJ mice were treated with AOM for 6 weeks and sacrificed after 24 weeks. AOM-treated A/J and Balb/CJ mice developed 9.2 and 1 tumor/mouse, respectively. Despite these differences, tumors had similar morphology regardless of strain. Immunohistochemistry with beta-catenin resulted in marked nuclear and cytoplasmic staining of tumor cells in FVB/N. However, fainter and heterogeneous beta-catenin staining was observed in A/J tumors, suggesting distinct pathways of tumorigenesis in different strains. Irrespective of cytological features of malignancy, tumor cells rarely breached the muscularis mucosa and showed no evidence of distant metastasis. Lack of invasiveness and metastasis in even the most sensitive strains provides a model system for studying the potential role of 'metastasis genes' in imparting a malignant phenotype.
Article
Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival rates based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and mortality rates are age standardized to the 2000 US standard million population. A total of 1,368,030 new cancer cases and 563,700 deaths are expected in the United States in 2004. Incidence rates stabilized among men from 1995 through 2000 but continued to increase among females by 0.4% per year from 1987 through 2000. Mortality rates have decreased by 1.5% per year since 1992 among men, but have stabilized from 1998 through 2000 among women. Cancer death rates continued to decrease from the three major cancer sites in men (lung and bronchus, colon and rectum, and prostate) and from female breast and colorectal cancers in women. In analyses by race and ethnicity, African-American men and women have 40% and 20% higher death rates from all cancers combined compared with White men and women, respectively. Cancer incidence and mortality rates are lower in other racial and ethnic groups than in Whites and African Americans for all sites combined and for the four major cancer sites. However, these groups generally have higher rates for stomach, liver, and cervical cancers than do Whites. Furthermore, minority populations are more likely to be diagnosed with advanced stage disease than are Whites. Progress in reducing the burden from cancer can be accelerated by applying existing cancer control knowledge into practice among all segments of the population.
Appendix 3:3:10 Ministry of Health and Family Welfare, Government of India
  • Indian Pharmacopoeia
Immunomodulatory effects of abnormal Savda munshiq, a traditional uighur on the combined stress mice
  • N Amat
  • H Upur
  • A Ablimit
  • A Matsidic
  • A Yusup
  • A Kijjoa
Immunomodulatory activity of W. somnifera as an adjuvant during radiation therapy. Ind
  • L Davis
  • G Kuttan
SreeBulab Kunvera Ayurvedic Society, India
  • S Charaka
Withania somnifera Dunnal-present status
  • K Sharma
  • P C Dandiaya
Changes in immunology indices in patients with brain tumors
  • N I Sianyi
  • M M Namytor