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Amygdalin alleviates renal injury by suppressing inflammation, oxidative stress and fibrosis in streptozotocin-induced diabetic rats
Abstract
Aims
To explore the protective efficacies and potent mechanism of amygdalin on high glucose-cultured renal cell HBZY-1 in vitro and streptozotocin (STZ)-induced diabetic nephropathy (DN) rat in vivo.
Main methods
The cellar proliferation and generation of ROS in high-glucose cultured HBZY-1 cell were assessed by MTT and DCFH-DA assay, respectively. The fasting blood glucose levels, renal function and inflammation indexes as well as oxidative stress markers in STZ-induced diabetic rats were all measured. The histologic renal section was stained with Mason and periodic acid-Schiff (PAS) method. Immunohistochemistry and western blotting methods were applied to assess expression levels of extracellular matrix (ECM), epithelial-mesenchymal transition (EMT)-related as well as TGF-β1/Smad signaling pathway-related proteins.
Key findings
Firstly, amygdalin significantly suppressed the excessive cell proliferation and ROS generation in HBZY-1 cells cultured with high glucose. The hyperglycemia, 24 h-UP excretion, BUN and Scr of DN rats were significantly attenuated after the chronic treatment of amygdalin. Moreover, MDA, SOD, IFN-γ and IL-12 levels in kidney tissues were all effectively reduced. Besides, amygdalin can suppress the ECM accumulation and EMT transformation by inhibiting Smad/TGF-β pathway to alleviate the renal fibrosis in renal tissues of DN model rats.
Significance
Amygdalin ameliorates excessive oxidative stress, inflammation and renal tissue fibrosis of DN mainly by suppressing TGF-β1/Smad signaling pathway and regulating the key enzymes of ECM degradation.
... Intramuscular administration of amygdalin treatment (0.005, 0.05, and 0.1 mg/kg) effectively alleviated responses to LPS treatment in RAW 264.7 cells and carrageenan-induced arthritis in mice and may serve as an analgesic for relieving inflammatory pain (Hwang et al. 2008). Chen et al. (2021) demonstrated that amygdalin can reduce kidney damage by suppressing inflammation, oxidative stress and fibrosis in mice with streptozotocin-induced diabetes (Chen et al. 2021). Though these studies offer preliminary data on the anti-inflammatory and protective benefits of amygdalin; nevertheless, they utilize in vitro and animal models, which may not fully reflect human physiology. ...
... Intramuscular administration of amygdalin treatment (0.005, 0.05, and 0.1 mg/kg) effectively alleviated responses to LPS treatment in RAW 264.7 cells and carrageenan-induced arthritis in mice and may serve as an analgesic for relieving inflammatory pain (Hwang et al. 2008). Chen et al. (2021) demonstrated that amygdalin can reduce kidney damage by suppressing inflammation, oxidative stress and fibrosis in mice with streptozotocin-induced diabetes (Chen et al. 2021). Though these studies offer preliminary data on the anti-inflammatory and protective benefits of amygdalin; nevertheless, they utilize in vitro and animal models, which may not fully reflect human physiology. ...
Laetrile, known as vitamin B17, is often used interchangeably with amygdalin. Laetrile is a semi‐synthesis product of amygdalin, whereas amygdalin is a naturally occurring substance in many plants. Both compounds have a nitrile functional group that, when activated by the intestinal enzyme β‐glucosidases, releases hydrogen cyanide. The two compounds have been considered for a long time as alternative therapy for cancer treatment however, findings available in the literature are discordant on the real efficacy of laetrile/amygdalin for the treatment of cancer, often highlighting a negative benefit‐risk ratio. In this regard, the study aimed to comprehensively analyze the scientific data on laetrile/amygdalin, with a special emphasis on their pharmacokinetics, underlying pharmacological properties, mode of action as a potent antitumor agent, and effect on human health. The results showed that there is no clear evidence on the efficacy of cancer therapy following laetrile/amygdalin administration, especially at the clinical trial level. However, the in vitro studies of the biological activity of these compounds showed positive effects related to their antifibrotic, anti‐inflammatory, antiasthmatic, and immunoregulatory processes. Laetrile's mechanism of action closely resembles amygdalin, affecting cancer signaling pathways. However, due to its cyanide toxicity, it was banned by the food and drug administration (FDA) due to safety concerns. Despite not receiving permission from the FDA, laetrile emerged as an alternative therapy in the 1970s. Nonetheless, continuing research is investigating safer methods of activating Laetrile for targeted cancer treatment. This opens interesting prospects in using these compounds in alternative medical therapies, for which, however, further research is needed.
... [12][13][14][15] Recent study found that amygdalin ameliorates renal and liver fibrosis mainly by suppressing TGF-β1/Smad signaling pathway and regulating the key enzymes of ECM degradation -Matrix Metalloproteinases-9 (MMP-9) and tissue Inhibitor of Metalloproteinases 1 (TIMP-1). 16,17 In addition, as an active ingredient of Fuzheng Huayu formula, which is a NMPA (National Medical Products Administration)-approved anti-fibrotic medicine in China, amygdalin is effective at alleviating liver fibrogenesis by inhibiting the proliferation and collagen production of active HSC, HSC activation and hepatocyte apoptosis. [18][19][20][21][22][23][24] However, due to the herbal products having multi-modulatory and multi-target action, comprehensive mechanism of anti-fibrotic effects of amygdalin remains elusive. ...
Purpose
Hepatic fibrosis is a major cause of morbidity and mortality for which there is currently limited therapy. Amygdalin, a cyanogenic glucoside derived from Semen Persicae, exerts significant anti-fibrotic effects in the liver. However, the molecular mechanism by which amygdalin inhibits the progression of liver fibrosis remains unclear. This study aimed to elucidate the potential mechanism of action of amygdalin against liver fibrosis.
Methods
Quantitative proteomic profiling of the mouse liver tissues from control, carbon tetrachloride (CCl4)-induced fibrosis, and amygdalin-treated groups was performed to explore the key effector proteins of amygdalin. Histology and immunohistochemistry as well as serum biochemical analysis were performed to evaluate amygdalin efficacy in mice. The key gene programmed cell death protein 4 (PDCD4) was overexpressed or knocked down in human hepatic stellate cells (HSCs). The mRNA and protein levels of related molecules were detected by RT-qPCR and Western blotting, respectively.
Results
Amygdalin could effectively ameliorated CCl4-induced liver fibrosis in mice. Bioinformatics analysis revealed that PDCD4 was downregulated in CCl4-induced liver fibrosis, but amygdalin treatment reversed these changes. An in vitro study showed that PDCD4 inhibited the activation of human hepatic stellate cell line LX-2 cells by regulating the JNK/c-Jun pathway and amygdalin inhibited the activation of LX-2 cells in a PDCD4-dependent manner. We further found that amygdalin inhibited the phosphorylation of PDCD4 at Ser67 by inhibiting the mTOR/S6K1 pathway to enhance PDCD4 expression.
Conclusion
Our data demonstrated a potential pharmaceutical mechanism by which amygdalin alleviates liver fibrosis by inhibiting the mTOR/PDCD4/JNK pathway in HSCs, suggesting that PDCD4 is a potential target for the treatment of liver fibrosis.
... Firstly, excessive reactive oxygen species (ROS) generation activates proinflammatory cascades, exacerbating ECM deposition and tubular injury. Conversely, inflammatory mediators such as tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 amplify ROS production via NADPH oxidase activation, establishing a self-perpetuating cycle (Mengqi et al., 2024;Samar et al., 2023;Xiao-Jun et al., 2024;Jiawei et al., 2020). TCM counteracts this axis by activating AMPK, enhancing energy homeostasis and reducing lipid peroxidation (Li et al., 2015;Nan et al., 2016). ...
Renal fibrosis represents the terminal pathological manifestation of most chronic kidney diseases, driving progressive loss of renal function. Natural products have emerged as promising therapeutic agents for preventing and ameliorating renal fibrosis due to their multi-target efficacy and favorable safety profiles. In this review, we conducted a comprehensive literature search on PubMed using the keywords “natural product” and “renal fibrosis” from 2004 to 2025, identifying 704 relevant articles. We systematically categorize and discuss the biological effects of key natural products and formulations with antifibrotic potential, focusing on five major classes: glycosides, flavonoids, phenolic compounds, anthraquinones, and terpenoids. Representative compounds from each category are highlighted for their mechanisms of action, including modulation of oxidative stress, inflammation, autophagy, and fibrosis signaling pathways. This review aims to provide a theoretical foundation for the development of natural product-based therapies to combat renal fibrosis, offering insights into their therapeutic potential and future research directions.
... Amygdalin, an active component found in the dried ripe seeds of Prunus armeniaca belonging to the Rosaceae family, exhibits anti-inflammatory, antioxidant, antitussive, and antiasthmatic pharmacological effects [63]. Studies have shown that amygdalin alleviates the progression of RF by inhibiting the expression of ECM, EMT, and related proteins in the TGF-β1/Smad signaling pathway in rat kidney tissue [64]. Astragaloside IV, a hallmark active constituent of Astragalus membranaceus from the Fabaceae family, possesses antioxidant, anti-tumor, and antiapoptotic properties [65]. ...
Renal fibrosis (RF), characterized by excessive deposition of extracellular matrix leading to tissue damage and scar formation, represents a refractory disease and a pivotal pathological basis for the progression to end-stage renal disease. The pathogenesis of RF is intricate, prominently implicating multiple key signaling pathways, including adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), transforming growth factor-β1/small mother against decapentaplegic (TGF-β1/Smad), toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB), wingless integrated/β-catenin (Wnt/β-catenin), hypoxia-inducible factor-1α (HIF-1α), Hedgehog, and mitogen-activated protein kinase (MAPK). The current Western medical practices primarily rely on supportive and replacement therapies, which are often costly and suboptimal in efficacy. In contrast, traditional Chinese medicine (TCM), with its inherent advantages of multi-target, multi-pathway, and multi-effect modulation, emerges as a promising new strategy for RF treatment. However, a systematic, comprehensive, and detailed summary of these advancements remains absent. Therefore, this review consolidates the recent research progress on TCM modulation of RF-related signaling pathways, aiming to provide a theoretical foundation for further investigations into RF and the development of TCM interventions.
... Prolonged elevation of blood glucose levels leads to exaggerated production of ROS, which are the key players in the stressmediated damage of various tissues which eventually leads to severe complications. [26,27] Since pancreatic -cell dysfunction plays a key role in the development and progression of DM and because the effects of diabetes on stomach tissues are still relatively limited in the literature compared to other organs such as the liver and kidney which may highlight an important area for further research to better understand these effects and their implications for managing diabetes-related complications. Therefore, this research aims to assess the therapeutic benefits of NR, Zn, and their combination which has not been previously explored in the stomach and pancreas of rats with STZ-induced diabetes. ...
Diabetes mellitus is a chronic metabolic disorder that affects multiple organs, including the stomach. This research examines the effects of naringin and/or zinc on stomach and pancreatic tissues of streptozotocin‐induced diabetic rats. Type 2 diabetes is induced by intraperitoneal injection of nicotinamide and streptozotocin. Three weeks after diabetes induction, rats receive eight weeks of treatment. Malondialdehyde and total antioxidant capacity are estimated colorimetrically. Asprosin and P‐selectin levels are assessed via ELISA. Quantitative RT‐PCR analysis of nuclear factor kappa B (NF‐кB), peroxisome proliferator‐activated receptor gamma (PPAR γ), and nuclear factor erythroid 2‐related factor 2 (Nrf‐2) genes is carried out. Tumor necrosis factor‐alpha (TNF‐α) is assessed immunohistochemically, and stomach and pancreatic tissues are examined histologically. Combined naringin and zinc treatment significantly reduces gastric Malondialdehyde, serum asprosin, and P‐selectin levels in serum, stomach, and pancreas compared to diabetic rats. Additionally, gastric NF‐кB expression is significantly lower, while PPAR γ and Nrf‐2 expressions are significantly higher compared to diabetic rats. Immunohistochemical analysis and histopathological examination confirm these findings. In conclusion, combined naringin and zinc treatment significantly improves gastric alterations in diabetic rats by reducing oxidative stress and inflammation. Nonetheless, it shows no additional impacts on pancreatic tissue compared to naringin or zinc alone.
... Firstly, the HFHSD/STZ-treated SD rats with fasting blood glucose consistently greater than 11.1 mmol/L were considered successful models of T2DM. The experimental findings revealed that SD rats exposed to HFHSD/STZ exhibited a marked elevation in the serum levels of BUN, SCR, and UA, indicator characteristics of diabetic nephropathy (DN), aligning with the observations reported in Chen's study [25]. Notably, mAPS supplementation significantly reversed this trend and alleviated the symptoms of increased drinking, eating, urination, and weight loss in the HFHSD/STZ rats. ...
We aimed to uncover the underlying mechanisms contributing to the therapeutic efficacy of Astragalus mongholicus Polysaccharides (mAPS) in alleviating diabetic nephropathy (DN). The rat model of DN was subjected to a high-sugar and high-fat diet (HSHFD) coupled with streptozotocin (STZ) injection. Our findings revealed that mAPS administration decreased fasting blood glucose (FBG), BUN, SCR, UA, and MDA levels, while elevating serum GSH, GSH-PX, and SOD activities in DN rats (p < 0.05). Furthermore, there was a notable rise in the mRNA and protein expression of renal Nrf-2, GCLC, NQO1, and HO-1 post mAPS treatment (p < 0.05). Additionally, mAPS supplementation led to reduced protein expression of TLR4, NLRP3, p-NF-κB, TGF-β, and Smad4. Concurrently, mAPS exerted a modulatory effect on gut microbiota, as evidenced by the increased abundance of Muribaculaceae, Ruminococcus_1, Phascolarctobacterium, and Lachnoclostridium-related genera. Spearman correlation analysis illustrated a negative association between the abundance of microbiota (Muribaculaceae, Lachnospiraceae_NK4A136, Ruminococcus_1, Clostridiales) and the levels of serum parameters (BUN, CR, UA, TC, TG). In summary, our data robustly attests to the potential of mAPS in modulating oxidative stress, inflammation, and gut microbiota, ultimately resulting in improved renal function in DN rats.
... For example, inhibition of methylenetetrahydrofolate dehydrogenase 2 significantly increased ROS levels and induced apoptosis [40]. Moreover, ROS-inducing drugs can bind to iron, increase ROS cellular levels, and subsequently trigger pyrosis in melanoma cells [41]. Studies have shown that amygdalin could effectively reduce ROS levels in HBZY-1 cells induced by high sugar stress. ...
Neuroinflammation and microglial activation play critical roles in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Modulating microglial activation may help prevent the progression of these disorders. This study aimed to investigate the effects and mechanisms of Melissa officinalis ethanol extract on lipopolysaccharide (LPS)-induced microglial activation in BV2 cells. Cell viability and nitric oxide (NO) production were assessed using MTT assay and Griess reagent, while inflammatory cytokine levels were measured by qPCR. Key inflammatory pathways, including MAPK, TLR4, and antioxidant biomarkers, were analyzed through western blot and immunofluorescence. Rosmarinic acid content in M. officinalis was determined using high-performance liquid chromatography (HPLC). The results demonstrated that M. officinalis ethanol extract significantly inhibited LPS-induced NO production and reduced inflammatory cytokine expression. Additionally, it downregulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TLR4, NF-κB, and MAPK signaling pathways (p38, JNK, ERK), while increasing the expression of antioxidant markers, including Nrf2, HO-1, catalase, and SOD2. In conclusion, M. officinalis ethanol extract exerts neuroprotective effects by modulating inflammation and enhancing antioxidant defenses, suggesting its potential in the prevention and treatment of inflammation-related neurodegenerative diseases.
... AMY was reported to markedly depress the levels of TNF-a, IL-1β and IL-6 expression and the infiltration of inflammatory cells in the LPS-induced acute lung injury model [44]. Based on evidence that OS is an essential constituent of the inflammatory response and recent studies indicating that AMY can decrease the expression of both OS and inflammatory response-related proteins to ameliorate hypertension-induced heart damage and diabetic nephropathy [45,46] will have to undergo revision surgery 20-25 years after primary THA, so how to delay the process of GANFH is particularly important [1]. Our in vivo study showed that 5 mg/kg/d and 10 mg/kg/d doses of AMY had varying degrees of therapeutic effects on GANFH, with the 10 mg/kg/d dose being the most effective and superior to ALN. ...
... In this study, we confirmed that AMY treatment at 3 mg/kg/day significantly preserved cardiac function in MI rats. This dose of AMY showed protective effects in various rat disease models, such as diabetic nephropathy and hepatic fibrosis, and no apparent toxicity was reported (Guo et al. 2013;Chen et al. 2021;Wang et al. 2021). To our knowledge, this is the first study to evaluate the in vivo cardioprotective function of AMY, suggesting the potential of AMY in treating CVDs. ...
This study investigated the effects of amygdalin (AMY, a cyanogenic glycoside widely distributed in the fruits and seeds of Rosaceae plants) on cardiac performance and ventricular remodeling in a rat model of myocardial infarction (MI). We also investigated whether the combination of AMY with exercise training (ExT) has a beneficial synergistic effect in treating MI rats. MI was induced by the ligation of the left anterior descending coronary artery in male SD rats. ExT or AMY treatment was started 1 week after MI and continued for 1 week (short-term) or 8 weeks (long-term). Cardiac function was evaluated by echocardiographic and hemodynamic parameters. Heart tissues were harvested and subjected to 2,3,5-triphenyl-tetrazolium chloride, Masson's trichrome, hematoxylin-eosin, and immunohistochemical staining. Gene expression was determined by quantitative polymerase chain reaction. Western blot gave a qualitative assessment of protein levels. AMY or ExT improved cardiac function and reduced infarct size in MI rats. AMY or ExT also suppressed myocardial fibrosis and attenuated inflammation in the infarct border zone of hearts from MI rats, as evidenced by inhibition of collagen deposition, inflammatory cell infiltration, and pro-inflammatory markers (interleukin 1β, interleukin 6, tumor necrosis factor-α, and cyclooxygenase 2). Notably, the effects of AMY combined with ExT were superior to those of AMY alone or ExT alone. Mechanistically, these beneficial functions were correlated with the inhibition of MI-induced activation of the transforming growth factor-β/Smad pathway. Collectively, AMY and ExT exert a synergistic effect on improving cardiac performance and ameliorating cardiac inflammation and fibrosis after MI, and the effects of long-term intervention were better than short-term intervention.
... Albogami et al. (2020) found that amygdalin (100 mg/kg) exhibited upregulated mRNA expression of GSH and SOD and significantly decreased lipid peroxidation in hepatic and testicular tissues. Two other studies have demonstrated that amygdalin enhanced the levels of the antioxidant indicators CAT, GSH, and SOD against Ehrlich solid tumor (EST) oxidative stress (El-Masry et al., 2019) and reduced oxidative stress in the renal tissue of rats accompanying streptozotocin (STZ)-mediated diabetic nephropathy(Chen et al., 2021). ...
Amygdalin (AMY), a plant secondary metabolite containing nitrile, is a major component of the seeds of Rosaceae family plants. It is known that this compound has many pharmacological activities such as cancer prevention, antipyretic, and cough suppressant. In this study, the genotoxic and modulatory effects of amygdalin were assessed by chromosomal aberration (CA), sister chromatid exchange (SCE), and cytokinesis‐block micronucleus assay (CBMN) assays using human peripheral lymphocytes (HPLs) in the absence and presence of metabolic activator (S9 mix). Lymphocytes were exposed to various concentrations of amygdalin (0.86, 1.72, 3.43, 6.86, and 13.75 μg/mL) alone and in combination with mitomycin‐C (MMC, 0.20 μg/mL) or cyclophosphamide (CP, 12 μg/mL). The mitotic index (MI), replication index (RI), cytokinesis‐block proliferation index (CBPI), and cytostasis were also evaluated to determine cytotoxicity. Amygdalin alone did not exhibit genotoxic and cytotoxic effects at all the tested concentrations both in the absence and presence of the S9 mix. In contrast, amygdalin significantly reduced the frequencies of CA (especially at 48 h treatments), SCE, and MN (except 0.86 μg/mL in pre‐ and simultaneous treatment) induced by MMC in all the tested concentrations and treatment protocols. It has also considerably decreased CP‐induced CA and SCE frequencies at all the concentrations (except 0.86 μg/mL) in simultaneous treatment. This study demonstrated that amygdalin alone was not genotoxic, on the contrary, it has revealed modulatory effects against chemotherapy agents that induced genomic damage in human lymphocytes, suggesting its chemopreventive potential.
... GPX is a peroxide-degrading enzyme that removes harmful peroxide products produced in cells and blocks the peroxidation reaction. Accordingly, the results suggest that MTG may alleviate LPS-induced ALI by increasing the activity of antioxidant enzymes and suppressing lipid peroxidation, which may ascribe to Ephedra Herba [21], Semen Armeniacae Amarum [22], and Glycyrrhizae Radix et Rhizome [23]. ...
Makyo‐kanseki‐to has been used for the treatment of pneumonia, becoming a basic formula for coronavirus disease 2019. However, the chemical profile of Makyo‐kanseki‐to granule and its possible mechanism against acute lung injury from terminal metabolic regulation have been unclear. The aim of this study was to characterize the constituents in Makyo‐kanseki‐to granule and reveal the potential related mechanism of Makyo‐kanseki‐to granule treatment for acute lung injury using a rat model of lipopolysaccharide‐induced acute lung injury. Totally, 78 constituents were characterized based on ultra‐performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry. Makyo‐kanseki‐to granule could alleviate acute lung injury through modulating rectal temperature, pulmonary edema, histopathology, and processes of inflammatory and oxidative stress. Twenty‐two potential biomarkers in acute lung injury rats were identified by metabolomics based on ultra‐performance liquid chromatography coupled with quadrupole exactive high‐field mass spectrometry. They were mainly involved in amino acids and glycerophospholipid metabolism, which were regulated by Makyo‐kanseki‐to granule. The present results not only increase the understanding of the chemical profile and molecular mechanism of Makyo‐kanseki‐to granule mediated protection against acute lung injury but also provide an experimental basis and new ideas for further development and clinical application of Makyo‐kanseki‐to granule.
... MDA, a common index of peroxidation, is the end product of lipid oxidation, which can damage the stability of the mitochondrial membrane and aggravate the degree of injury to mitochondria. 47 Cyto C is the terminal protein of the mitochondrial oxidative respiratory chain, and an increased level of C-Cyto C indicates mitochondrial damage. Mitochondria are key players in producing physiological sources of ROS, and free radicals can also attack mitochondria. ...
Diabetic nephropathy is a progressive kidney disease resulting from long-term hyperglycaemia in diabetic patients, and the underlying mechanism is complex and lacks effective treatments. Various active ingredients in Chinese herbs have been shown to alleviate renal injury and improve DN in recent years. Phillyrin, a natural medicinal active compound extracted from the Oleaceae family, has various pharmacological effects, including antioxidative, antiapoptotic and antiobesity effects. However, the role of phillyrin and its underlying mechanism in DN have not yet been explored. To investigate the effects of phillyrin on DN and its potential mechanisms of action, we performed experiments using streptozotocin (STZ)-induced DN mice as models. Phillyrin significantly reduced the levels of fasting blood glucose (FBG) and glycosylated haemoglobin A1c (HbA1c), downregulated the levels of serum blood urea nitrogen (BUN), serum creatinine (Scr), serum and urine β2-microglobulins (β2-MG) and improved the pathological changes of the kidney in a DN mouse model. Phillyrin also increased the level of antioxidants and attenuated oxidative damage in DN model mice. In addition, phillyrin inhibited Glycogen synthase kinase-3β (GSK-3β) activity by activating the PI3K/Akt signalling pathway, increased the Bcl-2/Bax ratio, reduced the release of cytochrome c from the mitochondria to the cytoplasm, subsequently inhibited the activation of caspase-3 and ultimately suppressed renal cell apoptosis. These findings suggested that phillyrin could be a new promising therapeutic strategy for DN, and this protective effect might be related to suppressing oxidative stress and apoptosis via the PI3K/Akt/GSK-3β pathway.
... Tang et al. [149] demonstrated in their research the inhibition of IL-6 expression by amygdalin, which, at a deep molecular level, prevented the translocation of NF-κB from the cytosol to the nucleus and, thus, prevented its transcription. Moreover, amygdalin ameliorates excessive oxidative stress, inflammation, and the renal tissue fibrosis of diabetic nephropathy mainly by suppressing the TGF-β1/Smad signaling pathway and regulating the key enzymes of ECM degradation [203]. ...
The inflammatory reaction accompanies in part or in full any disease process in the vascularized metazoan. This complicated reaction is controlled by regulatory mechanisms, some of which produce unpleasant symptomatic manifestations of inflammation. Therefore, there has been an effort to develop selective drugs aimed at removing pain, fever, or swelling. Gradually, however, serious adverse side effects of such inhibitors became apparent. Scientific research has therefore continued to explore new possibilities, including naturally available substances. Amygdalin is a cyanogenic glycoside present, e.g., in bitter almonds. This glycoside has already sparked many discussions among scientists, especially about its anticancer potential and related toxic cyanides. However, toxicity at different doses made it generally unacceptable. Although amygdalin given at the correct oral dose may not lead to poisoning, it has not yet been accurately quantified, as its action is often affected by different intestinal microbial consortia. Its pharmacological activities have been studied, but its effects on the body’s inflammatory response are lacking. This review discusses the chemical structure, toxicity, and current knowledge of the molecular mechanism of amygdalin activity on immune functions, including the anti-inflammatory effect, but also discusses inflammation as such, its mediators with diverse functions, which are usually targeted by drugs.
... The pathological changes in the kidneys were observed under the biomicroscope. Semiquantitative measurement of the changes was performed using Image J software according to the previous study [17]. ...
Objective
To investigate the effect of baicalin on diabetic nephropathy (DN) rats and podocytes and its mechanism.
Methods
The rat models with DN were established by high-fat and high-sugar diet and intraperitoneal injection of streptozotocin. The fasting blood glucose (FBG) and weight of rats in each group were measured at 0, 1, 2, 3, and 4 weeks. Their biochemical indicators, expression of inflammatory, and antioxidant factors were measured using an automatic biochemical analyzer together with ELISA. Hematoxylin–eosin staining and periodic acid-schiff staining were used to observe the morphological changes in the kidneys of rats in each group. Finally, the expressions of related molecules and PI3K/Akt/mTOR signaling pathway proteins in renal tissues and podocytes were examined by qRT-PCR and Western blot.
Results
Compared with the DN group, the FBG and weight, serum creatinine, blood urea nitrogen, total cholesterol, triacylglycerol, microalbumin, and albumin/creatinine ratio were all significantly decreased in the Baicalin treatment groups in a concentration-dependent manner. The levels of inflammatory factors in kidney tissue and podocytes were decreased. In addition, the activities of lactate dehydrogenase and malondialdehyde in tissue were decreased, while the superoxide dismutase was increased. The pathological sections showed that glomerular atrophy and glomerular basement membrane thickening caused by hyperglycemia were improved in the Baicalin treatment groups. Meanwhile, baicalin inhibited the downregulation of Nephrin and Podocin expressions and upregulation of Desmin expression caused by DN, and inhibited the expressions of p-PI3K, p-Akt, and p-mTOR proteins.
Conclusion
Baicalin slows down podocyte injury caused by DN by inhibiting the activity of PI3K/Akt/mTOR signaling pathway.
... Amygdalin increases the proapoptotic Bax protein secretion and declines the anti-apoptotic Bcl-2 protein expression on the breast cancer cell line; therefore, amygdalin is a suitable agent for treating breast cancer [55]. Amygdalin improves the inflammation, oxidative stress, and renal tissue fibrosis of diabetic nephropathy by controlling the key enzymes of matrix degradation [56]. Amygdalin amends chronic mild stress-induced alopecia areata injury in the skin of mice by decreasing the levels of interleukin-6, interleukin-1β, tumor necrosis factor-α, and osteopontin [57]. ...
Semen armeniacae refers to the seeds of Prunus armeniaca L. (Rosaceae). The Prunus armeniaca L. plant is spreading in the Korean peninsula, China, India, Japan, North Africa, and the United States of America. The Prunus armeniaca contains 3% amygdalin, titratable acidity, sugars (saccharose, fructose, and glucose), and organic acids (citric and malic acids) in addition to prunasin and mandelonitrile. Semen armeniacae is used for the treatment of asthma and cough (with expectoration and fever). It is used in constipation therapy. It is also used as eardrops for inflammation
and tinnitus and the treatment of skin diseases. The pharmacological effect of Semen armeniacae includes experimental and clinical pharmacology. Experimental pharmacology includes anti-cholinesterase, neuroprotective, analgesic, antipyretic, antitumor, antibacterial, antimicrobial, antifungal, and antitussive activities. Decoction of Semen armeniacae to 2275 patients with COVID-19 improves clinical parameters such as lung state, clinical cure rate, number of cough reduction cases, symptom score of cough, viral nucleic acid testing, and inflammatory biomarkers. Oral intake of Semen
armeniacae extract for 28 days did not cause any hematological, biochemical, or histological changes in rats. The Prunus armeniaca plant declines oxidative stress, inflammation, fat degeneration, and necrosis in alcohol-induced in-vivo and in-vitro liver injury models. There is no effect on fertility in rats after eating Semen armeniacae for 5 weeks. The average daily dose= 3-9 g of Semen armeniacae rinsing in boiling water then adding to a decoction. In conclusion, Semen armeniacae has anti-cholinesterase, neuroprotective, analgesic, antipyretic, antitumor, antibacterial, antimicrobial, antifungal, and antitussive activities.
... The activation of TGF-β1 or its downstream signaling pathway promotes the accumulation of extracellular matrix, leading to basement membrane thickening and glomerulosclerosis [9]. Amygdalin can reduce renal brosis in DN model rats by inhibiting TGF-β/Smad signaling pathway to inhibit ECM deposition and EMT [10]. Similar studies have con rmed that dapagli ozin can reduce the expression of TGF-β1 in the kidney and reduce the EMT of renal tubular epithelial cells, thereby reducing renal interstitial brosis in diabetic nephropathy [11]. ...
Background: Diabetic nephropathy is one of the main complications of diabetes, inflammation and fibrosis play an important role in its progress. NAD (P) H: quinone oxidoreductase 1 (NQO1) protects cells from oxidative stress and toxic quinone damage. In present study, we aimed to investigate the protective effects and underlying mechanisms of NQO1 on diabetes-induced renal inflammation and fibrosis.
Methods: In vivo, adeno-associated virus serotype 9 was used to infect the kidneys of type 2 diabetes model db/db mice to overexpress NQO1. In vitro, human renal tubular epithelial cells (HK-2) transfected with NQO1 pcDNA were cultured in high glucose. The gene and protein expression were assessed by quantitative real-time PCR, western blot, immunofluorescence, and immunohistochemical staining. Mitochondrial reactive oxygen species was detected by MitoSox red.
Result: Our study revealed that the expression of NQO1 was markedly down-regulated, Toll-like receptor 4 (TLR4) and TGF-β1 upregulated in vivo and in vitro under diabetic conditions. Overexpression of NQO1 suppressed pro-inflammatory cytokines secretion (IL-6, TNF-α, MCP-1), extracellular matrix (ECM) accumulation (collagen Ⅳ, Fibronectin) and epithelial-mesenchymal transition (EMT) (α-SMA, E-cadherin) in db/db mice kidney and high glucose cultured human renal tubular cells (HK-2). Furthermore, NQO1 overexpression ameliorated high glucose-induced TLR4/NF-κB and TGF-β/Smad pathway activation. Mechanistic studies demonstrated that TLR4 inhibitor (TAK-242) suppressed TLR4/NF-κB signaling pathway, pro-inflammatory cytokines secretion, EMT and ECM-related protein expression in HG-exposed HK-2 cells. In addition, we found that antioxidants NAC and tempol increased the expression of NQO1, decreased the expression of TLR4, TGF-β1, Nox1, Nox4 and ROS production in HK-2 cells cultured with high glucose.
Conclusions: These above data suggest that NQO1 alleviates diabetes-induced renal inflammation and fibrosis by regulating TLR4/NF-κB and TGF-β/Smad signaling pathways.
Renal fibrosis (RF) is an inevitable outcome of nearly all progressive chronic kidney diseases (CKD). However, effective therapies that can halt or reverse the development of RF and CKD progression remain limited. Traditional Chinese Medicine (TCM) offers a unique therapeutic approach, demonstrating significant anti-fibrotic potential through its antioxidant and anti-inflammatory pharmacological properties. However, comprehensive reviews focusing on the role of TCM in targeting signaling pathways associated with RF are still scarce. In this review, the literature was screened according to the clarity of the relevance of TCM, including the types and mechanisms of TCM. We summarize the pivotal role of the TGF-β/Smad signaling pathway in RF and provide an overview of single Chinese botanical drug, their active ingredients, and TCM compounds that ameliorate RF by modulating this pathway, aiming to establish a solid foundation for future basic and clinical research in the field of RF. While TCM holds unique advantages in treating RF, its limitations need to be addressed through scientific research and technological innovation. Future studies will focus on elucidating mechanisms, improving quality control, validating clinical efficacy, and fostering international collaboration to promote the scientific and global application of TCM in modern medicine.
To explore the impact of amygdalin on the proliferation, migration, and invasion of human endometrial stromal cells (HESCs) and the possible underlying mechanism. HESCs were incubated with 50, 100, and 200 µg/mL of amygdalin. The malignant activities of HESCs were analyzed by functional experiments. The activation of the Wnt/β-catenin signaling was tested using TOP/FOPFlash. The mRNA expressions of genes were validated by qRT-PCR. The endometriosis (EMS) mouse model was induced and the impact of amygdalin on the growth of ectopic endometrial lesions were assessed. It was observed that amygdalin markedly lessened the malignant activities of HESCs in a dose-dependent way (p < 0.05). Amygdalin dose-dependently declined the activation of TOPFlash and mRNA levels of β-catenin, cyclinD1 and c-Myc in HESCs (p < 0.05). Additionally, the increasing dose of amygdalin progressively inhibited the growth of ectopic endometrial lesions in EMS mouse model (p < 0.05). We reached a conclusion that amygdalin could inhibit the malignant activities of HESCs and alleviate EMS, which was related to Wnt/β-catenin signaling activation.
Inflammatory injury is a critical factor in the occurrence and development of diabetic kidney disease (DKD). Signal transduction pathways such as the nuclear factor kappa beta (NF-κB), mitogen-activated protein kinase (MAPK), NOD-like receptor protein 3, and Smads are important mechanisms of inflammatory kidney injury in DKD, and the NF-κB pathway plays a key role. The inflammatory factor network formed after activation of the NF-κB pathway connects different signaling pathways and exacerbates renal inflammatory damage. Many traditional Chinese medicine compounds, single agents, effective components and active ingredients can regulate the expression of key molecules in the signaling pathways associated with inflammatory injury, such as transforming growth factor-β activated kinase 1, NF-κB, p38MAPK, NOD-like receptor protein 3, and Smad7. These treatments have the characteristics of multiple targets and have multiple and overlapping effects, which can treat DKD kidney inflammation and injury through multiple mechanisms and apply the “holistic concept” of traditional Chinese medicine.
Armeniacae semen amarum—seeds of Prunus armeniaca L. (Rosaceae) (ASA), also known as Kuxingren in Chinese, is a traditional Chinese herbal drug commonly used for lung disease and intestinal disorders. It has long been used to treat coughs and asthma, as well as to lubricate the colon and reduce constipation. ASA refers to the dried ripe seed of diverse species of Rosaceae and contains a variety of phytochemical components, including glycosides, organic acids, amino acids, flavonoids, terpenes, phytosterols, phenylpropanoids, and other components. Extensive data shows that ASA exhibits various pharmacological activities, such as anticancer activity, anti-oxidation, antimicrobial activity, anti-inflammation, protection of cardiovascular, neural, respiratory and digestive systems, antidiabetic effects, and protection of the liver and kidney, and other activities. In clinical practice, ASA can be used as a single drug or in combination with other traditional Chinese medicines, forming ASA-containing formulas, to treat various afflictions. However, it is important to consider the potential adverse reactions and pharmacokinetic properties of ASA during its clinical use. Overall, with various bioactive components, diversified pharmacological actions and potent efficacies, ASA is a promising drug that merits in-depth study on its functional mechanisms to facilitate its clinical application.
Bcl-2-associated transcription factor-1 (BCLAF1), an apoptosis-regulating protein of paramount significance, orchestrates the progression of various malignancies. This study reveals increased BCLAF1 expression in hepatocellular carcinoma (HCC) patients, in whom elevated BCLAF1 levels are linked to escalated tumor grades and diminished survival rates. Moreover, novel BCLAF1 expression is particularly increased in HCC patients who were not sensitive to the combined treatment of atezolizumab and bevacizumab, but not in patients who had tumors that responded to the combined regimen. Notably, overexpression of BCLAF1 increases HCC cell proliferation in vitro and in vivo, while the conditioned medium derived from cells overexpressing BCLAF1 strikingly enhances the tube-formation capacity of human umbilical vein endothelial cells. Furthermore, compelling evidence demonstrates that BCLAF1 attenuates the expression of prolyl hydroxylase domain protein 2 (PHD2) and governs the stability of hypoxia-inducible factor-1α (HIF-1α) under normoxic conditions without exerting any influence on transcription, as determined by Western blot and RT‒qPCR analyses. Subsequently, employing coimmunoprecipitation and immunofluorescence, we validated the reciprocal interaction between BCLAF1 and Cullin 3 (CUL3), through which BCLAF1 actively upregulates the ubiquitination and degradation of PHD2. The Western blot and RT‒qPCR results suggests that programmed death ligand-1 (PD-L1) is one of the downstream responders to HIF-1α in HCC. Thus, we reveal the pivotal role of BCLAF1 in promoting PD-L1 transcription and, through binding to CUL3, in promoting the accumulation of HIF-1α under normoxic conditions, thereby facilitating the ubiquitination and degradation of PHD2.
Purpose
To investigate the role of puerarin on renal fibrosis and the underlying mechanism in renal ischemia and reperfusion (I/R) model.
Methods
Rats were intraperitoneally injected with puerarin (50 or 100 mg/kg) per day for one week before renal I/R. The level of renal collagen deposition and interstitial fibrosis were observed by hematoxylin and eosin and Sirius Red staining, and the expression of α-smooth muscle actin (α-SMA) was examined by immunohistochemical staining. The ferroptosis related factors and TLR4/Nox4-pathway-associated proteins were detected by Western blotting.
Results
Puerarin was observed to alleviate renal collagen deposition, interstitial fibrosis and the α-SMA expression induced by I/R. Superoxide dismutase (SOD) activities and glutathione (GSH) level were decreased in I/R and hypoxia/reoxygenation (H/R), whereas malondialdehyde (MDA) and Fe²⁺ level increased. However, puerarin reversed SOD, MDA, GSH and Fe²⁺ level changes induced by I/R and H/R. Besides, Western blot indicated that puerarin inhibited the expression of ferroptosis related factors in a dose-dependent manner, which further demonstrated that puerarin had the effect to attenuate ferroptosis. Moreover, the increased expression of TLR/Nox4-pathway-associated proteins were observed in I/R and H/R group, but puerarin alleviated the elevated TLR/Nox4 expression.
Conclusions
Our results suggested that puerarin inhibited oxidative stress and ferroptosis induced by I/R and, thus, delayed the progression of renal fibrosis, providing a new target for the treatment of renal fibrosis.
Key words:
Chronic Kidney Disease; Ferroptosis; Reperfusion Injury; Oxidative Stress
Objective:
Diabetic nephropathy (DN) is one of the main complications of diabetes, and inflammation and fibrosis play an important role in its progression. NAD(P)H: quinone oxidoreductase 1 (NQO1) protects cells from oxidative stress and damage caused by toxic quinones. In the present study, we aimed to investigate the protective effects of NQO1 against diabetes-induced renal inflammation and fibrosis and the underlying mechanisms.
Methods:
In vivo, the kidneys of type 2 diabetes model db/db mice were infected with adeno-associated virus vectors to induce NQO1 overexpression. In vitro, human renal tubular epithelial (HK-2) cells transfected with NQO1 pcDNA3.1(+) were cultured under high-glucose (HG) conditions. Gene and protein expression was assessed by quantitative real-time PCR, Western blotting, immunofluorescence, and immunohistochemical staining. Mitochondrial reactive oxygen species (ROS) were detected with MitoSOX Red.
Result:
Our study revealed that the expression of NQO1 was markedly downregulated and that Toll-like receptor (TLR)4 and TGF-β1 expression was upregulated in vivo and in vitro under diabetic conditions. Overexpression of NQO1 suppressed proinflammatory cytokine (IL-6, TNF-α, MCP-1) secretion, extracellular matrix (ECM) (collagen IV, fibronectin) accumulation and epithelial-mesenchymal transition (EMT) (α-SMA, E-cadherin) in the db/db mouse kidneys and HG-cultured HK-2 cells. Furthermore, NQO1 overexpression ameliorated HG-induced TLR4/NF-κB and TGF-β/Smad pathways activation. Mechanistic studies demonstrated that a TLR4 inhibitor (TAK-242) suppressed the TLR4/NF-κB signaling pathway, proinflammatory cytokine secretion, EMT and ECM-related protein expression in HG-exposed HK-2 cells. In addition, we found that the antioxidants N-acetylcysteine (NAC) and tempol increased the expression of NQO1 and decreased the expression of TLR4, TGF-β1, Nox1, and Nox4 and ROS production in HK-2 cells cultured under HG conditions.
Conclusions:
These data suggest that NQO1 alleviates diabetes-induced renal inflammation and fibrosis by regulating the TLR4/NF-κB and TGF-β/Smad signaling pathways.
Ethnopharmacological relevance:
Armeniacae Semen Amarum (Prunus armeniaca L. var. ansu Maxim., Ku xingren, bitter almond, ASA) is an important medicine in Traditional Chinese Medicine (TCM). It is widely used because of its remarkable curative effect in relieving cough and asthma, moistening intestines and defecating.
Aim of the review:
This review aims to enlighten the deeper knowledge about ASA, giving a comprehensive overview of its traditional uses, phytochemistry, pharmacology and toxicology for future investigation of plant-based drugs and therapeutic applications.
Materials and methods:
The databases used are Web of Science, PubMed, Baidu academic, Google academic, CNKI, Wanfang and VIP . In addition, detailed information on ASA was obtained from relevant monographs such as Chinese Pharmacopoeia.
Results:
The active components of ASA mainly include amygdalin, bitter almond oil, essential oil, protein, vitamin, trace elements and carbohydrates. The pharmacological studies have shown that ASA has beneficial effects such as antitussive, antiasthmatic, anti-inflammatory, analgesic, antioxidant, antitumour, cardioprotective, antifibrotic, immune regulatory, bowel relaxation, insecticidal, etc. CONCLUSIONS: Many reports have been published on ASA's various active ingredients and biological uses. However, only a few reviews on its phytoconstituents and pharmacological uses. In addition, the exploration and development of ASA in other fields also deserve more attention in future research.
Amygdalin is non-toxic, but when placed with certain amino acids in the small intestine, it leads to the production of toxic hydrocyanic acid. In our study, we observed the effect of amygdalin on the activity of Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) in the kidney after a short administration. The experiment was performed on male California meat rabbits of the P91 rabbit line (n = 20). Amygdalin was applied intramuscularly in the experimental group E1 and E2 daily for 14 days. Animals from experimental groups E3 and E4 were fed crushed apricot seeds. Apricot seeds were mixed into the feed mixture. The control group of animals was fed with a standard commercial feed mixture. Significant differences (p < 0.05) were observed in GPx activity in the control group and experimental considerations E1 and E2, where amygdalin was administered i.m. A significant difference was also observed among the control group and the E4 group, where amygdalin was administered to the animals per os. We also observed differences among SOD activity. Significant differences (p < 0.05) were found out in the control group and the experimental group E2 where amygdalin was administered i.m. and between the control group and the E4 group, where amygdalin was administered to the animals per os. We found significant differences between experimental groups E1:E2 and between experimental group E1 and experimental group E4. We did not find significant differences among the other groups (p > 0.05). Many aspects of amygdalin administration have not yet been explored, requiring other research.
Amygdalin (Amy) is metabolized into cyanide in vivo, which may lead to fatal poisoning after oral administration. The defense mechanisms against toxic cyanide have not yet been adequately studied. In this study, comparative toxicokinetics study of Amy was performed in normal and pseudo germ-free rats. The efficiency of cyanide release was significant higher in normal group when given a single oral dose of 440 mg/kg (50% median lethal dose). Thiocyanate, the detoxification metabolite, was firstly detected in feces, caecum, and intestinal microbiota incubation enzymic system. The results suggest intestinal microbiota is involved in bidirectional regulation of toxicity and detoxification of Amy. We further identified the species related to cyanogenesis of Amy with metagenomic sequencing, such as Bifidobacterium pseudolongum, Marvinbryantia formatexigens, and Bacteroides fragilis. Functional analysis of microbiota reveals the detoxification potential of intestinal microbiota for cyanide. Sulfurtransferase superfamily, such as rhodanese, considered as main detoxification enzymes for cyanide, are largely found in Coriobacteriaceae bacterium, Butyricicoccus porcorum, Akkermansia muciniphila, etc. Besides, cyanoamino acid metabolism pathway dominated by Escherichia coli may contribute to the detoxification metabolism of cyanide. In summary, intestinal microbiota may be the first line of defense against the toxicity induced by Amy.
Diabetic nephropathy is one of the most common complications in diabetes. It has been shown to be the leading cause of end-stage renal disease. However, due to their complex pathological mechanisms, effective therapeutic drugs other than angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which have been used for 20 years, have not been developed so far. Recent studies have shown that diabetic nephropathy is characterized by multiple signalling pathways and multiple targets, including inflammation, apoptosis, pyroptosis, autophagy, oxidative stress, endoplasmic reticulum stress and their interactions. It definitely exacerbates the difficulty of therapy, but at the same time it also brings out the chance for natural products treatment. In the most recent two decades, a large number of natural products have displayed their potential in preclinical studies and a few compounds are under invetigation in clinical trials. Hence, many compounds targeting these singals have been emerged as a comprehensive blueprint for treating strategy of diabetic nephropathy. This review focuses on the cellular and molecular mechanisms of natural prouducts that alleviate this condition, including preclinical studies and clinical trials, which will provide new insights into the treatment of diabetic nephropathy and suggest novel ideas for new drug development.
Aim:
Diabetic kidney disease (DKD) is one of the severe microvascular complications of type 2 diabetes mellitus (T2DM), which eventually leads to irreversible renal damage and develops into end-stage renal disease (ESRD). Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of antidiabetic drugs that act on the kidney to reduce glucose reabsorption. Increasing evidence confirms that dapagliflozin exerts a protective effect on DKD, but the mechanisms have not been reported. The aims of this study were to observe the therapeutic efficacy of dapagliflozin on DKD and investigate the possible immunological mechanism.
Materials and methods:
T2DM was modeled by a high-sugar and high-fat diet combined with STZ. Then, rats were treated with 10 mg/kg dapagliflozin for 8 weeks. The protective efficacy of dapagliflozin was evaluated by observing body weight, blood glucose, blood serum creatinine, blood urea nitrogen, 24-h urine protein, renal histology and ultrastructure, and oxidative stress levels. The immunological mechanisms were monitored by measuring the levels of TLR2/Myd88/NF-κB by immunohistochemical staining, RT-qPCR and Western blotting.
Results:
After treatment with dapagliflozin, renal damage was greatly improved. The levels of blood glucose, renal function and proteinuria were significantly decreased, and renal pathological and ultrastructural damage was obviously extenuated, possibly due to the reduction in inflammation and the levels of oxidative stress.
Conclusions:
Dapagliflozin has therapeutic potential for DKD. This effect was possibly mediated by inhibiting inflammation and oxidative stress levels.
To investigate the interaction between long non-coding RNA4.9 (lncRNA4.9) and transforming growth factor-β1 (TGF-β1) in the model of HCMV DNA. The experiment was divided into 5 groups: NC group, PCDNA-lncRNA4.9 group, SH-lncRNA4.9 group, LV-TGF-β1) Group, and SH-lncRNA4.9 group. Compared with the NC group, overexpression of lncRNA4.9 could significantly increase ( P <0.05) the expression of TGF-β1 and decrease with time. The relative expression of HCMV DNA was significantly decreased ( P <0.05) with the overexpression of lncRNA4.9. Compared with the NC group, overexpression of TGF-β1 significantly increased the expression of lncRNA4.9 and decreased with time. The relative expression of HCMV DNA was significantly decreased ( P <0.05) with the overexpression of TGF-β1. However, silencing TGF-β1 could not reduce the relative expression of lncRNA4.9, but increased the relative expression of lncRNA4.9 on day 5, and the difference was statistically significant ( P <0.05). Silencing lncRNA4.9 could not reduce expression of TGF-β1, but increased expression of lncRNA4.9 on day 5 ( P <0.05). Overexpression of TGF-β1 could increase the relative expression level of lncRNA4.9 and decrease with time, and reduce the relative expression level of HCMV DNA, thus promoting HCMV into the latent infection state.
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. With the rising prevalence of diabetes, the occurrence of DN is likely to hit pandemic proportions. The current treatment strategies employed for DN focus on the management of blood pressure, glycemia, and cholesterol while neglecting DN’s molecular progression mechanism. For many theranostic uses, nano-technological techniques have evolved in biomedical studies. Several nanotechnologically based theranostics have been devised that can be tagged with targeting moieties for both drug administration and/or imaging systems and are being studied to identify various clinical conditions. The molecular mechanisms involved in DN are discussed in this review to assist in understanding its onset and progression pattern. We have also discussed emerging strategies for establishing a nanomedicine-based platform for DN-targeted drug delivery to increase drug’s efficacy and safety, as well as their reported applications.
Background
Chemical or drug-induced kidney damage has been recognized as a critical cause of kidney failure. The oxidative stress, inflammation, and imbalance of intestinal flora caused by carbon tetrachloride (CCl4) play a fundamental role in chronic kidney damage. Guizhi Fuling pills (GZFL) is a traditional formula consisting of five traditional Chinese medicinal herbs, which can promote blood circulation and improve kidney function. The underlying mechanisms of GZFL improving kidney damage are not fully understood yet.
Aim
The current study aimed to explore the effects of GZFL on CCl4-induced kidney damage and intestinal microbiota in mice.
Methods
Male ICR mice were intraperitoneally administered with 20% CCl4 (mixed in a ratio of 1:4 in soybean oil) twice a week, for 4 weeks to induce kidney damage. Creatinine (CRE), urea nitrogen, antioxidant enzymes, and inflammatory cytokines were measured and the histology of the kidney, jejunum, and colon examination to assess kidney and intestinal damage. The expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2) family members, nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in kidney tissues, and the tight junction proteins in colonic tissues were detected by Western blot. The gut microbiota was analyzed through 16S rRNA gene sequencing.
Results
GZFL treatment decreased the serum CRE and urea nitrogen levels. Moreover, GZFL reduced the levels of pro-inflammatory cytokines and increased antioxidant enzyme activities in kidney and colonic tissues. GZFL improved the kidney, jejunum, and colon histology. Furthermore, GZFL inhibited the expressions of NLRP3, ASC, and cleaved-Caspase-1, while Nrf2, HO-1, NQO1, GCLM, and tight junction proteins were increased. The dysbiosis of intestinal microbiota improved after GZFL treatment.
Conclusions
This study showed that GZFL could improve kidney damage, which might be mainly via the integrated regulations of the Nrf2 pathway, NLRP3 inflammasome, and composition of intestinal microbiota.
Amygdalin is a natural compound from Bitter Apricot Seed which is reported to have anti-inflammatory activity. Acetaminophen (APAP) resulted in drug-induced liver injury is the main cause of acute liver failure (ALI) worldwide and only N-acetylcysteine is the accepted detoxification drug. However, there is no effective medicine to perfect the hepatocyte death and secondary inflammation injury. In this study, we aim to investigate the protective effect of Amygdalin in the APAP-induced acute liver failure mice model. We establish the ALI model via intraperitoneal APAP injection and mice were treated with Amygdalin with intraperitoneal injection. We detected liver enzyme and histological change to evaluate the liver injury. We measured oxidative damage markers and inflammatory cell infiltration of liver tissues. At last, we investigated the mechanism of Amygdalin on protecting hepatocytes. Results showed that Amygdalin reduced ALT/AST level and decreased necrotic area of liver tissue. In addition, Amygdalin reduced the count of MPO+(neutrophils) and F4/80+(macrophages) of the liver and inhibited IL-6, TNF-a, and IL-1b expression. Amygdalin reduced liver SOD and MDA levels and increased Nrf2/NQO1/HO1 protein expression. Moreover, Amygdalin reduced TUNEL+ and P-MLKL + staining cells in liver tissue. Mechanically, Amygdalin promoted phosphorylation of AKT and suppressed JNK/RIP3/MLKL signaling.
This work was aimed to establish a quality control method for evaluating the effects on glucose and lipids of the fruiting body of Isaria cicadae Miquel from strain Ic-17-7 (Ic-17-7fb) using a rat model of type 2 diabetes (T2DM). Random amplified polymorphic DNA, sequence-characterized amplified region, and high-performance liquid chromatography (HPLC) were used for the quality control of Ic-17-7fb. The pharmacological effects on streptozocin (STZ)-induced high fat diet (HFD)-fed Albino Wistar rats were evaluated. The rats underwent the following treatments: control, metformin, Ic-17-7fb (0.166 and 0.5 g·kg⁻¹) or without treatment. The fasting blood glucose (FBG), blood glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL-c), and low-density lipoprotein (LDL-c) were measured. Ic-17-7fb amplified a single specific band by S11-2-F3 and S11-2-R3 primers. An HPLC-based quality and quantity method was established for industrial application. The contents of adenosine and N⁶-(2-hydroxyethyl) adenosine (HEA) of the cultivated Ic-17-7fb were analyzed. All of the validation lots of cultured Ic-17-7fb passed the quantity control of the training set (0.90 mg·g⁻¹ of adenosine and 0.89 mg·g⁻¹ of HEA). After two weeks of administration, the average FBG was 4.89 ± 0.42 (control), 26.10 ± 5.77 (model), 23.63 ± 6.15 (metformin), 17.96 ± 9.36 (Ic-17-7fb for 0.166 g·kg⁻¹), and 19.69 ± 8.71 mmol·L⁻¹ (Ic-17-7fb for 0.5 g·kg⁻¹). The FBG of Ic-17-7fb (0.166 g·kg⁻¹) treatment significantly reduced by 31.19%, compared with the model after two weeks of administration (P < 0.01). Metformin, Ic-17-7fb (0.166 g·kg ⁻¹), and Ic-17-7fb (0.5 g·kg⁻¹) reduced TC, TG, HDL-c, and LDL-c compared with the T2DM model treatment at the 6th week of treatment (P < 0.05). This study established the first quality standard for Ic-17-7fb, which can be effectively applied in the treatment of T2DM. The reliable quality control method and pharmacological effect will broaden its application space.
Circular RNAs, a family of covalently circularized RNAs with tissue-specific expression, were recently demonstrated to play important roles in mammalian biology. Regardless of extensive research to predict, quantify, and annotate circRNAs, our understanding of their functions is still in its infancy. In this study, we developed a novel computational tool: Competing Endogenous RNA for INtegrative Annotations (Cerina), to predict biological functions of circRNAs based on the competing endogenous RNA model. Pareto Frontier Analysis was employed to integrate ENCODE mRNA/miRNA data with predicted microRNA response elements to prioritize tissue-specific ceRNA interactions. Using data from several circRNA-disease databases, we demonstrated that Cerina significantly improved the functional relevance of the prioritized ceRNA interactions by several folds, in terms of precision and recall. Proof-of-concept studies on human cancers and cardiovascular diseases further showcased the efficacy of Cerina on predicting potential circRNA functions in human diseases.
Phytochemical composition, in vitro antioxidant and antiproliferative activity against HepG2 cells were studied in the kernels of apricot cultivars grown in the northern areas of Pakistan. Relatively, the kernel of Habbi cultivar/AP-12 depicted significant potential to scavenge DPPH and ABTS+ free radicals as well as oxygen radical absorbance capacity along with highest contents of total flavonoids, phenolics, chlorogenic and syringic acids on dry weight basis. The average concentration of quercetin ranged 0.072-1.343 mg/100 g, and of EGCG from 0.713 to 6.521 mg/100 g with maximum concentration in Hulappa/AP-3 and Kho Chali-Khatta 3/AP-17, respectively. Amygdalin content was highest (1145 mg/100 g) in the kernel of Balaani/AP-14. Highest inhibition of HepG2 cells was found in the kernel of Waflu Chuli/AP-9 (EC50 = 15.70 ± 3.77 mg/mL). The PCA showed significant contributions of polyphenols and flavonoids towards biochemical assays, while CA revealed similarities and associations among various cultivars. Our study revealed that Habbi, Waflu Chuli, Thukdeena and Balaani kernels are rich sources of bioactive compounds and possess significant antioxidant and anticancer activity and can contribute considerably in the prevention and treatment of chronic health disorders.
Acute liver injury (ALI) is a life-threatening syndrome accompanied by overwhelming inflammation. Amygdalin (AGD) has been reported to possess various biological activities, particularly anti-inflammatory activity. The current study was designed to assess the protective effects and underlying mechanisms of AGD against ALI induced by d-galactosamine (GalN) and lipopolysaccharide (LPS) in mice. The results indicated that AGD treatment effectively reduced the lethality, ameliorated the histopathological liver changes, reduced the malondialdehyde (MDA) and myeloperoxidase (MPO) levels, and decreased the alanine transaminase (ALT) and aspartate aminotransferase (AST) levels resulting from LPS/GalN challenge. Moreover, AGD significantly inhibited LPS/GalN-induced inflammatory responses in mice with ALI by reducing not only the secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 but also the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Additionally, our results demonstrated that the inhibitory effect of AGD was due to the suppressed activation of nuclear factor-kappa B (NF-κB) and nucleotide-binding domain (NOD-)like receptor protein 3 (NLRP3) inflammasome activity. Furthermore, AGD treatment substantially increased nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and enhanced NAD (P) H: quinoneoxidoreductase 1 protein expression, which was reversed by a Nrf2 inhibitor, in HepG2 cells. In summary, our investigations suggested that the ability of AGD to ameliorate LPS/GalN-induced ALI may involve the inhibition of the NLRP3 inflammasome and NF-κB signalling pathways and the upregulation of the Nrf2/NQO1 signalling pathway.
Klotho deficiency is relevant to renal fibrosis and podocyte injury in vivo and in vitro. We examined whether histological findings of renal biopsy specimens were associated with the levels of soluble klotho in humans. We investigated renal biopsy specimens of 67 patients and detailed microscopic findings were reviewed. Soluble serum/urinary klotho and urinary angiotensinogen were assessed by enzyme-linked immunosorbent assays, and tissue klotho expression was assessed by immunohistochemical staining. The median age of the study participants was 35.6 years. High serum klotho levels (≥14 pg/mL) were associated with decreased odds ratios (ORs) of interstitial fibrosis (OR = 0.019, P = 0.003) and segmental sclerosis (OR = 0.190, P = 0.022) in multivariable logistic regression analysis. Patients with a lower urinary klotho-to-creatinine ratio (UKCR) were significantly more likely to have diffuse foot process effacement (OR = 0.450, P = 0.010). The area under the receiver-operating characteristic curve (AUC) of serum klotho for predicting interstitial fibrosis was 0.920 (95% CI, 0.844–0.996), and the best cut-off value of serum klotho was 138.1 pg/mL. The AUC of UKCR for predicting diffuse foot process effacement was 0.754 (95% CI, 0.636–0.872), and the best cut-off value of UKCR was 96.7 pg/mgCr. Urinary angiotensinogen-to-creatinine ratio was not associated with serum klotho, UKCR, or any pathological finding. Our data suggested that soluble serum and urinary klotho levels represent a potential biomarker to predict renal fibrosis and podocyte injury in humans.
The acute lung injury (ALI) is a leading cause of morbidity and mortality in critically ill patients. Amygdalin is derived from the bitter apricot kernel, an efficacious Chinese herbal medicine. Although amygdalin is used by many cancer patients as an antitumor agent, there is no report about the effect of amygdalin on acute lung injury. Here we explored the protective effect of amygdalin on ALI using lipopolysaccharide (LPS)-induced murine model by detecting the lung wet/dry ratio, the myeloperoxidase (MPO) in lung tissues, inflammatory cells in the bronchoalveolar lavage fluid (BALF), inflammatory cytokines production, as well as NLRP3 and NF-κB signaling pathways. The results showed that amygdalin significantly reduced LPS-induced infiltration of inflammatory cells and the production of TNF-α, IL-1β, and IL-6 in the BALF. The activity of MPO and lung wet/dry ratio were also attenuated by amygdalin. Furthermore, the western blotting analysis showed that amygdalin remarkably inhibited LPS-induced NF-κB and NLRP3 activation. These findings indicate that amygdalin has a protective effect on LPS-induced ALI in mice. The mechanism may be related to the inhibition of NF-κB and NLRP3 signaling pathways.
The increase in the prevalence of diabetes mellitus (DM) and the secondary kidney damage produces diabetic nephropathy (DN). Early nephropathy is defined as the presence of microalbuminuria (30–300 mg/day), including normal glomerular filtration rate (GFR) or a mildly decreased GFR (60–89 mL/min/1.73 m 2), with or without overt nephropathy. The earliest change caused by DN is hyperfiltration with proteinuria. The acceptable excretion rate of albumin in urine is <30 mg/day. Albuminuria represents the excretion of >300 mg/day. Chronic kidney disease (CKD) is characterized by abnormalities in renal function that persist for >3 months with health implications. Alterations in the redox state in DN are caused by the persistent state of hyperglycemia and the increase in advanced glycation end products (AGEs) with ability to affect the renin-angiotensin system and the transforming growth factor-beta (TGF-í µí»½), producing chronic inflammation and glomerular and tubular hypertrophy and favoring the appearance of oxidative stress. In DN imbalance between prooxidant/antioxidant processes exists with an increase in reactive oxygen species (ROS). The overproduction of ROS diminishes expression of the antioxidant enzymes (manganese superoxide dismutase, glutathione peroxidase, and catalase). The early detection of CKD secondary to DN and the timely identification of patients would permit decreasing its impact on health.
Background Abroma augusta L. (Malvaceae) leaf is traditionally used to treat diabetes in India and Southern Asia. Therefore, current study was performed to evaluate the protective effect of defatted methanol extract of A. augusta leaves (AA) against type 2 diabetes mellitus (T2DM) and its associated nephropathy and cardiomyopathy in experimental rats.Methods
Antidiabetic activity of AA extracts (100 and 200 mg/kg, p.o.) was measured in streptozotocin-nicotinamide induced type 2 diabetic (T2D) rat. Fasting blood glucose level (at specific interval) and serum biochemical markers (after sacrifice) were measured. Redox status, transcription levels of signal proteins (NF-¿B and PKCs), mitochondria dependent apoptotic pathway (Bad, Bcl-2, caspase cascade) and histological studies were performed in kidneys and hearts of controls and AA treated diabetic rats.ResultsPhytochemical screening of extracts revealed the presence of taraxerol, flavonoids and phenolic compounds in the AA. T2D rats showed significantly (p¿<¿0.01) elevated fasting blood glucose level. Alteration in serum lipid profile and release of membrane bound enzymes like lactate dehydrogenase and creatine kinase, which ensured the participation of hyperlipidemia and cell membrane disintegration in diabetic pathophysiology. T2DM caused alteration in the serum biochemical markers related to diabetic complications. T2DM altered the redox status, decreased the intracellular NAD and ATP concentrations in renal and myocardial tissues of experimental rats. Investigating the molecular mechanism, activation PKC isoforms was observed in the selected tissues. T2D rats also exhibited an up-regulation of NF-¿B and increase in the concentrations of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-¿) in the renal and cardiac tissues. The activation of mitochondria dependent apoptotic pathway was observed in renal and myocardial tissues of the T2D rats. However, Oral administration of AA at the doses of 100 and 200 mg/kg body weight per day could reduce hyperglycemia, hyperlipidemia, membrane disintegration, oxidative stress, vascular inflammation and prevented the activation of oxidative stress induced signaling cascades leading to cell death. Histological studies also supported the protective characteristics of AA.Conclusions
Results suggest that AA could offer prophylactic role against T2DM and its associated reno- and cardio- toxicity.
Diabetic nephropathy is characterized by excessive deposition of extracellular matrix protein and disruption of the glomerular filtration barrier. Matrix metalloproteinases (MMPs) affect the breakdown and turnover of extracellular matrix protein, suggesting that altered expression of MMPs may contribute to diabetic nephropathy. Here we used an MMP-9 gene knockout mouse model, with in vitro experiments and clinical samples, to determine the possible role of MMP-9 in diabetic nephropathy. After 6 months of streptozotocin-induced diabetes, mice developed markedly increased albuminuria, glomerular and kidney hypertrophy, and thickening of the glomerular basement membrane. Gelatin zymographic analysis and western blotting showed that there was enhanced MMP-9 protein production and activity in the glomeruli. However, MMP-9 knockout in diabetic mice significantly attenuated these nephropathy changes. In cultured podocytes, various cytokines related to diabetic nephropathy including TGF-β1, TNF-α, and VEGF stimulated MMP-9 secretion. Overexpression of endogenous MMP-9 induced podocyte dedifferentiation. MMP-9 also interrupted podocyte cell integrity, promoted podocyte monolayer permeability to albumin, and extracellular matrix protein synthesis. In diabetic patients, the upregulation of urinary MMP-9 concentrations occurred earlier than the onset of microalbuminuria. Thus, MMP-9 seems to play a role in the development of diabetic nephropathy.Kidney International advance online publication, 26 March 2014; doi:10.1038/ki.2014.67.
Kidney fibrosis is a common process that leads to the progression of various types of kidney disease. We used an integrated computational and experimental systems biology approach to identify protein kinases that regulate gene expression changes in the kidneys of human immunodeficiency virus (HIV) transgenic mice (Tg26 mice), which have both tubulointerstitial fibrosis and glomerulosclerosis. We identified homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of kidney fibrosis. HIPK2 was upregulated in the kidneys of Tg26 mice and in those of patients with various kidney diseases. HIV infection increased the protein concentrations of HIPK2 by promoting oxidative stress, which inhibited the seven in absentia homolog 1 (SIAH1)-mediated proteasomal degradation of HIPK2. HIPK2 induced apoptosis and the expression of epithelial-to-mesenchymal transition markers in kidney epithelial cells by activating the p53, transforming growth factor β (TGF-β)-SMAD family member 3 (Smad3) and Wnt-Notch pathways. Knockout of HIPK2 improved renal function and attenuated proteinuria and kidney fibrosis in Tg26 mice, as well as in other murine models of kidney fibrosis. We therefore conclude that HIPK2 is a potential target for anti-fibrosis therapy.
Although pathologic classifications exist for several renal diseases, including IgA nephropathy, focal segmental glomerulosclerosis, and lupus nephritis, a uniform classification for diabetic nephropathy is lacking. Our aim, commissioned by the Research Committee of the Renal Pathology Society, was to develop a consensus classification combining type1 and type 2 diabetic nephropathies. Such a classification should discriminate lesions by various degrees of severity that would be easy to use internationally in clinical practice. We divide diabetic nephropathy into four hierarchical glomerular lesions with a separate evaluation for degrees of interstitial and vascular involvement. Biopsies diagnosed as diabetic nephropathy are classified as follows: Class I, glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV. Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel-Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel-Wilson) without changes described in class IV. Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy. A good interobserver reproducibility for the four classes of DN was shown (intraclass correlation coefficient = 0.84) in a test of this classification.
The ECM remodeling is a finely orchestrated process that involves changes in expression of the ECM genes and the activity of proteinases to clear the previous ECM deposit. Among enzymes involved in ECM remodeling, zinc-dependent proteinases--matrix metalloproteinases (MMPs) are believed to be the ones of major importance. MMPs degrade the ECM components and regulate the bioavailability and/or activity of growth factors by cleavage of both matrix and non-matrix substrates or by mediating receptor turnover. This review introduces the members of the MMP family and discusses their domain structure and function, proenzyme activation and the mechanism of inhibition.
Amygdalin is a cyanogenic glycoside plant compound found in the seeds of rosaceous stone fruits. We evaluated the antiinflammatory and analgesic activities of amygdalin, using an in vitro lipopolysaccharide (LPS)-induced cell line and a rat model with carrageenan-induced ankle arthritis. One mM amygdalin significantly inhibited the expression of TNF-alpha and IL-1beta mRNAs in LPS-treated RAW 264.7 cells. Amygdalin (0.005, 0.05, and 0.1 mg/kg) was intramuscularly injected immediately after the induction of carrageenan-induced arthritic pain in rats, and the anti-arthritic effect of amygdalin was assessed by measuring the weight distribution ratio of the bearing forces of both feet and the ankle circumference, and by analyzing the expression levels of three molecular markers of pain and inflammation (c-Fos, TNF-alpha, and IL-1beta) in the spinal cord. The hyperalgesia of the arthritic ankle was alleviated most significantly by the injection of 0.005 mg/kg amygdalin. At this dosage, the expressions of c-Fos, TNF-alpha, and IL-1beta in the spinal cord were significantly inhibited. However, at dosage greater than 0.005 mg/kg, the painrelieving effect of amygdalin was not observed. Thus, amygdalin treatment effectively alleviated responses to LPStreatment in RAW 264.7 cells and carrageenan-induced arthritis in rats, and may serve as an analgesic for relieving inflammatory pain.
Inflammation is emerging as an important mechanism for micro- and macrovascular complication of diabetes. The macrophage plays a key role in the chronic inflammatory response in part by generating particular cytokines. IL-1beta, IL-6, IL12, IL-18, TNFalpha, and interferon-gamma are produced primarily in macrophages and have been associated with accelerated atherosclerosis and altered vascular wall function. In this study, we evaluated the effect and mechanism of high glucose (HG) on gene expression of these cytokines in mouse peritoneal macrophages (MPM). HG led to a 2-fold increase in the mRNA expression of these cytokines, with IL-12 showing the highest activation (5.4-fold) in a time-dependent (3-12 h) and dose-dependent (10, 17.5, and 25 mmol/liter) manner. The effects were specific to HG because mannitol and 3-O-methyl-glucose had no effect on cytokine mRNA expression. HG also increased IL-12 protein accumulation from MPM. We also explored the role of induced and spontaneous diabetes on inflammatory cytokine expression in MPM. Increases in expression in MPM of multiple inflammatory cytokines, including a 20-fold increase in IL-12 mRNA, were observed in streptozotocin-induced type 1 diabetic mice as well as type 2 diabetic db/db mice, suggesting that cytokine gene expression is increased by hyperglycemia in vivo. We next explored potential mechanisms of HG-induced increases in IL-12 mRNA. HG increased the activity of protein kinase C, p38 MAPK (p38), c-Jun terminal kinase, and inhibitory-kappaB kinase in MPM. Furthermore, inhibitors of these signaling pathways significantly reduced HG-induced IL-12 mRNA expression in MPM. These results provide evidence for a potentially important mechanism linking elevated glucose and diabetes to inflammation.
Interleukin-12 (IL-12) has been identified as a pro-inflammatory cytokine which is thought to contribute to the development of atherosclerosis. However, to date, the various associations between factors related to the course of type 2 diabetes, like metabolic compensation, beta cell secretory dysfunction, insulin resistance and IL-12 serum levels, remain unclear. Our study involved 41 patients with type 2 diabetes, 19 patients with coronary artery disease (CAD), and 19 healthy controls. We measured serum levels of fasting glucose, HbA(1)c, 1,5-anhydro-d-glucitol, and lipids. In addition, serum levels of C-peptide, insulin, proinsulin and IL-12 were assayed. HOMA(IR) score was calculated. The serum concentrations of IL-12 were higher in diabetics than in either patients with CAD or healthy controls, and were correlated with BMI, C-peptide, insulin, HOMA(IR), proinsulin and HDL serum levels. Multiple regression analysis revealed that the IL-12 serum level in type 2 diabetics primarily is dependent upon fasting proinsulin concentration. Our results demonstrate that elevated IL-12 serum levels in type 2 diabetics treated with sulphonylureas are induced especially by peripheral insulin resistance and beta cells dysfunction, as expressed by fasting serum proinsulin levels. This finding gives us hope that treatment to decrease peripheral insulin resistance and to avoid excessive proinsulin secretion might be successful in the prevention of IL-12-induced atherosclerosis.
Between 20% and 40% of patients with diabetes ultimately develop diabetic nephropathy, which in the US is the most common cause of end-stage renal disease requiring dialysis. Diabetic nephropathy has several distinct phases of development and multiple mechanisms contribute to the development of the disease and its outcomes. This Review provides a summary of the latest published data dealing with these mechanisms; it focuses not only on candidate genes associated with susceptibility to diabetic nephropathy but also on alterations in various cytokines and their interaction with products of advanced glycation and oxidant stress. Additionally, the interactions between fibrotic and hemodynamic cytokines, such as transforming growth factor beta1 and angiotensin II, respectively, are discussed in the context of new information concerning nephropathy development. We touch on the expanding clinical data regarding markers of nephropathy, such as microalbuminuria, and put them into context; microalbuminuria reflects cardiovascular and not renal risk. If albuminuria levels continue to increase over time then nephropathy is present. Lastly, we look at advances being made to enable identification of genetically predisposed individuals.
at a Glance
This review summarizes the treatment of diabetic kidney disease (DKD) with Chinese herbal medicine (CHM) based on literature reports during the last 10 years. Commonly used CHMs and their underlying mechanisms are discussed.
Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease in order to be the causal mechanism. In order to establish if hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared to normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined in order to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia three days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy.
The understanding of renal fibrosis in chronic kidney disease (CKD) remains as a challenge. More than 10% of the population of developed countries suffer from CKD. Proliferation and activation of myofibroblasts and accumulation of extracellular matrix proteins are the main features of kidney fibrosis, a process in which a large number of cytokines are involved. Targeting cytokines responsible for kidney fibrosis development might be an important strategy to face the problem of CKD. The increasing knowledge of the signaling pathway network of the transforming growth factor beta (TGF-β) superfamily members, such as the profibrotic cytokine TGF-β1 or the bone morphogenetic proteins (BMPs), and their involvement in the regulation of kidney fibrosis, has stimulated numerous research teams to look for potential strategies to inhibit profibrotic cytokines or to enhance the anti-fibrotic actions of other cytokines. The consequence of all these studies is a better understanding of all these canonical (Smad-mediated) and non-canonical signaling pathways. In addition, the different receptors involved for signalling of each cytokine, the different combinations of type I-type II receptors, and the presence and function of co-receptors that can influence the biological response have been also described. However, are these studies leas to suitable strategies to block the appearance and progression of kidney fibrosis? In this review, we offer a critical perspective analyzing the achievements using the most important strategies developed up till now: TGF-β antibodies, chemical inhibitors of TGF-β receptors, miRNAs and signaling pathways and BMP agonists with a potential role as therapeutic molecules against kidney fibrosis.
In this publication we described amygdalin. It was isolated for the first time in the 19th century. Amygdalin is called interchangeably vitamin B17 or laetrile. Since more than a hundred years, there has been reports about its unique anticancer properties. We tried to introduce the present knowledge about therapeutic efficacy of laetrile. Most of these studies has been made in the in vitro environment. The lack of appropriate studies forced scientists to examine the positive influence of amygdalin on many diseases like: bladder cancer, prostate cancer, cervical cancer, colon cancer, promyelocytic leukemia, chronic kidney disease, psoriasis and other.
© 2015 MEDPRESS.
Amygdalin is a controversial anti-tumor natural product that has been used as an alternative cancer drug for many years. The anti-tumor mechanism and metabolism of amygdalin have been the focus of many studies. However, previous studies by our group demonstrated that amygdalin itself has no anti-tumor activity, but rather the active ingredients were determined to be amygdalin degradation products. To screen novel drugs with anti-tumor activity, the extracellular enzymes from Aspergillus niger were used to degrade amygdalin. Within 4h of the catalytic reaction at 37°, amygdalin was rapidly degraded into four products. The products were then extracted and purified by column chromatography. By comparing the HPLC chromatograms, 1H NMR, 13C NMR and MS data, the products were identified as mandelonitrile, prunasin, benzaldehyde and phenyl-(3,4,5-trihydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-acetonitrile (PTMT), a novel hydroxyl derivative of prunasin. Furthermore, pharmacology studies of these compounds demonstrated that 10mg/kg of PTMT significantly suppressed the growth of S-18 tumor cells within 11 days in a concentration-dependent manner.
Renal interstitial fibrosis is a common outcome of chronic renal diseases. Amygdalin is one of a number of nitrilosides, the natural cyanide‑containing substances abundant in the seeds of plants of the prunasin family that are used to treat cancer and relieve pain. However, whether amygdalin inhibits the progression of renal fibrosis or not remains unknown. The present study aimed to assess the therapeutic potential of amygdalin by investigating its effect and potential mechanism on the activation of renal interstitial fibroblast cells and renal fibrosis in rat unilateral ureteral obstruction (UUO). Treatment of the cultured renal interstitial fibroblasts with amygdalin inhibited their proliferation and the production of transforming growth factor (TGF)‑β1. In the rat model of obstructive nephropathy, following ureteral obstruction, the administration of amygdalin immediately eliminated the extracellular matrix accumulation and alleviated the renal injury on the 21st day. Collectively, amygdalin attenuated kidney fibroblast (KFB) activation and rat renal interstitial fibrosis. These results indicate that amygdalin is a potent antifibrotic agent that may have therapeutic potential for patients with fibrotic kidney diseases.
Diabetic nephropathy is a leading cause of end-stage renal failure worldwide. Its morphologic characteristics include glomerular hypertrophy, basement membrane thickening, mesangial expansion, tubular atrophy, interstitial fibrosis and arteriolar thickening. All of these are part and parcel of microvascular complications of diabetes. A large body of evidence indicates that oxidative stress is the common denominator link for the major pathways involved in the development and progression of diabetic micro- as well as macro-vascular complications of diabetes. There are a number of macromolecules that have been implicated for increased generation of reactive oxygen species (ROS), such as, NAD(P)H oxidase, advanced glycation end products (AGE), defects in polyol pathway, uncoupled nitric oxide synthase (NOS) and mitochondrial respiratory chain via oxidative phosphorylation. Excess amounts of ROS modulate activation of protein kinase C, mitogen-activated protein kinases, and various cytokines and transcription factors which eventually cause increased expression of extracellular matrix (ECM) genes with progression to fibrosis and end stage renal disease. Activation of renin-angiotensin system (RAS) further worsens the renal injury induced by ROS in diabetic nephropathy. Buffering the generation of ROS may sound a promising therapeutic to ameliorate renal damage from diabetic nephropathy, however, various studies have demonstrated minimal reno-protection by these agents. Interruption in the RAS has yielded much better results in terms of reno-protection and progression of diabetic nephropathy. In this review various aspects of oxidative stress coupled with the damage induced by RAS are discussed with the anticipation to yield an impetus for designing new generation of specific antioxidants that are potentially more effective to reduce reno-vascular complications of diabetes.
Diabetic nephropathy (DN) is one of the most important causes of end stage renal disease in the world. Its hallmark is proteinuria. Therefore, we set out to clarify the structural changes that occur in the glomerular filtration barrier in Chinese patients with true type 2 diabetic nephropathy, and to examine the relationship between these structural changes and proteinuria.
42 Chinese patients with true T2DN were divided into three groups according to urinary protein excretion. Glomerular volume, endothelial cell density, endothelial cell number, glomerular basement membrane (GBM) width, podocyte density, podocyte number and foot process width were evaluated using light and electron microscopic morphometry.
Glomerular volume and endothelial cell number were increased in diabetic patients, but there was no difference between patients with respect to the degree of proteinuria. As proteinuria progressed, endothelial cell density remained unchanged, while the glomerular basement membrane (GBM) and podocyte foot process width increased, podocyte density and number decreased.
Podocyte and GBM change more obviously during the development of proteinuria. Besides, proteinuria was inversely related to podocyte density, and directly related to GBM and glomerular volume.
Conventional genetic analysis focuses on the genes that account for specific phenotypes, while traditional epidemiology is more concerned with the environmental causes and risk factors related to traits. Genetic epidemiology is an alliance of the 2 fields that focuses on both genetics, including allelic variants in different populations, and environment, in order to explain exactly how genes convey effects in different environmental contexts and to arrive at a more complete comprehension of the etiology of complex traits. In this review, we discuss the epidemiology of diabetes and the current understanding of the genetic bases of obesity and diabetes and provide suggestions for accelerated accumulation of clinically useful genetic information.