Hepatoprotective effects of Xiaoyao San formula on hepatic steatosis and inflammation via regulating the sex hormones metabolism

BACKGROUND The modified Xiaoyao San(MXS)formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer,which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival.However,the molecular mechanisms underlying that remain unclear.AIM To investigate the role and mechanisms of MXS in ameliorating hepatic injury,steatosis and inflammation.METHODS A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis(NASH)model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes.Liver tissues were collected for western blotting and immunohisto chemistry(IHC)assays.Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining.The serum samples were collected for biochemical assays and NMR-based metabonomics analysis.The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH.RESULTS MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress.The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation,inflammation and hepatic fibrosis in the pathogenesis of NASH.The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis.Mechanistically,we found that MXS protected against NASH by attenuating the sex hormone-related metabolism,especially the metabolism of male hormones.CONCLUSION MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones.Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.

Understanding the Novel Approach of Nanoferroptosis for Cancer Therapy

As a new form of regulated cell death,ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells.The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells.Due to their high loading and structural tunability,nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting.This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis.Additionally,we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy.

Decision-Making and Management of Self-Care in Persons with Traumatic Spinal Cord Injuries: A Preliminary Study

Patients and physicians understand the importance of self-care following spinal cord injury (SCI), yet many individuals with SCI do not adhere to recommended self-care activities despite logistical supports. Neurobehavioral determinants of SCI self-care behavior, such as impulsivity, are not widely studied, yet understanding them could inform efforts to improve SCI self-care. We explored associations between impulsivity and self-care in an observational study of 35 US adults age 18 - 50 who had traumatic SCI with paraplegia at least six months before assessment. The primary outcome measure was self-reported self-care. In LASSO regression models that included all neurobehavioral measures and demographics as predictors of self-care, dispositional measures of greater impulsivity (negative urgency, lack of premeditation, lack of perseverance), and reduced mindfulness were associated with reduced self-care. Outcome (magnitude) sensitivity, a latent decision-making parameter derived from computationally modeling successive choices in a gambling task, was also associated with self-care behavior. These results are preliminary;more research is needed to demonstrate the utility of these findings in clinical settings. Information about associations between impulsivity and poor self-care in people with SCI could guide the development of interventions to improve SCI self-care and help patients with elevated risks related to self-care and secondary health conditions.

Investigating the genetic diversity of several varieties of Iranian tomato (Solanum lycopersicum) using RAPD and ISSR molecular markers

Background:Numerous studies have demonstrated the existence of approximately 7,500 genetic tomato varieties worldwide.Hence,it is crucial to assess the genetic diversity among tomato cultivars.This study aimed to investigate the genetic diversity of selected Iranian tomato cultivars(Solanum lycopersicum)using RAPD and ISSR molecular markers.Method:Ten RAPD primers and ten ISSR primers were employed to assess the genetic diversity among 10 tomato cultivars:Matin,RFT 112,Hirad,Golsar,Raha,Hengam,Hedah,Fasa,JS12,and Emerald.Data analysis involved the UPGMA algorithm and NTYSYSpc software.Results:RAPD analysis revealed close genetic proximity between Fasa and JS12,as well as between Raha and Hadieh.Conversely,the RFT 112,Hengam,Hirad,and Emerald cultivars exhibited significant genetic diversity within this group.ISSR primer analysis identified Hengam as the most diverse variety,while Matin,Emerald,and Vibrid,as well as Raha and JS12,displayed genetic similarities with minimal observed diversity.Furthermore,the overall analysis of the cultivars using RAPD and ISSR markers indicated that Hengam exhibited the highest diversity among all the varieties.Notably,Raha and JS12 demonstrated limited diversity in this analysis.Conclusion:This research demonstrates substantial genetic diversity among the investigated tomato varieties,with Hengam displaying the highest diversity within this group.Furthermore,ISSR markers proved more effective in determining genetic diversity in tomato plants.

Vascular endothelial growth factor:a double-edged sword in the development of white matter lesions

As the population ages,the burden of age-related diseases becomes greater.Currently,over 55 million people suffer from dementia worldwide,with Alzheimer’s disease being the most common form.However,it is becoming clearer that underlying vascular pathology such as cerebral small vessel disease(cSVD)may be a more detrimental cause for dementia(Cuadrado-Godia et al.,2018).It is estimated that 10%-30%of the elderly population and 35%-90%of all dementia patients exhibit signs of cSVD.The term cSVD refers to pathology affecting the small vessels of the brain,which can lead to lacunar cerebral infarcts,enlarged perivascular spaces,and cortical hemorrhages(Cuadrado-Godia et al.,2018).CSVD is often associated with cognitive decline,gait problems,and dementia(Cuadrado-Godia et al.,2018).

Inhibition of signal transducer and activator of transcription 3 expression by RNA interference suppresses invasion through inducing anoikis in human colon cancer cells

AIM:To investigate the roles and mechanism of signal transducer and activator of transcription 3 (STAT3) in invasion of human colon cancer cells by RNA interference. METHODS: Small interfering RNA (siRNA) targeting Signal transducer and activator of transcription 3 (STAT3) was transfected into HT29 colon cancer cells. STAT3 protein level and DNA-binding activity of STAT3 was evaluated by western blotting and electrophoretic mobility shift assay (EMSA), respectively. We studied the anchorage-independent growth using colony formation in soft agar, and invasion using the boyden chamber model, anoikis using DNA fragmentation assay and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL), respectively. Western blot assay was used to observe the protein expression of Bcl-xL and survivin in colon cancer HT29 cells. RESULTS: RNA interference (RNAi) mediated by siRNA leads to suppression of STAT3 expression in colon cancer cell lines. Suppression of STAT3 expression by siRNA could inhibit anchorage-independent growth, and invasion ability, and induces anoikis in the colon cancer cell line HT29. It has been shown that knockdown of STAT3 expression by siRNA results in a reduction in expression of Bcl-xL and survivin in HT29 cells. CONCLUSION: These results suggest that STAT3 siRNA can inhibit the invasion ability of colon cancer cells through inducing anoikis, which antiapoptotic genes survivin and Bcl-xL contribute to regulation of anoikis.These studies indicate STAT3 siRNA could be a useful therapeutic tool for the treatment of colon cancer.

Interstitial cells of Cajal, the Maestro in health and disease

Interstitial cells of Cajal (ICC) are important players in the symphony of gut motility. They have a very signif icant physiological role orchestrating the normal peristaltic activity of the digestive system. They are the pacemaker cells in gastrointestinal (GI) muscles. Absence, reduction in number or altered integrity of the ICC network may have a dramatic effect on GI system motility. More understanding of ICC physiology will foster advances in physiology of gut motility which will help in a future breakthrough in the pharmacological interventions to restore normal motor function of GI tract. This mini review describes what is known about the physiologic function and role of ICCs in GI system motility and in a variety of GI system motility disorders.

Use of arrays to investigate the contribution of ATP-binding cassette transporters to drug resistance in cancer chemotherapy and prediction of chemosensitivity

Multidrug resistance （MDR） is a major problem in cancer chemotherapy. One of the best known mechanisms of MDR is the elevated expression of ATP-binding cassette （ABC） transporters. While some members of human ABC transporters have been shown to cause drug resistance with elevated expression, it is not yet known whether the over-expression of other members could also contribute to drug resistance in many model cancer cell lines and clinics. The recent development ofmicroarrays and quantitative PCR arrays for expression profiling analysis of ABC transporters has helped address these issues. In this article, various arrays with limited or full list of ABC transporter genes and their use in identifying ABC transporter genes in drug resistance and chemo-sensitivity prediction will be reviewed.

Resveratrol and fenofibrate ameliorate fructose-induced nonalcoholic steatohepatitis by modulation of genes expression

AIM: To evaluate the effect of resveratrol, alone and in combination with fenofibrate, on fructose-induced metabolic genes abnormalities in rats.METHODS: Giving a fructose-enriched diet (FED) to rats for 12 wk was used as a model for inducing hepatic dyslipidemia and insulin resistance. Adult male albino rats (150-200 g) were divided into a control group and a FED group which was subdivided into 4 groups, a control FED, fenofibrate (FENO) (100 mg/kg), resveratrol (RES) (70 mg/kg) and combined treatment (FENO + RES) (half the doses). All treatments were given orally from the 9th week till the end of experimental period. Body weight, oral glucose tolerance test (OGTT), liver index, glucose, insulin, insulin resistance (HOMA), serum and liver triglycerides (TGs), oxidative stress (liver MDA, GSH and SOD), serum AST, ALT, AST/ALT ratio and tumor necrosis factor-α (TNF-α) were measured. Additionally, hepatic gene expression of suppressor of cytokine signaling-3 (SOCS-3), sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), malonyl CoA decarboxylase (MCD), transforming growth factor-β1 (TGF-β1) and adipose tissue genes expression of leptin and adiponectin were investigated. Liver sections were taken for histopathological examination and steatosis area were determined.RESULTS: Rats fed FED showed damaged liver, impairment of glucose tolerance, insulin resistance, oxidative stress and dyslipidemia. As for gene expression, there was a change in favor of dyslipidemia and nonalcoholic steatohepatitis (NASH) development. All treatment regimens showed some benefit in reversing the described deviations. Fructose caused deterioration in hepatic gene expression of SOCS-3, SREBP-1c, FAS, MDA and TGF-β1 and in adipose tissue gene expression of leptin and adiponectin. Fructose showed also an increase in body weight, insulin resistance (OGTT, HOMA), serum and liver TGs, hepatic MDA, serum AST, AST/ALT ratio and TNF-α compared to control. All treatments improved SOCS-3, FAS, MCD, TGF-β1 and leptin genes expression while only RES and FENO + RES groups showed an improvement in SREBP-1c expression. Adiponectin gene expression was improved only by RES. A decrease in body weight, HOMA, liver TGs, AST/ALT ratio and TNF-α were observed in all treatment groups. Liver index was increased in FENO and FENO + RES groups. Serum TGs was improved only by FENO treatment. Liver MDA was improved by RES and FENO + RES treatments. FENO + RES group showed an increase in liver GSH content.CONCLUSION: When resveratrol was given with half the dose of fenofibrate it improved NASH-related fructose-induced disturbances in gene expression similar to a full dose of fenofibrate.

Molecular mechanism and functional consequences of lansoprazole-mediated heme oxygenase-1 induction

AIM： To investigate the molecular mechanism and functional consequences of heme oxygenase-1 （HO-1） activation by lansoprazole in endothelial cells and macrophages. METHODS： Expression of HO-1 mRNA was analyzed by Northern blotting. Western blotting was used to determine the HO-1 and ferritin protein levels. NADPH-dependent reactive oxygen species （ROS） formation was measured with lucigenin-enhanced chemiluminescence. HO-1 promoter activity in mouse fibroblasts, stably transfected with a 15-kb HO-1 gene that drives expression of the reporter gene luciferase, was assessed usingin vivo bioluminescence imaging. RESULTS： Lansoprazole levels in endothelial cells increased HO-1 mRNA and HO-1 protein levels in macrophages. In addition, lansoprazole-induced ferritin protein levels in both cell systems. Moreover, induction of the antioxidant proteins HO-1 and ferritin by lansoprazole was followed by a decrease in NADPH- mediated ROS formation. The radical scavenging properties of lansoprazole were diminished in the presence of the HO inhibitor, chromium mesoporphyrin IX. Induction of HO-1 gene expression by lansoprazole was not related to oxidative stress or to the activation of the mitogen-activated protein kinase pathway. However, the phosphatidylinositol 3-kinase inhibitor LY294002 showed a concentration-dependent inhibition of HO-1 mRNA and promoter activity.CONCLUSION： Activation of HO-1 and ferritin may account for the gastric protection of lansoprazole and is dependent on a pathway blocked by LY294002.

Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus

AIM To investigate the role of glucagon-like peptide-1(GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS Chronic high-fat diet fed C57 BL/6 J mice, streptozotocintreated high-fat diet fed C57 BL/6 J mice and diabeticC57 BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocintreated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes(SREBP-1 C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation(CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-?. Coagonist treatment reduced expression of inflammatory(TNF-α, MCP-1, and MMP-9) and pro-fibrotic(TGF-β, COL1 A1, and α-SMA) genes and also improved histological derangement in renal tissue.CONCLUSION Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.

Inhibition of methionine adenosyltransferase II induces FasL expression, Fas-DISC formation and caspase-8-dependent apoptotic death in T leukemic cells

Methionine adenosyltransferase Ⅱ（MAT Ⅱ） is a key enzyme in cellular metabolism and catalyzes the formation of S-adenosylmethionine （SAMe） from L-methionine and ATE Normal resting T lymphocytes have minimal MAT Ⅱ activity, whereas activated proliferating T lymphocytes and transformed T leukemic cells show significantly enhanced MAT Ⅱ activity. This work was carried out to examine the role of MAT Ⅱ activity and SAMe biosynthesis in the survival of leukemic T cells. Inhibition of MAT Ⅱ and the resultant decrease in SAMe levels enhanced expression of FasL mRNA and protein, and induced DISC （Death Inducing Signaling Complex） formation with FADD （Fasassociated Death Domain） and procaspase-8 recruitment, as well as concomitant increase in caspase-8 activation and decrease in c-FLIPs levels. Fas-initiated signaling induced by MAT Ⅱ inhibition was observed to link to the mitochondrial pathway via Bid cleavage and to ultimately lead to increased caspase-3 activation and DNA fragmentation in these cells. Furthermore, blocking MAT 2A mRNA expression, which encodes the catalytic subunits of MAT Ⅱ, using a small-interfering RNA approach enhanced FasL expression and cell death, validating the essential nature of MAT Ⅱ activity in the survival of T leukemic cells.

Pivotal role of long non-coding ribonucleic acid-X-inactive specific transcript in regulating immune checkpoint programmed death ligand 1 through a shared pathway between miR-194-5p and miR-155-5p in hepatocellular carcinoma

BACKGROUND Anti-programmed death therapy has thrust immunotherapy into the spotlight.However,such therapy has a modest response in hepatocellular carcinoma(HCC).Epigenetic immunomodulation is a suggestive combinatorial therapy with immune checkpoint blockade.Non-coding ribonucleic acid(ncRNA)driven regulation is a major mechanism of epigenetic modulation.Given the wide range of ncRNAs that co-opt in programmed cell-death protein 1(PD-1)/programmed death ligand 1(PD-L1)regulation,and based on the literature,we hypothesized that miR-155-5p,miR-194-5p and long non-coding RNAs(lncRNAs)X-inactive specific transcript(XIST)and MALAT-1 are involved in a regulatory upstream pathway for PD-1/PD-L1.Recently,nutraceutical therapeutics in cancers have received increasing attention.Thus,it is interesting to study the impact of oleuropein on the respective study key players.AIM To explore potential upstream regulatory ncRNAs for the immune checkpoint PD-1/PD-L1.METHODS Bioinformatics tools including microrna.org and lnCeDB software were adopted to detect targeting of miR-155-5p,miR-194-5p and lncRNAs XIST and MALAT-1 to PD-L1 mRNA,respectively.In addition,Diana tool was used to predict targeting of both aforementioned miRNAs to lncRNAs XIST and MALAT-1.HCC and normal tissue samples were collected for scanning of PD-L1,XIST and MALAT-1 expression.To study the interaction among miR-155-5p,miR-194-5p,lncRNAs XIST and MALAT-1,as well as PD-L1 mRNA,a series of transfections of the Huh-7 cell line was carried out.RESULTS Bioinformatics software predicted that miR-155-5p and miR-194-5p can target PDL1,MALAT-1 and XIST.MALAT-1 and XIST were predicted to target PD-L1 mRNA.PD-L1 and XIST were significantly upregulated in 23 HCC biopsies compared to healthy controls;however,MALAT-1 was barely detected.MiR-194 induced expression elevated the expression of PD-L1,XIST and MALAT-1.However,overexpression of miR-155-5p induced the upregulation of PD-L1 and XIST,while it had a negative impact on MALAT-1 expression.Knockdown of XIST did have an impact on PD-L1 expression;however,following knockdown of the negative regulator of X-inactive specific transcript(TSIX),PD-L1 expression was elevated,and abolished MALAT-1 activity.Upon co-transfection of miR-194-5p with siMALAT-1,PD-L1 expression was elevated.Co-transfection of miR-194-5p with siXIST did not have an impact on PD-L1 expression.Upon co-transfection of miR-194 with siTSIX,PD-L1 expression was upregulated.Interestingly,the same PD-L1 expression pattern was observed following miR-155-5p cotransfections.Oleuropein treatment of Huh-7 cells reduced the expression profile of PD-L1,XIST,and miR-155-5p,upregulated the expression of miR-194-5p and had no significant impact on the MALAT-1 expression profile.CONCLUSION This study reported a novel finding revealing that opposing acting miRNAs in HCC,have the same impact on PD-1/PD-L1 immune checkpoint by sharing a common signaling pathway.

Evaluation of chemopreventive effect of Fumaria indica against N-nitrosodiethylamine and CCl_4-induced hepatocellular carcinoma in Wistar rats

Objective:To investigation the chemopreventive potential of Fumaria indica（F.indica） extract（FIE） on N-nitrosodiethylamine and CCl4-induced hepatocarcinogenesis in Wislar rats.Methods:The experimental animals were divided into six groups（n=6）.Hepatocellular carcinoma was induced by single intraperitoneal injection of N-nitrosodiethylamine（NDEA） in normal saline at a dose of 200 mg/kg body weight followed by weekly subcutaneous injections of CCl4（3 mL/kg/week） for 6 weeks,as the promoter of carcinogenic effect.After administration of the carcinogen,200 and 400 mg/kg of FIE were administered orally once a day throughout the study.At the end of 20 weeks,the body weight,liver weight and relative liver weight were measured.The percentage of nodule incidence and liver cancer markers such as aspartate transaminase（AST）,alanine transaminase（ALT）,alkaline phosphatase（ALP）,γ-glutamyl transferase（γ-GT）,total bilirubin level（TBL）,α-feto protein（AFP） and carcinoembryonic antigen were estimated along with histopathological investigation in experimental groups of rats. Results:Obtained results demonstrated that the cotreatment with FIE significantly prevented the decrease of the body weight and also increased in relative liver weight caused by NDEA. The treatment with FIE significantly reduced the nodule incidence and nodule multiplicity in the rats after NDEA administration.The levels of liver cancer markers such as AST,ALT,ALP,γ-glutamyl transferase,TBL,AFP and carcinoembryonic antigen were substantially increased by NDEA treatment.However,FIE treatment significantly reduced the liver injury and restored the entire liver cancer markers.Histological observations of liver tissues too correlated with the biochemical observations.Conclusions:These finding powerfully supports that F.indica exert chemopreventive effect by suppressing the tumor burden and restoring the activities of hepatic cancer marker enzymes on NDEA and CCl4-induced hepatocarcinogenesis in Wistar rats.

MMP-1 Over-expression Promotes Malignancy and Stem-Like Properties of Human Osteosarcoma MG-63 Cells In Vitro

Osteosarcoma is the most common primary malignant bone tumor in childhood,and it maintains a high level of recurrence.Matrix metalloproteinase-1(MMP-1)was found to contribute to cancer progression.The present study was to investigate the in vitro effects of MMP-1 over-expression on the proliferation,invasion,metastasis and stem-like properties of osteosarcoma MG-63 cells.The MG-63 cells were cultured and had a full length MMP-1 cDNA inserted by the tentiviral vector (MG-63^MMP-1+).MG-63 negative control and MG-63 blank control groups were established as well.MMP-1 expression was detected in MG-63^MMP-1+,MG-63 negative control and MG-63 blank control cells using qPCR,Western blotting and immunofluorescence after 24h of culture. The cell proliferation assay was performed with a camera attached to a bioreactor,which was programmed to photograph five regions of each well every 10 min over a period of 48 h.The cell invasion assay was conducted with Matrigel to assess the invasive potential,of MG-63 cells over 24h,the qPCR analysis to measure stem cell markers,including Oct4, Sox-2,Nanog,and Pax-7,and Western blot analysis to detect invasive and metastatic potential markers TIMP-1,VEGF and BMP2/4,after 24h of culture.Immunofluorescence was used to investigate the presence of the stem cell marker Pax-7 after 24-h culture. The results showed that over-expression of MMP-1 after transfection could significantly increase minor cell proliferation and invasion (P<0.05,MG-63^MMP-1+ versus controls).Pax-7 was highly expressed in MG-63^MMP-1+ cells,with no significant changes of Oct-4,Sox-2, and Nanog observed (P<0.05).MG-63^MMP-1+ cells showed higher expression of VEGF and BMP 2/4 proteins and lower expression of TIMP-1 protein than controls (P<0.05).It was concluded that MMP-1 over-expression in MG-63 cells contributed to the proliferation, invasion,metastasis and stem-like properties of osteosarcoma cells.Future studies should focus on in vivo effects of MMP-1 over-expression and the application of MMP-1 and Pax-7 inhibition in vivo to osteosarcoma theraoies.

Impact of cytokine storm and systemic inflammation on liver impairment patients infected by SARS-CoV-2:Prospective therapeutic challenges

Coronavirus disease 2019(COVID-19)is a devastating worldwide pandemic infection caused by a severe acute respiratory syndrome namely coronavirus 2(SARS-CoV-2)that is associated with a high spreading and mortality rate.On the date this review was written,SARS-CoV-2 infected about 96 million people and killed about 2 million people.Several arguments disclosed the high mortality of COVID-19 due to acute respiratory distress syndrome or change in the amount of angiotensin-converting enzyme 2(ACE2)receptor expression or cytokine storm strength production.In a similar pattern,hepatic impairment patients co-infected with SARS-CoV-2 exhibited overexpression of ACE2 receptors and cytokine storm overwhelming,which worsens the hepatic impairment and increases the mortality rate.In this review,the impact of SARS-CoV-2 on hepatic impairment conditions we overviewed.Besides,we focused on the recent studies that indicated cytokine storm as well as ACE2 as the main factors for high COVID-19 spreading and mortality while hinting at the potential therapeutic strategies.

Effects of co-administration of methanol leaf extract of Catharanthus roseus on the hypoglycemic activity of metformin and glibenclamide in rats

Objective:To investigate the interacting effects of co-administration of methanol leaf extract of Catharanthus roseus（C.roseus） on the hypoglycemic activity of metformin as well as glibenclamide using experimental rats.Methods:Phytochemical analysis as well as acute toxicity and lethality(LD50) test were carried out on its methanol leaf extract.The alloxan model for experimental induction of diabetes in rats was employed.Six groups comprising five rats each were used.GroupsⅡ,ⅢandⅣreceived 250 mg/kg of extract,100 mg/kg of metformin and 1 mg/kg of glibenclamide respectively,while V and VI were administered metformin-extract and glibenclamide-extract combinations respectively at doses as above.Group I served as negative control and received only distilled water.All administration was done once daily for seven days. Fasting blood glucose was determined at 2,12,24,72 and 168 h using a glucometer.One-way ANOVA with post-hoc tests was used to assess for significant difference due to administration of drug alone and with co-administration of drug and extract.Results:The LD50 was 2 121.32 mg/kg. The phytochemical studies indicated the presence of saponins,tannins,alkaloids,phlotatannins, flavonoids,triterpenoids,reducing sugars,anthraquinones and glycosides.All medicaments significantly reduced blood glucose levels when compared with control alone（P【0.05） with the highest percentage reduction in blood glucose（64.86%） exhibited by metformin-extract combination.Conclusions:The leaf extract of C.roseus significandy increases the hypoglycemic effect of metformin.

Promising effect of Magliasa, a traditional Iranian formula, on experimental colitis on the basis of biochemical and cellular findings

AIM: To investigate the efficacy of Magliasa, a traditional Iranian formula, on experimental colitis. METHODS: After botanical authentication of herbal ingredients, formulation of Magliasa, quantitative determination of total glucosinolates and total phenolic content, and analysis of the thin layer chromatography profile were performed. Colitis was then induced in male rats by instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in all groups, aside from the Sham group.The experimental groups consisted of: the Sham group that received only normal saline; the Mag-50, Mag-100 and Mag-200 groups, which received 50, 100 and 200 mg/kg per day of Magliasa, respectively; the control group, which received vehicle water orally; the infliximab group, which received infliximab (5 mg/kg per day, subcutaneously); and the Dexa group, which received dexamethasone (1 mg/kg per day, orally). After completing the treatment period (2 wk), the rats were sacrificed, the colon was removed, its macroscopic and microscopic changes were recorded, and tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1b), total antioxidant capacity, myeloperoxidase (MPO), and lipid peroxidation (LPO) were assessed in colon homogenate.RESULTS: The mean value of total glucosinolates in one gram of Magliasa was 19 ± 1 μmol. The mean value of the total phenolic content was 293.8 ± 17.6 mg gallic acid equivalents per 100 gram of Magliasa. Macroscopic scores were significantly decreased in Mag-100 (1.80 ± 0.58, P = 0.019) and Mag-200 (1.20 ± 0.20, P = 0.001) compared to the control group (3.40 ± 0.24), although some inflammation and hyperemia were evident. Treatment of rats by dexamethasone (0.33 ± 0.21, P < 0.001) and infliximab (0.83 ± 0.31, P < 0.001) remarkably attenuated scores where mild hyperemia was observed macroscopically. In comparison to the control group (4.00 ± 0.32), only Mag-200 (1.60 ± 0.40) showed a significant decrease in colonic histopathological scores (P = 0.005). Minimal mucosal inflammation was observed in the Dexa group (0.67 ± 0.21, P < 0.001). The levels of TNF-α, IL-1b and MPO were significantly lower in all groups compared to the controls (P < 0.05). A significant decrease in LPO was seen in the Mag-200 (3.27 ± 0.77, P = 0.01) and Dexa (3.44 ± 0.22, P = 0.011) groups in comparison to the control group (6.43 ± 0.61). Only dexamethasone caused a significant increase in antioxidant power in comparison to the control group (346.73 ± 9.9 vs 228.33 ± 2.75, P < 0.001). Infliximab and different doses of Magliasa did not show any remarkable increase in antioxidant capacity (P > 0.05). The effect of Magliasa in all of mentioned parameters, except antioxidant capacity, was dose dependent.CONCLUSION: The effects of Magliasa in TNBS-induced colitis are encouraging and warrant clinical trials for further confirmation.

Mechanism of Learning and Memory Impairment in Rats Exposed to Arsenic and/or Fluoride Based on Microbiome and Metabolome

Objective Arsenic(As) and fluoride(F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, leading to cognitive, learning, and memory impairments. However, early biomarkers of learning and memory impairment induced by As and/or F remain unclear. In the present study, the mechanisms by which As and/or F cause learning memory impairment are explored at the multi-omics level(microbiome and metabolome).Methods We stablished an SD rats model exposed to arsenic and/or fluoride from intrauterine to adult period.Results Arsenic and/fluoride exposed groups showed reduced neurobehavioral performance and lesions in the hippocampal CA1 region. 16S rRNA gene sequencing revealed that As and/or F exposure significantly altered the composition and diversity of the gut microbiome, featuring the Lachnospiraceae_NK4A136_group, Ruminococcus_1, Prevotellaceae_NK3B31_group, [Eubacterium]_xylanophilum_group. Metabolome analysis showed that As and/or F-induced learning and memory impairment may be related to tryptophan, lipoic acid, glutamate, gamma-aminobutyric acidergic(GABAergic) synapse, and arachidonic acid(AA) metabolism. The gut microbiota, metabolites, and learning memory indicators were significantly correlated.Conclusion Learning memory impairment triggered by As and/or F exposure may be mediated by different gut microbes and their associated metabolites.

Studies on the anti-asthmatic and antitussive properties of aqueous leaf extract of Bryophyllum pinnatum in rodent species

Objective:To evaluate the antiasthmatic and antitussive properties of the aqueous leaf extract of Bryophyilum pinnatum {B.pinnatum)(BP) Lam.Methods:Ovalbiunin-sensilized guinea pigs which were treated with BP for 21 consecutive days were exposed to 0.2%histamine aerosol in a glass chamber.Mucus viscosity,white blood cell and lymphocyte counts and tracheal wall morphometry were measured.Bouts of cough were counted pre and post acute exposure of extract-treated(X7 d) guinea pigs to 7.5%citric acid aerosol in a chamber.Phenol red expectoration was estimated in mice after 7 d of daily administration of BP.Results:Doses of 200 and 400 mg/kg/day(×21 d) BP significantly increased the time for guinea pigs to experience preconvulsive dyspnoea.BP and salbutamol(0.5 mg/kg/day×21 d) reduced mucus viscosity in the sensitized group to values comparable with controls.White blood cell,lymphocyte counts and tracheal morphometry were not significantly altered.Both doses of BP also significantly reduced the bouts of cough but only 400 mg/kg/day significantly inhibited the amount of phenol red secreted.Conclusions:BP has demonstrated antiasthmatic and antitussive properties in these rodent models.These properties may underscore its use in Nigerian ethnomedicine.