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Oral traumatic ulcers (OTU) are common in dental routine, and the control of proinflammatory cytokines, such as the tumor necrosis factor-alpha (TNF-α), may interfere with OTU repair. Our aim was to evaluate the role of TNF-α in the healing process of OTU in rats. Wistar male rats were divided into six groups: a control-group (treated with 0.1 mL/kg of saline) and five groups treated with anti-TNF-α infliximab (INF) at 1, 3, 5, 7, and 10 mg/kg immediately before OTU production. The animals were weighed (day 0) and euthanized on days 1, 3, 7, 14 and 21 after ulceration. The ulcers were clinically measured, and the mucosa samples were histologically (scores 0–4), histochemically (collagen assay (pircrosirius)), histomorphometrically (cell counting), and immunohistochemically (TNF-α, α-smooth-muscle-actin (α-SMA), monocyte-chemoattractive-protein-1 (MCP-1), interleukin-8 (IL-8), and fibroblast-growth-factor (FGF)) analyzed. The Evans blue assay was used to measure the vascular permeability. ANOVA-1–2-way/Bonferroni, Kruskal–Wallis/Dunn, and correlation analyses were performed (GraphPad Prism 5.0, p < 0.05). High doses of INF reduced the OTU area (p = 0.043), body mass loss (p = 0.023), vascular permeability (p < 0.001), and reduced delayed histologic scores (p < 0.05), polymorphonuclear (p < 0.001) and mononuclear (p < 0.001) cells, blood vessel counting (p = 0.006), and total (p < 0.001), type-I (p = 0.018), and type-III (p < 0.001) collagen. INF treatment reduced TNF-α immunostaining and delayed MPC-1, FGF, and α-SMA expression, with little/none influence in IL-8 immunostaining. TNF-α blockage by INF reduced acute inflammation in OTU but delayed cell migration and wound healing.
Pathological effects of cytokine storm following the entry and replication of COVID-19 to host cells
The Covid-19, a threatening pandemic, was originated from China in December 2019 and spread quickly to all over the world. The pathogenesis of coronavirus is linked with the disproportionate response of the immune system. This involves the systemic inflammatory reaction which is characterized by marked pro-inflammatory cytokine release commonly known as cytokine release storm (CRS). The pro inflammatory cytokines are involved in cascade of pulmonary inflammation, hyper coagulation and thrombosis which may be lethal for the individual. That’s why, it is very important to have understanding of pro inflammatory cytokines and their pathological role in SARS-CoV-2. The pathogenesis of Covid is not the same in every individual, it can vary due to the presence of pre-existing comorbidities like suffering from already an inflammatory disease such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), an immune-compromised patients suffering from Diabetes Mellitus (DM) and Tuberculosis (TB) are more vulnerable morbidity and complications following COVID-19. This review is particularly related to COVID-19 patients having comorbidity of other inflammatory diseases. We have discussed the brief pathogenesis of COVID-19 and cytokines release storm with reference to other co-morbidities including RA, IBD, COPD, DM and TB. The available therapeutic regimens for COVID-19 including cytokine inhibitors, anti-viral, anti-biotic, bronchodilators, JAK- inhibitors, immunomodulators and anti-fibrotic agents have also been discussed briefly. Moreover, newly emerging medicines in the clinical trials have also been discussed which are found to be effective in treating Covid-19.
Background and Aim Multiple sclerosis (MS) is a demyelinating neurodegenerative inflammatory disease affecting mainly young adults. Microgliosis-derived neuroinflammation represents a key hallmark in MS pathology and progression. Nebivolol (Neb) demonstrated antioxidant, anti-inflammatory and neuroprotective properties in several brain pathologies. This study was conducted to investigate the potential neuroprotective effect of Neb in the cuprizone (Cup) model of MS. Methods C57Bl/6 mice were fed 0.2% Cup mixed into rodent chow for 5 weeks. Neb (5 and 10 mg/kg/day) was administered by oral gavage during the last 2 weeks. Results Neb prevented Cup-induced weight loss and motor deficits as evidenced by increased latency to fall in the rotarod test and enhanced locomotor activity as compared to Cup-intoxicated mice. Neb reversed Cup-induced demyelination as confirmed by Luxol fast blue staining and myelin basic protein western blotting. Administration of Neb modulated microglial activation status by suppressing M1 markers (Iba-1, CD86, iNOS, NO and TNF-α) and increasing M2 markers (Arg-1 and IL-10) as compared to Cup-fed mice. Furthermore, Neb hindered NLRP3/caspase-1/IL-18 inflammatory cascade and alleviated oxidative stress by reducing lipid peroxidation, as well as increasing catalase and superoxide dismutase activities. Conclusion These findings suggest the potential neuroprotective effect of Neb in the Cup-induced model of MS in mice, at least partially by virtue of shifting microglia towards M2 phenotype, mitigation of NLRP3 inflammasome activation and alleviation of oxidative stress.
The efficacy of the sulforaphane derivative JY4 was evaluated in acute and chronic mouse models of ulcerative colitis induced by dextran sodium sulfate. Oral administration of JY4 led to significant improvements in symptoms, with recovery of body weight and colorectal length, together with reduced diarrhoea, bloody stools, ulceration of colonic tissue and infiltration of inflammatory cells. The oral bioavailability of JY4, determined by comparing oral dosing with injection into the tail vein, was 5.67%, which was comply with the idea in the intestinal function. Using a dual-luciferase reporter assay, immunofluorescence studies, western blot analysis and immunohistochemical staining, JY4 was shown to significant interfere with the NF-κB-p65 signaling pathway. By preventing the activation of NF-κB-p65, JY4 inhibited the overexpression of downstream inflammatory factors, thereby exerting an anti-inflammatory effect on the intestinal tract. This study thus provides a promising candidate drug, and a new concept for the treatment of ulcerative colitis. Graphical Abstract
Objective The present study was designed to explore the potential anti-inflammatory and anti-arthritic effects of ellagic acid (EA) in collagen-induced arthritis (CIA). Methods CIA rats were treated with MTX (0.25 mg/kg body wt.) and EA (50 mg/kg b.wt.) for a period of 20 days. The effects of treatment in the rats were assessed biochemically by analyzing inflammatory mediators (NF-kB, iNOS, TNF-α, IL-1β, IL-6 and IL-10) and oxidative stress related parameters (MPO, NO, LPO, catalase, SOD, GSH). In addition, we also assessed the expression of some inflammatory mediators TNF-α, CD8 + though immunohistochemistry in the joint tissue. Results In the present study, we found expression and synthesis of transcription factor NF-kB was prominent in CIA rats. In addition, main pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and the anti-inflammatory IL-10, was also stand out. Further, reactive oxygen/nitrogen species was also elevated in CIA rats. Treatment with EA ameliorates all the above mentioned inflammatory and oxidative stress related parameters to near normal. Further, we also confirmed the expression of TNF-α, CD8⁺ T cells through immunohistochemistry was mitigates in joint tissue of EA treated rats. We find EA significantly inhibited the developmental phase of arthritis. Conclusion These results suggest that EA act as potent anti-arthritic and anti-inflammatory agent that could be used as a tool for the development of new drug for the treatment of arthritis. Graphical abstract
Parkinson’s disease (PD) remains a disease of little known etiology. In addition to the motor symptoms, depression is present in about 40% of patients, contributing to the loss of quality of life. Recently, the involvement of the autophagy mechanism in the pathogenesis of depression has been studied, in addition to its involvement in PD as well. In this study, we tested the effects of metformin, an antidiabetic drug also with antidepressant effects, on depressive-like behavior in a rotenone-induced PD model and on the autophagy process. Mice 8-week-old male C57BL/6 were induced with rotenone for 20 consecutive days (2.5 mg/kg/day) and treated with metformin (200 mg/kg/day) from the 5th day of induction. All the animals were submitted to rotarod, sucrose preference and tail suspension tests. After euthanasia, the substantia nigra and hippocampus were removed for analysis by western blotting or fixed and analyzed by immunofluorescence. The results show that there was an impairment of autophagy in animals induced by rotenone both in nigral and extranigral regions as well as a depressive-like behavior. Metformin was able to inhibit depressive-like behavior and increase signaling pathway proteins, transcription factors and autophagosome-forming proteins, thus inducing autophagy in both the hippocampus and the substantia nigra. In conclusion, we show that metformin has an antidepressant effect in a rotenone-induced PD model, which may result, at least in part, from the induction of the autophagy process.
The study aims to assess the antihemolytic and antioxidant activities of geraniol versus 2, 2′-azobis, 2-amidinopropane dihydro-chloride- (AAPH-) induced oxidative damage and hemolysis to erythrocytes and its anti-infammatory potential against lipopolysaccharide- (LPS-) induced infammation in white blood cells (WBCs) with a focus on its integrated computational strategies against diferent targeted receptors participating in infammation and coagulation. The rats’ erythrocyte suspension was incubated with diferent geraniol concentrations. Molecular docking and simulation were used to explore the possible interaction patterns of geraniol against the potential targeted proteins for therapeutic screening. The results displayed that geraniol had a prolonged noteworthy efect on activated partial thromboplastin time and thromboplastin time. Geraniol displayed strong antioxidant efects via reduced malondialdehyde (MDA) formation and increased GSH level and SOD activity. We observed dose-dependent prevention of K+ ion leakage along with a remarkable decline of hemolysis in erythrocytes pretreated with geraniol. Geraniol 100 µg/mL and diclofenac 100 µM were nontoxic to WBCs. Geraniol significantly reduces the expression and release of cellular pro-inflammatory factors TNF-α, IL-1β, IL-8, and nitric oxide, accompanied by a significant upregulation of gene expression of anti-inflammatory cytokine IL-10 in LPS-induced WBCs compared to nontreated cells. It demonstrates a much stronger inhibition potential than diclofenac in terms of inflammation inhibition. When comparing molecular docking and simulation data, current work showed that geraniol has a good affinity toward apoptosis signal-regulating kinase 1 (ASK1) and human P2Y12 receptors and could be developed as an antioxidant, anti-inflammatory, and anticoagulant medication in the future. Consequently, geraniol is recommended to have a defensive influence against oxidative stress, and hemolysis also could be developed as a promising anti-inflammatory, antioxidant, and anticoagulant medication.
Autoimmune disease is a complex chronic disease that triggers immune activation against autoantigens resulting in tissue damage. Epidemiological data showed that autoimmune diseases are increasing worldwide over the last decades owing to increased environmental pollution. This study investigates the therapeutic effect of myrrh as a natural medicine compared to prednisolone in the treatment of immune-mediated glomerulonephritis induced by silicate. The autoimmune disease model in rats was induced by injecting 5 mg crystalline sodium silicate suspension subcutaneously once weekly for 20 weeks, and then the rats were treated either with myrrh extract or prednisolone or with both for 6 weeks. Liver and kidney function tests, histopathology, and immunohistochemistry of TNF-α expression in kidney tissue were performed. The creatinine significantly elevated in silica-treated group and decreased in other treated groups. Histopathology of the kidney revealed improvement of glomerular and tubular basement thickness in all treated groups, but the inflammatory cell count slightly decreased in the group treated with myrrh than the other treated groups which showed a marked decrease. TNF-α expression was significantly decreased in all treated groups. Interestingly, the myrrh did not produce hepatic lesions and improve the side effect of prednisolone in the liver when taken in combination. Therefore, myrrh extract possessed anti-inflammatory properties and counteracted the side effect of prednisolone on the liver. Myrrh extract can serve as a conjunctive therapy with prednisolone to treat autoimmune diseases.
Macroscopical and histological evaluation of cutaneous wounds after PEp-Cf topical treatment. 0.1%PEp-Cf or saline (control) was administered twice a day for 21 days (n = 6). A Macroscopical, Histological images; B H&E (200×); C Picrosirius red (NIKON microscope; 400×); D % collagen area (red) by Image J. software. Mean ± E.P.M. (n = 6). ANOVA/Bonferroni test. *p < 0.05 vs. saline. (Black arrow = cutaneous wound/ * = connective tissue/ Blue arrow = blood vessels) (Color figure online)
Polymorphonuclear cell, fibroblast and blood vessel in histological slides of cutaneous wounds after PEp-Cf topical treatment. 0.1% PEp-Cf or saline (control) was administered twice a day for 21 days. Five fields of H&E slides were photographed (NIKON microscope; 400×): A polymorphonuclears; B fibroblasts/myofibroblasts; C blood vessels (Image J. software). Mean ± E.P.M. (n = 6). ANOVA/Bonferroni. *p < 0.05 vs. saline
Quantification of myeloperoxidase (MPO), nitrate (NO3⁻), malondialdehyde (MDA) and proteins in cutaneous wounds after PEp-Cf topical treatment. 0.1% PEp-Cf or saline (control) was administered twice a day for 21 days. A MPO (mg/tissue); B nitrate (µM/100 mg tissue); C MDA (µM/mg tissue); D protein (mg/mL). Mean ± E.P.M. (n = 6). ANOVA/Bonferroni test. *p < 0.05 vs. saline
Pods of Caesalpinia ferrea, popularly used to treat inflammatory processes, were collected to obtain the polysaccharide-rich extract, presenting anti-inflammatory and antinociceptive effects in acute inflammation models. This study aimed to evaluate the anti-inflammatory, antinociceptive and healing activities of the polysaccharide-rich extract from Caesalpinia ferrea pods (PEp-Cf) in the rat model of cutaneous excisional wound. PEp-Cf (0.025–0.1%) or 0.9% NaCl was topically applied in the wounds at dorsal thoracic region (2×/day) during 21 days for measurement of clinical signs (hyperemia, inflammatory exudate, edema, nociception), wound size, histopathological/histomorphometric, oxidative/inflammatory markers and systemic toxicity. PEp-Cf at 0.1% reduced wound area and increased ulcer contraction [days 2 and 10 (21–78%)]. PEp-Cf reduced clinical signs [days 2 and 5 (2.2–2.8×)] and modulated the healing inflammatory phase via stimulation of epithelialization (days 10 and 14), and inhibition of polymorphonuclears [days 2 and 5 (71–74%)], protein leakage [days 2 and 5 (28–41%)], nitrate [days 2 and 5 (2.2–6×)] and malondialdehyde [days 2 and 5 (46–49%)]. PEp-Cf increased the number of blood vessels [days 5 and 7 (3.1–9.6×)], fibroblasts [days 5 and 7 (2.1–6.4×)] and collagen [days 5 to 14 (1.5–1.8×)]. In conclusion, the topical application of PEp-Cf at 0.1% accelerates the healing process of rat cutaneous wounds via modulation of the inflammatory and proliferative phases, being devoid of systemic alterations.
Background and objective Tauopathy is a group of neurodegenerative diseases in which the pathogenesis processes are related to tau protein. The imbalances between the activities of kinases and phosphatases of tau protein lead to tau hyperphosphorylation and subsequent neurodegeneration. Numerous studies suggest a strong linkage between type 2 diabetes mellitus (T2D) and neurodegenerative diseases. Therefore, finding a drug with a dual therapeutic activity against T2D and neuroprotective will be a promising idea. Hence, the potential neuroprotective effect of Glimepiride (GPD) against tauopathy was evaluated in the current study. Methods P301S mice model was employed for tauopathy and C57BL/6 wild type mice (WT) was used as control. Phosphorylated and acetylated tau protein levels was assessed in cortex and hippocampus by western blot. Effect of GPD on tauopathy related enzymes, neuroinflammation, apoptotic markers were evaluated. Furthermore, the neuroprotective effects against anxiety like behavior and motor impairment was analyzed using Parallel rod floor and Open field tests. Results GPD significantly ameliorates motor impairment, anxiety like behavior and neurodegeneration in P301S mice. Phosphorylated tau and acetylated tau were significantly decreased in both cortex and hippocampus of P301S mice via decreasing GSK3β, increasing ratio of phosphorylated-AKT to total-AKT, increasing PP2A and normalization of CDK5 levels. Furthermore, GPD treatment also decreased neuroinflammation and apoptosis by reducing NF-kB, TNF-α and caspase 3 levels. Conclusion The current data suggests that GPD exerts a protective effect against tauopathy, behavioural consequences, neurodegeneration, neuroinflammation and apoptosis. GPD is therefore a promising agent for the treatment of neurodegenerative diseases associated with tauopathy. Graphical abstract
Ursolic acid Chemical Structure
The probable role of ursolic acid in Covid-19: Ursolic acid inhibits release of pro-inflammatory cytokines as well as SARS-CoV-2 proliferation. Ursolic acid augments antioxidants and release of anti-inflammatory cytokines, which reduce oxidative stress and inflammatory disorders leading suppression development of ALI and ARDS
The potential effects of ursolic acid on RAS in Covid-19. Angiotensin I (AngI) is converted by ACE to AngII which activates AT1R leading to the induction of oxidative stress and inflammation. Covid-19 down-regulates ACE2 causing the elevation in AngII with reduction of Ang1-7 and Ang1-9. Ursolic acid inhibits ACE with increasing expression of ACE2. These changes by ursolic acid decrease the risk of development of ALI and ARDS
The potential effects of ursolic acid on inflammatory signaling pathways in Covid-19. SARS-CoV-2 infection activates nod-like receptor pyrin 3 (NLRP3) inflammasome, mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3(STAT3), phosphatidylinositol 3 kinase/Akt (PI3K/Akt), nuclear factor kappa B (NF-κB), advanced glycation end-products (AGEs) and its receptors (RAGE), high mobility group box protein 1(HMGB1) and mechanistic target of rapamycin (mTOR) pathway with inhibition of autophagy. ursolic acid inhibits these inflammatory signaling pathways and activates autophagy
SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2) has been identified as the source of a world coronavirus pandemic in 2019. Covid-19 is considered a main respiratory disease-causing viral pneumonia and, in severe cases, leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Although, extrapulmonary manifestations of Covid-19 like neurological, cardiovascular, and gastrointestinal have been confirmed. Exaggerated immune response and release of a high amount of pro-inflammatory cytokines may progress, causing a cytokine storm. Consequently, direct and indirect effects of SARS-CoV-2 infection can evolve into systemic complications due to the progression of hyper inflammation, oxidative stress and dysregulation of the renin-angiotensin system (RAS). Therefore, anti-inflammatory and antioxidant agents could be efficient in alleviating these disorders. Ursolic acid has anti-inflammatory, antioxidant, and antiviral effects; it reduces the release of pro-inflammatory cytokines, improves anti-inflammatory cytokines, and inhibits the production of reactive oxygen species (ROS). In virtue of its anti-inflammatory and antioxidant effects, ursolic acid may minimize SARS-CoV-2 infection-induced complications. Also, by regulating RAS and inflammatory signaling pathways, ursolic acid might effectively reduce the development of ALI in ARDS in Covid-19. In this state, this perspective discusses how ursolic acid can mitigate hyper inflammation and oxidative stress in Covid-19.
Long-term sun exposure is the commonest cause of photoaging, where mutual interplay between autophagy, oxidative stress, and apoptosis is incriminated. In combating photoaging, pharmacological approaches targeted to modulate autophagy are currently gaining more ground. This study aimed to examine repurposing metformin use in such context with or without the antioxidant coenzyme Q10 (coQ10) in ultraviolet A (UVA) irradiation-induced skin damage. The study was conducted on 70 female CD1 mice that were randomly assigned into seven groups (10/group): normal control, vehicle-treated-UVA-exposed mice, three metformin UVA-exposed groups (Topical 1 and 10%, and oral 300 mg/kg), topical coQ10 (1%)-treated mice, and combined oral metformin with topical coQ10-treated UVA-exposed mice. After UVA-exposure for 10 weeks (3 times/week), macroscopic signs of photoaging were evaluated. Mice were then euthanized, and the skin was harvested for biochemical estimation of markers for oxidative stress, inflammation, matrix breakdown, and lysosomal function. Histopathological signs of photoaging were also evaluated with immunohistochemical detection of associated changes in autophagic and apoptotic markers. Metformin, mainly by topical application, improved clinical and histologic signs of photoaging. This was associated with suppression of the elevated oxidative stress, IL-6, matrix metalloproteinase 1, and caspase, with induction of cathepsin D and subsequent change in anti-LC3 and P62 staining in skin tissue. In addition to metformin antioxidant, anti-inflammatory, and antiapoptotic activities, its anti-photoaging effect is mainly attributed to enhancing autophagic flux by inducing cathepsin D. Its protective effect is boosted by coQ10, which supports their potential use in photoaging.
The current work explored the influences of time dependent Sildenafil (SILD) administration, and the possible outcomes from its concomitant administration with dexamethasone against acetic acid-induced ulcerative colitis in rats. Rats were assigned into six random groups: diseased group (AA), injected once with 2 ml acetic acid (3%) intrarectally, 2 days before sacrification. SILD + AA, received sildenafil (25 mg/kg, orally) for 6 days starting 3 days pre-injection of AA; SILD-t + AA, received sildenafil (25 mg/kg, orally), starting at time of AA injection and continued for 3 days; DEXA + AA, received dexamethasone (2 mg/kg, i.p.) for 3 days, starting at time of AA injection; SILD-t + DEXA + AA, received sildenafil (25 mg/kg, orally) and dexamethasone (2 mg/kg, i.p.), as mentioned. Sildenafil markedly ameliorated disease activity index (DAI), ulcer scores, colon length shortening and colonic histopathological changes. Mechanistically, Sildenafil markedly attenuated immunoexpression of NF-κB p65/ TNF-α and COX-2, diminished oxidative stress (↓ MDA/NO levels and ↑ GSH level and SOD activity), increased levels of Nrf-2/HO-1, compared to untreated group. Taken together, Sildenafil treatment suppressed acetic acid-induced ulcerative colitis, probably via inhibiting NF-κB/TNF-α signaling dependent of Nrf-2/HO-1 pathway, reducing oxidative stress and attenuating inflammation. Surprisingly, effects of sildenafil were unpromoted in a time dependant manner. Short term treatment with sildenafil was sufficient to exert its coloprotective effect, while longer term pretreatment was only superior among other treatments in the macroscopical changes. Moreover, concurrent administration of sildenafil and dexamethasone had the preference in boosting the antioxidant defense and anti-inflammatory mechanisms, visualized by histopathological/immunohistochemical changes.
The mechanism of NEK7 regulating NLRP3 inflammasome activation The first step (priming) is microbes or endogenous molecules promoting NF-κB into the nuclear to regulate the transcriptional expression of NLRP3, pro-IL-1β and pro-IL-18. Besides, the second step (activation) is assembly of NLRP3 inflammasome to activate caspase-1 and mediate maturation of IL-1β and IL-18, which triggered by ATP, pore-forming toxins, viral RNA and particulate matter. In the downstream response of NLRP3 inflammasome activation, NEK7 binds to the LRR in the NLRP3 in a kinase-independent manner. Inactive NLRP3 is induced through the NF-κB pathway. By the stimulation of ROS pathway, chloride efflux, potassium outflow and lysosomal rupture, as well as the coordination of NEK7, the inactive NLRP3 inflammasome is aggregated and activated, which eventually leads to the maturation and secretion of IL-1β and IL-18
NIMA-related kinase 7 (NEK7) is a serine/threonine kinase, which is the smallest one in mammalian NEK family. At present, many studies have reported that NEK7 has a physiological role in regulating the cell cycle and promoting the mitotic process of cells. In recent years, an increasing number of studies have proposed that NEK7 is involved in the activation of the NLRP3 inflammasome. Under normal conditions, NEK7 is in a low activity state, while under pathological conditions, NEK7 is abnormally expressed and therefore plays a key role in the progression of multiple tumors and chronic inflammatory diseases. This review will concentrate on the mechanism of NEK7 participates in the process of mitosis and regulates the activation of NLRP3 inflammasome, the aberrant expression of NEK7 in a variety of tumors and chronic inflammatory diseases, and some potential inhibitors, which may provide some new ideas for the treatment of diverse tumors and chronic inflammatory diseases associated with NEK7.
Plant-derived medicinal compounds are increasingly being used to treat acute and chronic inflammatory diseases, which are generally caused by aberrant inflammatory responses. Stephania pierrei Diels, also known as Sabu-lueat in Thai, is a traditional medicinal plant that is used as a remedy for several inflammatory disorders. Since aporphine alkaloids isolated from S. pierrei tubers exhibit diverse pharmacological characteristics, we aimed to determine the anti-inflammatory effects of crude extracts and alkaloids isolated from S. pierrei tubers against lipopolysaccharide (LPS)-activated RAW264.7 macrophages. Notably, the n-hexane extract strongly suppressed nitric oxide (NO) while exhibiting reduced cytotoxicity. Among the five alkaloids isolated from the n-hexane extract, the aporphine alkaloid oxocrebanine exerted considerable anti-inflammatory effects by inhibiting NO secretion. Oxocrebanine also significantly suppressed prostaglandin E2, tumour necrosis factor-α, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, and cyclooxygenase (COX)-2 protein expression by inactivating the nuclear factor κB, c-Jun NH2-terminal kinase, extracellular signal-regulated kinase 1/2, and phosphatidylinositol 3-kinase/Akt inflammatory signalling pathways. Molecular docking analysis further revealed that oxocrebanine has a higher affinity for toll-like receptor 4/myeloid differentiation primary response 88 signalling targets and the COX-2 protein than native ligands. Thus, our findings highlight the potential anti-inflammatory effects of oxocrebanine and suggest that certain alkaloids of S. pierrei could be used to treat inflammatory diseases.
Study flow chart
Change of outcome indexes. Change of anterior chamber cell grade (A), vitreous haziness grade (B), central macular thickness (C) from baseline to M6
Change of visual acuity
Background Tumor necrosis factor inhibitor (TNFi) is recently reported to treat noninfectious uveitis (NIU) effectively. However, as a new kind of TNFi, golimumab is just on the market in China for several years, and its administration for NIU treatment lacks sufficient evidence. Therefore, the current study aimed to investigate the efficacy and safety of golimumab in refractory NIU patients. Methods Thirty NIU patients with 49 affected eyes refractory to conventional treatments (corticosteroids and immunosuppressive agents) were consecutively enrolled. They received treatment of TNFi (50 mg golimumab every 4 weeks) for at least 6 months. The anterior chamber cell grade, vitreous haziness grade, central macular thickness, and visual acuity were evaluated at baseline, month (M) 1, M3, and M6. Results After treatment, the anterior chamber cell grade declined from baseline (0.6 ± 0.7) to M6 (0.3 ± 0.5) (P < 0.001); the vitreous haziness grade decreased from baseline (1.2 ± 1.2) to M6 (0.4 ± 0.5) (P < 0.001); meanwhile, the central macular thickness also reduced from baseline (351.4 ± 90.8 μm) to M6 (271.8 ± 54.4 μm) (P < 0.001). In terms of visual acuity (LogMAR), it showed a declined trend from baseline (0.5 ± 0.3) to M6 (0.4 ± 0.2), but without statistical significance (P = 0.096). Subgroup analyses revealed that TNFi history related to decreased golimumab efficacy. In addition, 13.3% of patients had adverse events, including elevated liver enzymes (6.7%), fatigue (3.3%), and rash (3.3%). Conclusion Golimumab is effective and safe for refractory NIU treatment, while a large-scale trial is still needed for verification.
Various signalling pathways that affect the human brain (primarily neurons) in TBI
Traumatic brain injury (TBI) is an important global health concern that represents a leading cause of death and disability. It occurs due to direct impact or hit on the head caused by factors such as motor vehicles, crushes, and assaults. During the past decade, an abundance of new evidence highlighted the importance of inflammation in the secondary damage response that contributes to neurodegenerative and neurological deficits after TBI. It results in disruption of the blood–brain barrier (BBB) and initiates the release of macrophages, neutrophils, and lymphocytes at the injury site. A growing number of researchers have discovered various signalling pathways associated with the initiation and progression of inflammation. Targeting different signalling pathways (NF-κB, JAK/STAT, MAPKs, PI3K/Akt/mTOR, GSK-3, Nrf2, RhoGTPase, TGF-β1, and NLRP3) helps in the development of novel anti-inflammatory drugs in the management of TBI. Several synthetic and herbal drugs with both anti-inflammatory and neuroprotective potential showed effective results. This review summarizes different signalling pathways, associated pathologies, inflammatory mediators, pharmacological potential, current status, and challenges with anti-inflammatory drugs.
Combination tetrahydrocannabinol (THC)/cannabidiol (CBD) medicines or CBD-only medicines are prospective treatments for chronic pain, stress, anxiety, depression, and insomnia. THC and CBD increase signaling from cannabinoid receptors, which reduces synaptic transmission in parts of the central and peripheral nervous systems and reduces the secretion of inflammatory factors from immune and glial cells. The overall effect of adding CBD to THC medicines is to enhance the analgesic effect but counteract some of the adverse effects. There is substantial evidence for the effectiveness of THC/CBD combination medicines for chronic pain, especially neuropathic and nociplastic pain or pain with an inflammatory component. For CBD-only medication, there is substantial evidence for stress, moderate evidence for anxiety and insomnia, and minimal evidence for depression and pain. THC/CBD combination medicines have a good tolerability and safety profile relative to opioid analgesics and have negligible dependence and abuse potential; however, should be avoided in patients predisposed to depression, psychosis and suicide as these conditions appear to be exacerbated. Non-serious adverse events are usually dose-proportional, subject to tachyphylaxis and are rarely dose limiting when patients are commenced on a low dose with gradual up-titration. THC and CBD inhibit several Phase I and II metabolism enzymes, which increases the exposure to a wide range of drugs and appropriate care needs to be taken. Low-dose CBD that appears effective for chronic pain and mental health has good tolerability and safety, with few adverse effects and is appropriate as an initial treatment.
Curcuma longa L. is one of the traditional Chinese herbs in the list of medicinal and food homology. Aromatic-turmerone is the main ingredient in turmeric essential oil. The aim of the present study is to investigate the treatment of Aromatic-turmerone on DSS-included colitis and its regulatory effect on intestinal flora disorder. Male KM mice supplemented with different concentration of aromatic-turmerone and mesalazine are subjected to 2% DSS in drinking water to induce colitis. Colon and cecum contents were collected for colitis lesion evaluation and inflammation-related gene analysis and colon contents for gut microbiota. The results show that treatments with Aromatic-turmerone significantly prevents colon shortening, alleviates the damage of colonic tissue, and reduces colonic inflammatory cytokines TNF-α and COX-2. Furthermore, the 16S rDNA gene sequence data indicate that Aromatic-turmerone improve the abundance of bacterial species, maintain some beneficial bacteria, and reduce harmful bacteria. Aromatic-turmerone downregulates the colonic inflammatory cytokines and modulates the abundance of intestinal flora, which is conductive to ameliorates DSS-induced colitis. Regularly intake of the edible herb may be help to prevent ulcerative colitis-related diseases.
Trial profile. *Withdrawal = participants who withdrew consent during the study. #Dropout = participants who were not contactable or who did not turn up for a follow-up visit. ^Data not considered = any protocol violation or major protocol deviation finding during the study period
Pain VAS (mean ± SD) vs. study visit for the MD-BO and Placebo groups
Objective To explore the safety, and efficacy of a proprietary hydrolyzed oil extract from seeds of Biota orientalis (hBO/Epiitalis®, Interpath Pty Ltd) in patients with knee pain due to osteoarthritis (OA). Methods Patients aged 40–65 with X-ray diagnosed knee OA and knee pain ≥ 60 on a 100-point VAS (visual analog scale) were enrolled and randomized into four groups to receive daily hBO for 56 days as high (hBO-HD, 640 mg), mid (hBO-MD, 320 mg) or low (hBO-LD, 160 mg) doses, or a matched placebo oil. The primary outcome was change in VAS knee pain from baseline to 56 days in the mITT (modified intention to treat) population. Exploratory outcomes were the mWOMAC (modified Western Ontario and McMaster Universities Arthritis Index), and the SF-36 QoL (quality of life) questionnaire. The OMERACT-OARSI (Outcome Measures in Arthritis Clinical Trials–Osteoarthritis Research Society International) responder index was also calculated. Results 223 patients were included in the mITT population. Reductions in VAS scores between baseline and day 56 [Least square mean (LS mean) and 95% confidence interval (CI) of LS mean] were 36.4 (31.7–41.0), 37.9 (33.2–42.7), 35.7 (31.2–40.1) and 9.8 (14.5–15.2) for the hBO-HD, hBO-MD, hBO-LD, and placebo groups respectively. The VAS changes in all hBO groups were significantly different (p < 0.0001) vs. changes in the placebo group. hBO treatment led to similar quantitative beneficial changes in mWOMAC, SF-36 and OMERACT-OARSI responder index. There were no SAEs and no adverse events ascribed to the intervention. Conclusion In a 56-day trial, hBO was safe, and was efficacious at reducing symptoms in patients with knee OA. Registration: NCT04117490; Oct 7, 2019.
CONSORT 2010 flow diagram. Patients’ randomization was represented during the study
Cytokine storm is the most prominent hallmark in patients with coronavirus disease 2019 (COVID-19) that stimulates the free radical storm, both of which induce an overactive immune response during viral infection. We hypothesized that owning to its radical-scavenging and anti-inflammatory properties, Edaravone could reduce multi-organ injury, clinical complications, and mortality in severe COVID-19 cases. This single-center randomized clinical trial was accompanied in the intensive care units (ICUs) of the teaching hospital of Tabriz University of Medical Sciences to evaluate the effect of Edaravone on the outcome of patients with severe COVID-19. Thirty-eight patients admitted to ICU were included and randomized into two control and intervention arms. Patients in the intervention group received 30 mg Edaravone by slow intravenous infusion for three days in addition to receiving national therapy. The primary outcome was the need for intubation, the intubation length, and mortality rate. Secondary endpoints were clinical improvement. Edaravone administration improved the primary outcomes; it decreased the need for endotracheal intubation and mechanical ventilation [10.52% (n = 2) versus 42.1% (n = 8); p = 0.03] and intubation length [3 (1–7) versus 28 (4–28), p = 0.04] compared to control group. Baseline characteristics and laboratory tests were similar between the studied groups. No marked differences were observed in secondary endpoints (p > 0.05). Administration of Edaravone could decrease the need for mechanical ventilation and length of intubation in severe COVID-19 patients admitted to ICU.
Gout is a chronic disease caused by monosodium urate (MSU) crystal deposition in the joints and surrounding tissues. We examined the effects of Taxifolin, a natural flavonoid mainly existing in vegetables and fruits, on MSU-induced gout. Pretreatment with Taxifolin significantly reduced IL-1β, Caspase-1 and HMGB1 levels, upregulation of autophagy-related protein, LC3, as well as improved phagocytosis of macrophages. This study indicated that Taxifolin-attenuated inflammatory response in MSU-induced acute gout model by decreasing pro-inflammatory cytokine production and promoting the autophagy and phagocytic capacity of macrophages. Dietary supplementation with Taxifolin induces the autophagy and attenuated inflammatory response, which in consequence modulates acute gout. A preventive strategy combining dietary interventions with Taxifolin may offer a potential therapeutic alternative to pharmacological treatment to reduce inflammatory response to gout.
Microglial inflammatory responses play a central role in the pathogenesis of S. aureus induced brain infections. Upon activation, microglia produces free radicals (ROS/RNS) and disrupts the cellular antioxidant defense to combat invading microorganisms. Despite conventional antibiotic or steroid therapy, microglial over-activation could not be controlled. So, an attempt had been taken by using a natural antioxidant ascorbic acid along with ciprofloxacin to regulate microglial over-activation by involving TLR-2 and glucocorticoid receptor (GR) in an in-vitro cell culture-based study. Combinatorial treatment during TLR-2 neutralization effectively reduced the bacterial burden at 60 min compared to the GR blocking condition (p < 0.05). Moreover, the infection-induced H2O2, O2.−, and NO release in microglial cell culture was diminished possibly by enhancing SOD and catalase activities in the same condition (p < 0.05). The arginase activity was markedly increased after TLR-2 blocking in the combinatorial group compared to single treatments (p < 0.05). Experimental results indicated that combinatorial treatment may act through up-regulating GR expression by augmenting endogenous corticosterone levels. However, better bacterial clearance could further suppress the TLR-2 mediated pro-inflammatory NF-κB signaling. From Western blot analysis, it was concluded that ciprofloxacin-ascorbic acid combination in presence of anti-TLR-2 antibody exhibited 81.25% inhibition of TLR-2 expression while the inhibition for GR was 3.57% with respect to the infected group. Therefore, during TLR-2 blockade ascorbic acid combination might be responsible for the restoration of redox balance in microglia via modulating TLR-2/GR interaction. The combination treatment could play a major role in the neuroendocrine-immune regulation of S. aureus induced microglial activation.
Relationship between COVID-19 and the cardiovascular system
The coronavirus disease-2019 (COVID-19) pandemic has become a major global health problem. COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and exhibits pulmonary and extrapulmonary effects, including cardiovascular involvement. There are several attempts to identify drugs that could treat COVID-19. Moreover, many patients infected with COVID-19 have underlying diseases, particularly cardiovascular diseases. These patients are more likely to develop severe illnesses and would require optimized treatment strategies. The current study gathered information from various databases, including relevant studies, reviews, trials, or meta-analyses until April 2022 to identify the impact of SARS-CoV-2 treatment on the cardiovascular system. Studies have shown that the prognosis of patients with underlying cardiovascular disease is worsened by COVID-19, with some COVID-19 medications interfering with the cardiovascular system. The COVID-19 treatment strategy should consider many factors and parameters to avoid medication-induced cardiac injury, mainly in elderly patients. Therefore, this article provides a synthesis of evidence on the impact of different COVID-19 medications on the cardiovascular system and related disease conditions.
The diagram of the study selection process
Forest plot detailing standardized mean differences (SMD) and 95% confidence intervals (CIs) in the studies reporting the effect of apigenin on inflammation parameters such as TNF-α, IL-6, IL-1β, TGF-β, and NF-κB in intervention group compared to control
Forest plot detailing standardized mean differences (SMD) and 95% confidence intervals (CIs) in the studies reporting the effect of apigenin on OS parameters such as CAT, GSH, SOD, MPO, and MDA in intervention group compared to control
Forest plot detailing standardized mean differences (SMD) and 95% confidence intervals (CIs) in the studies reporting the effect of apigenin on WD weight ratio in intervention group compared to control
Background/objective Apigenin is a member of the flavonoid family that can regulate various biological processes, which is characterized as a treatment of different inflammatory disorders and pathological problems associated with oxidative stress (OS). Recent research has focused on apigenin immunomodulatory properties as a potential treatment for different types of lung injuries. This meta-analysis was designed to determine the impact of apigenin treatment on inflammatory markers and OS parameters in animal models of lung injuries. Methods The comprehensive literature search was conducted using electronic databases such as Google Scholar, PubMed, Web of Science, Scopus, and Embase up to August 2021. To assess apigenin’s effect on inflammatory mediators and OS biomarkers in lung injury animal models, we used the I² statistic to determine the heterogeneity. We then pooled data as standardized mean difference (SMD) with a 95% confidence interval (CI). Results Our meta-analysis of the pooled data for inflammatory biomarkers demonstrated that the apigenin administration significantly decreased the NF-κB expression (SMD − 1.60, 95% CI [− 2.93 to − 0.26]; I² = 89.0%, p < 0.001), IL-1β (SMD − 4.30, 95% CI [− 6.24 to − 2.37]; I² = 67.3%, p = 0.047), IL-6 (SMD − 4.10, 95% CI [− 5.04 to − 3.16]; I² = 72.6%, p < 0.001), TNF-α (SMD − 3.74, 95% CI [− 4.67 to − 2.82]; I² = 84.1%, p < 0.001), and TNF-α gene expression (SMD − 3.44, 95% CI [− 4.44 to − 2.43]; I² = 0.0%, p = 0.622). This study also indicated the efficacy of apigenin in increasing the level of CAT (SMD 4.56, 95% CI [3.57 to 5.55]; I² = 15.3%, p = 3.15), GSH (SMD 5.12, 95% CI [3.53 to 6.70]; I² = 77.6%, p < 0.001), and SOD (SMD 3.45, 95% CI [2.50 to 4.40]; I² = 79.2%, p < 0.001), and decreasing the level of MDA (SMD − 3.87, 95% CI [− 5.25 to − 2.49]; I² = 80.3%, p < 0.001) and MPO (SMD − 4.02, 95% CI [− 5.64 to − 2.40]; I² = 88.9%, p < 0.001), TGF− β (SMD − 3.81, 95% CI [− 4.91 to − 2.70]; I² = 73.4%, p = 0.001) and W/D level (SMD − 3.22, 95% CI [− 4.47 to − 1.97]; I² = 82.1%, p < 0.001) than control groups. Conclusion Overall, our findings showed the immunomodulatory potential of apigenin as an alternative treatment for the suppression of inflammatory responses and OS in different types of lung injury diseases. Nevertheless, due to the paucity of clinical studies, reliable preclinical models, and clinical settings, evaluating the influence of apigenin on lung injury is required in the future. Before conducting large-scale clinical trials, detailed human pharmacokinetic studies are also needed to establish dosage ranges and determine the initial safety and tolerability of apigenin.
Coronavirus disease 2019 (COVID-19) causes transmissible viral illness of the respiratory tract prompted by the SARS-CoV-2 virus. COVID-19 is one of the worst global pandemics affecting a large population worldwide and causing catastrophic loss of life. Patients having pre-existing chronic disorders are more susceptible to contracting this viral infection. This pandemic virus is known to cause notable respiratory pathology. Besides, it can also cause extra-pulmonary manifestations. Multiple extra-pulmonary tissues express the SARS-CoV-2 entry receptor, hence causing direct viral tissue damage. This insightful review gives a brief description of the impact of coronavirus on the pulmonary system, extra-pulmonary systems, histopathology, multiorgan consequences, the possible mechanisms associated with the disease, and various potential therapeutic approaches to tackle the manifestations.
The schematic overview of the RAS and its opposing classical and protective arms. Ang; angiotensin, ACE; angiotensin-converting enzyme, ACE2; angiotensin-converting enzyme 2, MasR; Mas receptor, AT1R; angiotensin II type 1 receptor, AT2R; angiotensin II type 2 receptor, NEP; neutral endopeptidase, PEP; prolyl endopeptidase
An illustration of ACE2 inactivation by its specific autoantibodies. ACE2; angiotensin-converting enzyme 2
Ang-(1-7) and Ang II plasma concentration (ng/mL) in the active (n=5) and remission (n=7) groups (A), and the ratio of Ang-(1-7)/Ang II (B). Data are presented in mean ± SEM, *significantly different from the remission group, p<0.05
The plasma anti-ACE2 autoantibodies ELISA scores of RA patients in the active and remission stages. Data are presented as mean ± SD, *significantly different from the remission group, p <0.05
Correlations between the Ang II concentration, anti-ACE2 autoantibodies ELISA, and RAPID3 scores (A), Ang II plasma concentration, CRP levels, and anti-ACE2 autoantibodies ELISA score (B), Ang-(1-7)/Ang II ratio, anti-ACE2 autoantibodies ELISA score, CRP levels, and RAPID3 scores (C)
Background This study aimed to explore a correlation between plasma angiotensin II/(1–7) (Ang II/Ang-(1–7)) ratio, anti-ACE2 autoantibodies level and disease activity in rheumatoid arthritis (RA) patients. Methods In a pilot study, the plasma level of Ang II, Ang-(1–7), and anti-ACE2 autoantibodies of twelve RA patients (five in active stage and seven in remission) were measured using an LC–MS/MS method and an ELISA kit, respectively. Results The Ang-(1–7) level was significantly higher in the remission group than in the active RA patients (7.63 ± 2.61 vs. 1.29 ± 0.81 ng/mL). On the contrary, the Ang II level was higher in those with active RA compared to the remission group (5.43 ± 1.82 vs. 0.87 ± 0.16 ng/mL). The mean ELISA score of anti-ACE2 autoantibodies in patients with active RA was significantly higher than patients in remission (1.41 ± 0.11 vs. 1.81 ± 0.11, p < 0.05). Conclusion This study result suggests that the angiotensin peptides concentration and anti-ACE2 autoantibodies levels can be used as biomarkers of RA. This will help clinicians evaluate better treatment success rates and disease prognosis to prevent long-term complications of RA.
Uncontrolled inflammation plays a central role in the pathogenesis of various diseases. Currently available anti-inflammatory agents on prolonged use may lead to ulcers or thrombus formation. The present study was designed to evaluate the anti-inflammatory, anti-arthritic and anti-angiogenic potentials of methanol extract of Viola betonicifolia using battery of in vivo models. Methanol extract of Viola betonicifolia (Vb.Me) was prepared through maceration. High performance liquid chromatography (HPLC) and gas chromatography mass spectrometery (GC–MS) were performed to identify bioactive compounds present in Vb.Me. In vivo safety profile of Vb.Me was evaluated following OECD 425 acute toxicity guidelines. Anti-inflammatory potential of Vb.Me at three different dose levels was evaluated in in vivo acute (carrageenan and, histamine-induced paw oedema), sub-chronic (cotton pellet-induced granuloma) and chronic (Complete Freund’s adjuvant-induced arthritis) models. Blood and paws samples were collected to study effects of Vb.Me treatment on the expression of various pro- and anti-inflammatory genes (RT-PCR) and to study the histopathological changes at tissue levels. Effects of Vb.Me on neovasculature development were studied in ex-ovo chicken chorioallantoic membrane (CAM) assay. Quercetin and n-hexadecanoic were identified as one of the major bioactive molecules in HPLC and GC–MS analysis of Vb.Me. Toxicity data revealed that Vb.Me was safe for administration up to the dose of 2000 mg/kg. Findings of inflammatory models showed that Vb.Me produced time and dose-dependent effects. 500 mg/kg Vb.Me showed significantly (p < 0.05) better effects as compared with 125 and 250 mg/kg. 500 mg/kg Vb.Me also showed comparable anti-inflammatory effects with indomethacin in both acute and chronic models respectively. RT-PCR data exhibited significant (p < 0.05) down-regulation of IL-6, IL-1ß, NF-kß, TNF-α and COX-2 genes with simultaneous up-regulation of IL-4 and IL-10 genes in the blood samples of animals treated with 500 mg/kg of Vb.Me and 10 mg/kg of indomethacin respectively. CAM assay data revealed arrest of microvessel outgrowth in Vb.Me-treated eggs. Altogether, findings of the current study indicate that Vb.Me exerts in vivo anti-inflammatory and anti-angiogenic effects through regulation of expression of various pro- and anti-inflammatory genes. Synergist actions of various bioactive molecules in Vb.Me are proposed to be responsible for these attributes. However, further studies to standardize the extract and evaluation of its potential in various inflammation-induced diseases are warranted. Graphical abstract
Chemical structures of main corticosteroids: A: cortisol, B: aldosterone
Mechanism of corticosteroids action: corticosteroid (CS) activates corticosteroid receptor (CR) with activation expression of DNA; this effect activates anti-inflammatory mediators and inhibits inflammatory mediators (Sibila et al. 2015)
The possible effects of corticosteroids in COVID-19. IL-8 (interleukin 8), MCP-1 (monocyte chemoattractant protein 1), IP-10 (interferon-γ-inducible protein 10), IL-6 (interleukin 6), IFN-γ (interferon-gamma, TNF-α (tumor necrosis factor-alpha) and IL-4 (interleukin 4)
It has been reported that corticosteroid therapy was effective in the management of severe acute respiratory syndrome (SARS) and the Middle East Respiratory Syndrome (MERS), and recently in coronavirus disease 2019 (COVID-19). Corticosteroids are potent anti-inflammatory drugs that mitigate the risk of acute respiratory distress syndrome (ARDS) in COVID-19 and other viral pneumonia, despite a reduction of viral clearance; corticosteroids inhibit the development of cytokine storm and multi-organ damage. The risk-benefit ratio should be assessed for critical COVID-19 patients. In conclusion, corticosteroid therapy is an effective way in the management of COVID-19, it reduces the risk of complications primarily acute lung injury and the development of ARDS. Besides, corticosteroid therapy mainly dexamethasone and methylprednisolone are effective in reducing the severity of COVID-19 and associated comorbidities such as chronic obstructive pulmonary diseases (COPD), rheumatoid arthritis, and inflammatory bowel disease (IBD).
Flowchart of studies included in qualitative synthesis
Risk of bias assessment of studies (n = 26)
Possible therapeutic aims of Coriandrum sativum L
This study is designed to systematically review the accessible researches regarding influence of Coriandrum sativum L. on inflammatory mediators including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Databases Scopus, PubMed, WOS, ProQuest, and a Google Scholar were searched until February 2022 and search alerts were turned on to find papers published following the primary search. There was not any restriction in language and/or date. No human study was gained; thus, animal and in vitro researches were considered. The references of related papers were reviewed to access plausible researches. Twenty-four papers were entered in review. Inflammatory factors IL-1β, IL-6, and TNF-α considerably had a descending direction following C. sativum consumption. In other words, the pooled direction of influences was consistently lower for inflammatory mediators in 7 of 9 in vitro and 10 of 16 animal investigations. These results demonstrated the potential of C. sativum in reducing IL-1β, IL-6, and TNF-α. C. sativum is hopeful but not yet a confirmed natural ingredient to reduce systemic inflammation in subjects with inflammation-prone disorders. Additional investigations are required to concentrate on assessing the impact of C. sativum on inflammatory factors that are not exceedingly fluctuating and the clinical consequences of inflammation-linked diseases.
Pathophysiology of rheumatoid arthritis
Mechanism of action of anti-rheumatic drugs
Diagrammatic illustration of drug with polymeric nanoparticles and molecular targets of arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory illness caused by an autoimmune disorder of synovial membrane resulting in synovial membrane dysfunction. The available treatment particularly focuses on inhibiting macrophage proliferation and reducing the generation of pro-inflammatory cytokines. However, therapeutic success of current treatment options at targeted site is limited; therefore, development of promising therapeutic strategy is the need of time that may provide better targeted delivery of drug with added safety. In development of precision medicine to manage RA, nanotechnology is a viable option to be considered. Recent research using nanoparticles for the treatment of RA, particularly polymeric nanoparticles, has been discussed in this article. Using polymeric nanoparticles as a therapeutic method has shown considerable promise of enhancing treatment success over standard medications used in routine. It is exclusively evident that the viability of using nanoparticles is mainly owed due to their biocompatibility, chemical stability, controlled drug release, and selective drug delivery to inflamed tissues in RA model animals. The current analysis focuses on the critical design characteristics of RA-targeted nanotechnology-based strategies in quest of better therapeutic strategies for RA, and to identify leading polymer as the most effective medications in RA therapy.
Objectives As the main cause of osteoporosis, abnormal activity of osteoclasts could disrupt the balance between bone resorption and formation. Moreover, up-regulation of nuclear factor-kappa ligand (RANKL) expression by chronic inflammation-mediated inflammatory factors might contribute to the differentiation of osteoclast precursor cells. Therefore, an anti-inflammatory agent named yangonin was presented for inhibiting osteoclast and relieving inflammatory osteoporosis through down-regulating inflammatory factors. Methods We established a model of macrophage inflammation and then verified the anti-inflammatory effect of yangonin. The inhibitory effect of yangonin on osteoclasts was detected by tartrate-resistant acid phosphatase (TRAP) staining, Western blotting and quantitative real-time PCR (qRT-PCR). Finally, micro-CT, TRAP and hematoxylin–eosin (HE) staining were used to show the effect of yangonin on inflammatory osteoporosis in vivo. Results Our results suggested that yangonin was able to reduce the secretion of inflammatory factors, down-regulate osteoclast-related genes such as TRAP, RANKL, cathepsin K (CTSK) and nuclear factor-activated T-cell 1 (NFATc1). Furthermore, it was demonstrated that yangonin could suppress the function of inflammatory cytokines in osteoclast differentiation and reporting, wherein NF-κB, AKT and downstream c-Fos/NFATc1 signaling pathways were involved. In an in vivo study, we implied that yangonin has a relieving effect on inflammatory osteoporosis. Conclusion Our research shows that yangonin down-regulates inflammatory factors and inhibits the bone-breaking effect of inflammation through NF-κB, AKT and downstream c-Fos/NFATc1 signaling pathways to achieve the purpose of treating inflammatory osteoporosis.
Ischaemia and reperfusion (I/R)-induced gastrointestinal disorders are caused by free radicals, resulting in organ damage and functional disarrangement. This study aimed to investigate the healing effects of hydroalcoholic extracts from the leaves of Eugenia punicifolia (Kunth) DC. (HEEP) in male and female Wistar rats with I/R-induced peptic injuries, and the role of antioxidants in improving this response. After I/R-induced gastric and duodenal injuries, male and female [intact (INT) and ovariectomized (OVZ)] rats were orally treated with HEEP for 6 days. Biochemical analysis was used to determine the catalase (CAT), superoxide dismutase (SOD), and myeloperoxidase (MPO) activities, as well as malondialdehyde and reduced glutathione levels, to measure the gastric and duodenal healing process. Six days of HEEP treatment significantly decreased the I/R-induced gastric [male (73.68%), INT (52.83%), and OVZ (43.13%)] and duodenal damage [male (57.03%), INT (56.04%), and OVZ (54.83%)] in all groups. In OVZ rats, the healing effect of HEEP occurred because of the increased activity of SOD (2x) and CAT (1.16x) in the gastric mucosa. In the duodenal mucosa of INT rats, the extract reduced MPO (20.83%) activity. The 6-day HEEP treatment improved the healing of I/R-induced peptic ulcer injury, with the system acting differently in males and females. The antioxidant system is an important component of the HEEP activity during post-I/R mucosal recovery. This result revealed the importance of antioxidant compounds in minimizing the severity of I/R-related events.
Background: Nrf2 regulates cellular antioxidant defence in lung cells, including epithelial cells and alveolar macrophages (AM). The Nrf2/Keap-1 pathway can be modulated by activators with different modes of action; electrophilic compounds and protein-protein interaction (PPI) inhibitors. We assessed Nrf2 and Keap-1 protein and gene levels in COPD compared to controls and the effect of Nrf2 activators on COPD AM. Methods: Lung resected tissue from non-smokers, smokers and COPD patients were analysed for epithelial and AM expression of Nrf2 and Keap-1 by imunoshistochemistry and by qPCR in isolated AM. AM were cultured with Nrf2 activators CDDO, C4X_6665, GSK7, MMF and Sulforaphane. Expression of Nrf2 target genes NQO1, HMOX1 SOD1 and TXNRD1 and NQO1 activity were assessed. Results: Nrf2 and Keap-1 expression was not altered in the epithelium or AM of COPD patients compared to controls. NQO1 activity was downregulated, while NQO1, HMOX1, SOD1 and TXNRD1 gene expression increased in COPD patients. All Nrf2 activators increased NQO1 activity, and NQO1, HMOX1, SOD1 and TXNRD1 expression in AMs from both COPD and smokers. The potency of C4X_6665 on NQO1 activity and regulation of Nrf2 target gene expression was higher than other compounds. Conclusion: There is evidence of dysregulation of the Nrf2 signalling pathway in AM from COPD patients. The higher potency of the novel PPI Nrf2 compound C4X_6665 for inducing antioxidant activity and gene expression compared to electrophilic and other PPI Nrf2 activators highlights the therapeutic potential of this compound to address Nrf2 pathway dysregulation in COPD AM.
Cervical cancer is the most prevalent cancer in females. Melatonin, a neurohormone has been documented as a promising therapeutic molecule for cervical cancer. However, the underlying molecular mechanism is not known. We explored the dose-dependent anti-tumor response of melatonin against cervical cancer cell lines, HeLa (HPV-18 positive) and SiHa (HPV-16 positive). The anti-cancer effect of melatonin was evaluated by MTT assay, cell imaging, colony formation, DAPI, AO/PI, LDH, Flow cytometry, scratch assay, western blot analysis and real-time PCR. Results of DAPI, AO/PI, LDH, and Annexin/PI staining revealed that melatonin induces apoptosis. The results of cell cycle analysis revealed that melatonin arrests the HeLa and SiHa cells in sub-G1 and G1 phases, respectively. Western blot analysis revealed that melatonin downregulated the expression of pro-inflammatory transcription factor, NF-κB and the expression of COX-2 protein, a key mediator in cell proliferation. In addition, melatonin downregulated the expression of an invasive marker, MMP-9, an antiapoptotic protein, Bcl-2, and upregulated the expression of pro-apoptotic protein, Bax at both transcriptional and translational levels. Overall, the results suggest that melatonin exhibited strong anti-cancer therapeutic potential against human cervical cancer cell line progression possibly through inhibition of NF-κB signalling pathway.
Objectives Ventilation-induced lung injury (VILI) causes a huge economic and social burden, and its prevention and treatment have gained increasing attention in recent years. IL-9 is an important inflammatory factor, but its potential role in VILI remains unclear. This study intended to explore whether blocking IL-9 could alleviate VILI and explore its underlying mechanism. Methods Lung injury was induced by mechanical ventilation (MV) in C57BL/6 mice. Changes in inflammatory factors and NLRP3-related proteins were assessed using quantitative reverse transcription-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. Subsequently, Nlrp3−/− mice were used to further elucidate the underlying mechanism. Results The percentage of Th9 cells in the peripheral blood, bronchoalveolar lavage fluid (BALF), and lung tissues of MV mice was increased compared to those of control mice. Treatment with anti-IL-9 mAb significantly alleviated the changes in lung histopathology, wet/dry lung proportion, total protein content, and neutrophil content in BALF induced by VILI. Additionally, administering anti-IL-9 mAb significantly downregulated the expression levels of inflammatory factors in BALF and lung tissues of mice with VILI. In addition, administering anti-IL-9 mAb inhibited NLRP3 inflammasome activation, as evidenced by the observed downregulation of NLRP3, ASC, cleaved caspase-1, and GSDMD-N. Additionally, NLRP3-deficient mice had lower lung injury induced by VILI than wild-type mice. Furthermore, the anti-IL-9 mAb only partially inhibited VILI in Nlrp3−/− mice. Conclusions In MV mice, the anti-IL-9 mAb alleviated lung injury and reduced the secretion and expression of inflammatory factors partly by inhibiting the NLRP3 inflammasome pathway.
A-B-C-D The effects of irbesartan on HL-1 cells under conditions of control, hypoxia, pretreatment with Irbesartan, and expression of NO,TLR-2,BNP
The renin–angiotensin system (RAS) plays a crucial role and coordinates multiple body functions through its hormonal mechanism. The RAS is supported in its function by numerous peptides such as angiotensin II (Ang II), Ang IV, Ang III, angiotensin (1-7) and (1-9). The system formed by ACE2/Ang(1-7)/MASr is a regulatory pathway within the RAS system and its functions are different from those of the ACE/Ang II/AT-1r system. Recently, it has been discovered that a key role of the RAS and the ACE2/Ang(1-7)/MASr system is in inflammatory processes such as cardiac hypertrophy and heart failure. Studies are ongoing to better understand and comprehend the function of the RAS in inflammation. Recent evidence associates AT-1r antagonists with a cardioprotective, anti-inflammatory, and anti-hypertrophic role. In this in vitro study, we demonstrate the protective role of treatment (50 and 200 μM) of an AT-1r antagonist, irbesartan, on hypoxia and inflammation-induced damage in cardiomyocytes.
The images of some species from Boswellia. AB. carteri, BB. serrata
Antiviral activities of Boswellia species
The emergence of pathogenic viruses is a worldwide frequent cause of diseases and, therefore, the design of treatments for viral infections stands as a significant research topic. Despite many efforts, the production of vaccines is faced with many obstacles and the high rate of viral resistance caused a severe reduction in the efficacy of antiviral drugs. However, the attempt of developing novel natural drugs, as well as the exertion of medicinal plants, may be an applicable solution for the treatment of viral diseases. Boswellia species exhibited a wide range of pharmacological activities in various conditions such as bronchial asthma, rheumatism, and Crohn’s illness. Additionally, pharmacological studies reported the observance of practical antiviral activities from different parts of this substance, especially the oleo-gum-resin. Therefore, this work provided an overview on the antiviral properties of Boswellia species and their potential therapeutic effects in the field of COVID-19 pandemic.
Schizophrenia is a common mental disorder affecting patients’ thoughts, behavior, and cognition. Recently, the NRG1/ErbB4 signaling pathway emerged as a candidate therapeutic target for schizophrenia. This study investigates the effects of aripiprazole and sertindole on the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in ketamine-induced schizophrenia in rats. Young male Wistar rats received ketamine (30 mg/kg, intraperitoneally) for 5 consecutive days and aripiprazole (3 mg/kg, orally) or sertindole (2.5 mg/kg, orally) for 14 days. The proposed pathway was investigated by injecting LY294002 (a selective PI3K inhibitor) (25 μg/kg, intrahippocampal injection) 30 min before the drugs. Twenty-four hours after the last injection, animals were subjected to behavioral tests: the open field test, sucrose preference test, novel object recognition task, and social interaction test. Both aripiprazole and sertindole significantly ameliorated ketamine-induced schizophrenic-like behavior, as expected, because of their previously demonstrated antipsychotic activity. Besides, both drugs alleviated ketamine-induced oxidative stress and neurotransmitter level changes in the hippocampus. They also increased the gamma-aminobutyric acid and glutamate levels and glutamate decarboxylase 67 and parvalbumin mRNA expression in the hippocampus. Moreover, aripiprazole and sertindole increased the NRG1 and ErbB4 mRNA expression levels and PI3K, p-Akt, and mTOR protein expression levels. Interestingly, pre-injecting LY294002 abolished all the effects of the drugs. This study reveals that the antipsychotic effects of aripiprazole and sertindole are partly due to oxidative stress reduction as well as NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways activation. The NRG1/ErbB4 and PI3K signaling pathways may offer a new therapeutic approach for treating schizophrenia in humans.
Inflammation has a major role in the pathogenesis of heart failure (HF). It triggers a cascade that leads to the release of pro-inflammatory cytokines which in turn cause cardiac hypertrophy, fibrosis, apoptosis, negative inotorpy and leukocyte recruitment which worsen the condition. Neopterin is an inflammatory biomarker which is released as a response to macrophage activation. Levels of neopterin are elevated in conditions which has an immunological component such as autoimmune disease, viral and bacterial infections and malignancy. Neopterin levels were found to be elevated in patients with HF. This is due to the fact that inflammation takes place during the development of the condition. Studies demonstrated that neopterin can be used as a biomarker for diagnosing HF, determining severity of the disease and monitoring its progression. Neopterin levels were higher in patients with New York Heart Association classification (NYHA) III–IV more than class I–II. Moreover, neopterin levels correlated well with morbidity and mortality. It has been suggested that neopterin be monitored levels to determine effectiveness of HF treatment options. Graphical abstract
The effects of Piper malacophyllum (C. Pesl) C. DC extracts and its isolated compounds were analysed in a mouse model of primary dysmenorrhoea (PD). Female Swiss mice (6–8 weeks old) on proestrus were intraperitoneally treated with estradiol benzoate for 3 days, to induce PD. Twenty-four hours later, animals were treated 24 h later with vehicle, plant extract, gibbilimbol B, 4,6-dimethoxy-5-E-phenylbutenolide, mixture of 4,6-dimethoxy-5-E-phenylbutenolide and 4,6-dimethoxy-5-Z-phenylbutenolide, or ibuprofen. One hour later, oxytocin was injected and the numbers of abdominal writhing were counted. Then, mice were euthanized and uteri were collected for morphometrical and histological analyses. The effects of P. malacophyllum in inflammation were investigated in mouse peritoneal neutrophils culture stimulated with LPS or fMLP (chemotaxis and mediator release). Finally, uterus contractile and relaxing responses were assessed. Similar to ibuprofen, P. malacophyllum extract and isolated compounds reduced abdominal writhing in mice with PD. Histology indicated a marked neutrophil and mast cell infiltrate in the uterus of PD animals which was attenuated by the extract. The compounds and the extract reduced neutrophil chemotaxis and inflammatory mediator release by these cells. Reduced TNF levels were also observed in uteri of PD mice treated with P. malacophyllum. The extract did not affect spontaneous uterine contractions nor those induced by carbachol or KCl. However, it caused relaxation of oxytocin-induced uterine contraction, an effect blunted by H1 receptor antagonist. Overall the results indicate that P. malacophyllum may represent interesting natural tools for reliving PD symptoms, reducing the triad of pain, inflammation and spasmodic uterus behaviour.
Hypothesis; excessive inflammation may be a key in the pathology of COVID-19, and COX-2 could be a critical target for therapy. To test this hypothesis, COVID-19 patients received celecoxib, a specific inhibitor of COX-2, in the short term as adjuvant therapy to evaluate correlation with disease status
An overview of the study procedure
Blood O2 saturation in the first, third, and seventh study days. As results showed, O2 saturation on the seventh day was higher in group A and lower in group B compared to group C (p = 0.039)
Laboratory findings of patients. a WBC, b lymphocyte, and d platelets on the seventh day of the study showed a significant difference between the three groups (p < 0.05). c Neutrophil decreased on the seventh day in groups A and B compared to the first day, while the co\ntrol group showed vice versa results. At the same time, both e RBC and f Hb showed semi-stable levels
Background: It is known that severe acute respiratory coronavirus 2 (SARS-CoV-2) is the viral strain responsible for the recent coronavirus disease 2019 (COVID-19) pandemic. Current documents have demonstrated that the virus causes a PGE2 storm in a substantial proportion of patients via upregulating cyclooxygenase-2 (COX-2) and downregulating prostaglandin E2 (PGE2)-degrading enzymes within the host cell. Aim: Herein, we aimed to study how short-term treatment with celecoxib (Celebrex), a selective COX-2 inhibitor, affects demographic features, early symptoms, O 2 saturation, and hematological indices of cases with COVID-19. Methods: A total of 67 confirmed COVID-19 cases with a mild or moderate disease, who had been referred to an institutional hospital in southeastern Iran from October 2020 to September 2021, were enrolled. Demographic characteristics, symptoms, and hematological indices of the patients were recorded within different time periods. One-way ANOVA or Kruskal-Wallis tests were used to determine differences between data sets based on normal data distribution. Results: O2 saturation was statistically different between the control group and patients receiving celecoxib (p = 0.039). There was no marked difference between the groups in terms of the symptoms they experienced (p > 0.05). On the first days following Celebrex therapy, analysis of complete blood counts showed that white blood cell (WBC) counts were markedly lower in patients treated with a high dose of celecoxib (0.4 g/day) than in controls (p = 0.026). However, mean lymphocyte levels in patients receiving a high dose of celecoxib (0.4 g/day) were markedly higher than in patients receiving celecoxib with half of the dose (0.2 g/day) for one week or the untreated subjects (p = 0.004). Changes in platelet count also followed the WBC alteration pattern. Conclusion: Celecoxib is a relatively safe, inexpensive, and widely available drug with non-steroidal anti-inflammatory properties. The therapeutic efficacy of celecoxib depends on the administrated dose. Celecoxib might improve disease-free survival in patients with COVID-19.
Screening, Allocation, and Study Follow-up (F female, M Male)
The purpose of this study was to investigate the anti-inflammatory effect of an aqueous extract of seed of broccoli (AESB) in Helicobacter pylori (HP)-infected patients without atrophic gastritis. This was a double-centre, randomized, double-blind, controlled study. A total of 110 HP-infected subjects were randomized to receive either AESB or placebo for 2 months. Inflammatory cytokine (IL-8, IFN-γ, TNF-α, CRP, IL-17A, IL-1β, IL-18), pepsinogen I, II (PG I, PG II), and gastrin-17 (G-17) measurements and 13C-urea breath tests were performed at baseline and at 60 days. At 60 days, there was no significant difference in any of the inflammatory cytokines, pepsinogen or gastrin between the two groups. However, IL-8, IFN-γ, PG I, PG I/PG II ratio (PGR), and G-17 were reduced by 9.02 pg/mL, 5.08 pg/mL, 24.56 ng/mL, 1.75 and 0.3 pmol/L, respectively, in the AESB group compared with baseline (all P < 0.05). The HP eradication rates in the AESB group and placebo group were 11.11 and 3.70% at 60 days, respectively (P > 0.05). No treatment-related adverse events were reported. Thus, AESB may reduce the risk of gastric mucosal lesions and decrease the risk of gastric cancer by relieving inflammatory cytokines. The safety profile of AESB was satisfactory. This study is registered with the Chinese Clinical Trials Registry (Registration No. ChiCTR2100054249).
Background Rheumatoid arthritis (RA) is a known debilitating autoimmune disease. Immune-suppressants that are used for disease treatment have serious side effects, therefore, trivalent chromium (Cr (III)); which has shown evidence of its influences on some inflammatory pathways and cytokines; was used in this study for the first time to be assessed for its therapeutic effect in RA rat model and was compared to prednisolone in a trial to find a treatment with lesser side effects. Methods Adult male albino rats were randomly divided into four groups: normal, untreated RA, prednisolone treated RA (1.25 mg/kg/day) and Cr (III) treated RA groups (80 μg/kg/day), induction of RA was done by subcutaneous complete Freund adjuvant injection. Study duration was 4 weeks throughout which arthritis scoring and weight measurement were pursued. Histopathological examination and immunohistochemical FOXP3 assessment were done for joint biopsies. Serum inflammatory markers (interleukin 17, interleukin 10, CRP) and synovial erosive arthritis marker (Cathepsin G) were measured. HDL and non-HDL cholesterol were estimated as well. Results Cr (III) treatment showed marked clinical and histopathological improvement, also astonishing anti-inflammatory effects (increase in FOXP3 expression and interleukin 10, with decrease in interleukin 17, CRP and synovial Cathepsin G) to the extent that Cr (III) effects on inflammation abolishment were comparable to that of prednisolone and even better at some aspects. Moreover, Cr (III) was protective from side effects, i.e., weight gain and dyslipidemia that were seen with prednisolone treatment. Conclusions Cr (III) is promising in treating RA and it lacks some side effects of accustomed immune-modulatory agents including prednisolone. Further experimental studies and clinical trials should be held to see the efficacy of Cr (III) in different doses and to assess its long term side effects when used for rheumatoid arthritis and other autoimmune diseases treatment.
Background Cardiovascular disorders are major complications of rheumatoid arthritis (RA). Hence, finding effective agents that can target RA progression and its cardiovascular consequences is demanding. The present work aimed to explore the potential of lisinopril, an angiotensin-converting enzyme inhibitor, to mitigate adjuvant’s-induced arthritis with emphasis on the pro-inflammatory signals, articular degradation cues, and angiogenesis alongside JAK-2/STAT-3 and Nrf2/HO-1 pathways. Methods Lisinopril (10 mg/kg/day) was administered by oral gavage for 3 weeks and the target signals were examined by biochemical assays, ELISA, histopathology, immunoblotting, and immunohistochemistry. Results Lisinopril attenuated the progression of arthritis as proven by lowering paw edema, arthritic index, and gait scores alongside diminishing the immune-cell infiltration/aberrant histopathology in the dorsal pouch lining. These favorable actions were associated with curtailing the production of inflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-17) and the pro-inflammatory angiotensin II alongside upregulating the anti-inflammatory angiotensin-(1–7) in the hind paw of arthritic rats. At the molecular level, lisinopril inhibited the upstream JAK-2/STAT-3 pathway by downregulating the protein expression of p-JAK-2/total JAK-2 and p-STAT-3/total STAT-3 ratio and the nuclear levels of NF-κBp65. Meanwhile, lisinopril curbed the downstream cartilage degradation signals matrix metalloproteinases (MMP-3 and MMP-9) and the bone erosion cue RANKL. Equally important, the protein expression of the angiogenesis signal VEGF was downregulated in the hind paw/dorsal lining. With respect to oxidative stress, lisinopril suppressed the paw lipid peroxides and boosted GSH and Nrf-2/HO-1 pathway. Conclusion Lisinopril attenuated adjuvant-induced arthritis via inhibition of inflammation, articular degradation cues, and angiogenesis.
Comparison of CDC42 between RA patients and healthy controls. Comparison of CDC42 between RA patients and healthy controls (A); the ability of CDC42 to discriminate RA patients from healthy controls (B)
Correlation of CDC42 with Th1, Th17 cells and their secreted cytokines. Correlation of CDC42 with Th1 cells (A), IFN-γ (B), Th17 cells (C) and IL-17 (D)
Treatment response and longitudinal change of CDC42 after treatment. Treatment response from W0 to W12 among patients (A); change of CDC42 from W0 to W12 during treatment (B); comparison of CDC42 at W0, W4, W8 and W12 between response patients and no response patients (C)
CDC42 was involved in IFN-γ and IL-17A secretion in CD4⁺ T cells. Comparison of CDC42 mRNA expression among groups (A); example image of CDC42 detection through western blot (B); comparison of CDC42 protein expression among groups (C); comparison of IFN-γ (D) and IL-17A (E) among groups after transfection of control, CDC42 overexpression and knockdown lentivirus. *P < 0.05; **P < 0.01; ***P < 0.001; NS not significant
Effect of CDC42 on Th1 and Th17 cell differentiation. Detection of Th1 and Th17 cell differentiation through flow cytometry (A); comparison of Th1 cell percentage among groups (B); comparison of Th17 cell percentage among groups (C) after transfection. *P < 0.05; ***P < 0.001; NS not significant
Objective Previous research reports that cell division control protein 42 (CDC42) is dysregulated in rheumatoid arthritis (RA). This study aimed to further explore the linkage of CDC42 with T-helper (Th) 1 and Th17 cell differentiation, and its implication in RA management. Methods After enrolling 80 RA patients, their blood CDC42, Th1 and Th17 cells were detected by RT-qPCR and flow cytometry, respectively, IFN-γ and IL-17A were detected by ELISA. Based on the treatment response at week 12, the patients were classified as response patients and no response patients. In addition, blood CDC42 was also detected after enrolling 40 healthy controls. Subsequently, naïve CD4⁺ T cells from RA patients were transfected with control, CDC42 overexpression and knockdown lentivirus, followed by differentiation assay. Results CDC42 was reduced in RA patients versus healthy controls (P < 0.001). In RA patients, CDC42 was negatively correlated with IFN-γ (P = 0.023), Th17 cells (P = 0.011) and IL-17A (P = 0.003) but not Th1 cells (P = 0.200). CDC42 presented an increasing trend after treatment (P < 0.001); besides, CDC42 at week 8 (P = 0.027) and week 12 (P < 0.001) were increased in response patients versus no response patients. Subsequent experiment showed that in RA CD4⁺ T cells, CDC42 overexpression reduced IFN-γ and IL-17A (both P < 0.05), while CDC42 knockdown elevated IL-17A (P < 0.05) but not IFN-γ (P > 0.05). Moreover, CDC42 overexpression inhibited, while CDC42 knockdown increased Th17 cell percentage (P < 0.05) but not Th1 cell percentage (P > 0.05). Conclusions CDC42 negatively correlates with disease risk and its elevation predicts better treatment response; it also inhibits Th17 but not Th1 cell differentiation in RA.
The most prevalent type of dementia is Alzheimer's disease (AD), which is currently incurable. Existing treatments for Alzheimer's disease, such as acetylcholinesterase inhibitors, are only effective for symptom relief. Disease-modifying medications for Alzheimer's disease are desperately required, given the enormous burdens that the disease places on individuals and communities. Phosphodiesterase (PDE) inhibitors are gaining a lot of attention in the research community because of their potential in treating age-related cognitive decline. Cilostazol is a selective PDE III inhibitor used as antiplatelet agent through cAMP response element-binding (CREB) protein phosphorylation pathway (cAMP/CREB). The neuroprotective effect of cilostazol in AD-like cognitive decline in rats was investigated in this study. After 2 months of intraperitoneal administration of 10 mg/kg aluminum chloride, Morris water maze and Y-maze (behavioral tests) were performed. After that, histological and biochemical examinations of the hippocampal region were carried out. Aluminum chloride-treated rats showed histological, biochemical, and behavioral changes similar to Alzheimer's disease. Cilostazol improved rats' behavioral and histological conditions, raised neprilysin level while reduced levels of amyloid-beta protein and phosphorylated tau protein. It also decreased the hippocampal levels of tumor necrosis factor-alpha, nuclear factor-kappa B, FAS ligand, acetylcholinesterase content, and malondialdehyde. These outcomes demonstrate the protective activity of cilostazol versus aluminum-induced memory impairment.
The effects of NAC and Elaeagnus angustifolia on carrageenan-induced lung injury. Values are presented as mean ± SEM (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001 compared to the control group; #P < 0.05, ##P < 0.01, ###P < 0.001 compared to the carrageenan-induced lung injury group. A Total cell count in BALF. B Neutrophils counts in BALF
The effects of NAC and Elaeagnus angustifolia on carrageenan-induced lung injury. Values are presented as mean ± SEM (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001 compared to the control group; #P < 0.05, ##P < 0.01, ###P < 0.001 compared to the carrageenan-induced lung injury group. A lung wet/dry (W/D) weight ratio of rat in each group. B the comparison of lung injury scoring among the groups. C Pathological changes of lung tissues of rat detected by H&E staining
The effects of NAC and Elaeagnus angustifolia on carrageenan-induced lung injury. Values are presented as mean ± SEM (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001 compared to the control group; #P < 0.05, ##P < 0.01, ###P < 0.001 compared to the carrageenan-induced lung injury group. A Tumor necrosis factor alpha (TNF-α) in BALF. B Interleukin-6 (IL-6) levels in BALF. C Protein concentration in BALF
The effects of NAC and Elaeagnus angustifolia on carrageenan-induced lung injury. Values are presented as mean ± SEM (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001 compared to the control group; #P < 0.05, ##P < 0.01, ###P < 0.001 compared to the carrageenan-induced lung injury group. A lipid peroxidation (MDA) in serum B Total antioxidant capacity (TAC) in serum.C Thiol content in serum
N-Acetylcysteine (NAC) is a chemical compound with anti-inflammatory and antioxidant activity and acts as a free radical scavenger. Elaeagnus angustifolia (EA) is a plant native to the western part of Iran, with antioxidant and anti-inflammatory properties. The present study been taken evaluated the protective effect afforded by EA and NAC extracts on carrageenan-induced acute lung injury in Wistar rats. In this study, 42 rats were randomly assigned into seven groups. NAC and EA extracts were orally administered once/day for 21 continuous days. Pulmonary damage was induced by intratracheal injection of 100 μl of 2% λ-Carrageenan on day 21. Twenty-four hours post-surgery, the rats were euthanized and the samples were collected. Pretreatment with NAC and EA extracts reduced the total and differential cell accumulation as well as IL-6, and TNF-α cytokines. Antioxidant indicators demonstrate that in the groups receiving NAC and EA extract, MDA decreased while thiol and antioxidant capacity elevated. Treatment with NAC and EA significantly reduced Carrageenan-induced pathological pulmonary tissue injury. NAC and EA extract has protective effects on acute carrageenan-induced lung injury.
Top-cited authors
Kim Drummond Rainsford
  • Sheffield Hallam University
Garry Graham
  • St. Vincent's Hospital Sydney
Richard Day
  • UNSW Sydney
Kieran F Scott
  • Western Sydney University
Michael Davies
  • University of Copenhagen