Effect of garlic intake on inflammatory mediators: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Garlic is a species in the onion genus, Allium. Data have shown that garlic has anti-inflammatory activity; however, the findings are inconclusive and inconsistent. We aimed to evaluate the impact of garlic intake on inflammatory mediators through systematic review and meta-analysis of existing data. METHODS: Electronic databases were completely investigated using databases of ISI Web of Science, Medline, Scopus, Cochrane Library and EMBASE until October 2019. A random effects model and the generic reverse variance procedure were used for quantitative data production. Sensitivity analyses and prespecified subgroup were done to evaluate potential heterogeneity. Random effect meta-regression was conducted to investigate the effects of possible confounders on the assessed effect size. RESULTS: Ten trials with one observational study, including 530 participants, met the eligibility criteria. The findings showed reduction in the tumour necrosis factor alpha (TNF-α) (-0.31 pg/mL, 95% CI -1.07 to 0.46) and C reactive protein (CRP) levels (-0.20 mg/L, 95% CI -1.4 to 1.05) following supplementation with garlic, although it had no marked impact on the interleukin 6 (IL-6) level (0.37 pg/mL, 95% CI -0.58 to 1.33). In the subgroup analysis, we found that garlic supplementation significantly decreased TNF-α, highly sensitive CRP and IL-6 levels in subgroups of >8, >6 and ≥4 weeks of intervention duration, respectively, and dose of garlic consumption between 2 and 2.4 g/day. CONCLUSION: These findings suggested that current evidence may support garlic as an adjunct to pharmacological management of metabolic diseases. PROSPERO REGISTRATION NUMBER: CRD42018108816.

Quantitative proteomic analysis to determine differentially expressed proteins in axenic amastigotes of Leishmania tropica and Leishmania major.

Cutaneous leishmaniasis is commonly caused by Leishmania major and Leishmania tropica. In the present study, the differential expression of proteins was identified in the amastigote-like forms of L. tropica and L. major in Iranian isolates. Initially, the samples were cultured and identified using PCR-RFLP technique. The Leishmania isolates were then grown in host-free (axenic) culture and prepared to amastigote-like forms, followed by the extraction of their proteins. To identify significant differentially expressed proteins (DEPs) of two types of Leishmania, the label-free quantitative proteomic technique was used based on sequential window acquisition of all theoretical fragment ion spectra mass spectrometry. A total of 51 up/down-DEPs (fold change >2 and p-value <.05) were identified between the axenic amastigote forms of L. major and L. tropica. Of these, 34 and 17 proteins were up-regulated in L. major and L. tropica, respectively. Several enriched GO terms were identified via biological process analyses for DEPs; furthermore, the metabolic process and translation were disclosed as top category in the up-regulated proteins of both L. major and L. tropica species. Also, the KEGG analysis revealed carbon metabolism and metabolic pathways term as the top pathways in the proteins up-regulated in L. major and L. tropica, respectively. Taken together, the numerous novel DEPs identified between the studied species could help fully understand the molecular mechanisms of pathogenesis and provide potential drug targets and vaccine candidates.

Quantitative proteomic analysis reveals differentially expressed proteins in Leishmania major metacyclogenesis.

Leishmaniasis is an infectious disease caused by Leishmania that widespread in 98 countries. The differentiation of Leishmania (L) from procyclic to metacyclic promastigote has occurred along with morphological and biochemical changes in proteome scale. We aim here to identify the proteomes of two successive developmental forms (procyclic and metacyclic promastigotes) from Leishmania major isolates using SWATH-MS quantitative proteomics technique. Isolated proteins from procyclic and metacyclic lysate were digested, fractionated and subjected to SWATH-MS. Proteins significantly different in abundance were analyzed using gene ontology (GO) and protein-protein interaction network (PPIN). Our study showed that 52 proteins were changed in abundance between the two consecutive developmental stages. Differentially expressed proteins were classified into nine classes by GO analysis. Significant modulations in translation, antioxidant and stress-related defenses, energy metabolism, structural and motility-related proteins were detected between procyclic and metacyclic stages. We found that elongation factor-2 and various structural constituents of ribosome were down-regulated during metacyclogenesis, while motility related proteins including ADP-ribosylation factor-3, paraflegellar rod protein-2C and tubulin alpha-chain were up regulated. According to network analysis, ENOL has been introduced as main hub-bottleneck protein and EF-1b, Hsp60 and GDH have been determined as seed proteins. Our results show that significant proteins in abundance are crucial features of metacyclogenesis in L. major. The protein function analysis illustrated that synthetic pathway involved proteins were down-regulated in metacyclic, which is the main feature of this stage of parasite growth cycle, while up-regulation of motility and energy metabolism related proteins is consistent with infective feature of metacyclic stage. Based on our results, we suppose that differentially expressed proteins possibly play a critical role in L. major differentiation. In addition, our finding demonstrated the possibility of SWATH-MS as viable technique to faster detect new stage-specific proteins in Leishmania and further studies are required for the validation of the results.

Therapeutic effects of hydro-alcoholic extract of Achillea wilhelmsii C. Koch on indomethacin-induced gastric ulcer in rats: a proteomic and metabolomic approach.

BACKGROUND: Gastric ulcer is one of the most prevalent diseases worldwide. In Iranian folk medicine, Achillea wilhelmsii (AW) is used as a treatment for gastric ulcer. Previous reports also mentioned Antiulcerogenic properties for this herbal plant. This study investigated the therapeutic effects of Achillea wilhelmsii C. Koch extract on indomethacin-induced gastric lesion in rats, from both proteomic and metabolomic perspectives. METHODS: The rats were divided into 4 groups. Gastric ulceration was induced by a single dose of indomethacin (45 mg/kg) by oral gavage. An amount of 800 mg/kg of AW extract was administered orally. Serum and tissue samples were collected for further investigations. The metabolomic study was performed by 1H-NMR CPMG spectrometry. Proteomic analysis was also executed by using two dimensional gel electrophoresis (2DE) followed by liquid chromatography coupled to tandem mass spectrometry (LC-ESI/MS/MS). Real time PCR was used to confirm some of the genes. RESULTS: The macroscopic and microscopic investigations confirmed the effectiveness of the AW extract. There was a panel of metabolites which showed alteration during gastric lesion development. The levels of some of these metabolite reversed nearly to their control values after the administration of AW extract. There were also changes in the levels of some proteins including Alb, Fabp5, Hspb1, Tagln, Lgals7, Csta and Myl9 which were reversed after AW administration. CONCLUSIONS: Our findings suggested that Achillea wilhelmsii C. Koch extract could be a potential therapy to be used for indomethacin-induced gastric lesion treatment in the future. However, further investigations are needed to confirm the results.

Comprehensive Analysis of the Expression, Prognosis, and Immune Infiltrates for Chromodomain-Helicase-DNA-Binding Proteins in Breast Tumor.

BACKGROUND: Several recent studies suggest that chromodomain-helicase -DNA-binding domains (CHDs) are linked with cancers. We explored the association between chromodomain-Helicase-DNA-binding domain proteins and breast cancer (BrCa) and introduced potential prognostic markers using various databases. MATERIALS AND METHODS: We analyzed the expression of the CHD family and their prognostic value in BrCa by mining UALCAN, TIMER, and Kaplan-Meier plotter databases. The association of CHD expression and immune infiltrating abundance was studied via the TIMER database. In addition, microRNAs related to the CHD family were identified by using the MirTarBase online database. RESULTS: The present study indicated that compared to normal tissues, BrCa tissues showed increased mRNA levels of CHD3/4/7 but decreased CHD2/5/9 expression. Interestingly, We also found a positive correlation between CHD gene expression and the infiltration of macrophage, neutrophil, and dendritic cells in BrCa, except CHD3/5. The Kaplan-Meier Plotter analysis suggested that high expression levels of CHD1/2/3/4/6/8/9 were significantly related to shorter relapse-free survival (RFS), while higher mRNA expression of CHD1, CHD2, CHD8, and CHD9 was significantly associated with longer overall survival of BrCa patients. The miRNAs of hsa-miR-615-3p and hsa-let-7b-5p were identified as being more correlated with the CHD family. CONCLUSION: The altered expression of some CHD members was significantly related to clinical cancer outcomes, and CHD1/2/8/9 could serve as potential prognostic biomarkers to improve the survival of BrCa patients. However, to evaluate the studied CHD members in detail are needed further investigations including experimental validation.

Diagnostic and Prognostic Value of miR-451 Expression in Colorectal Cancer: A Meta-Analysis.

BACKGROUND: The miR-451 has been reported to play an important role in colorectal cancer (CRC) pathogenesis and can be a pivotal diagnosis biomarker of CRC. Given the contradictions in the diagnosis value of the miR-451 in patients with CRC, deciphering the diagnostic/prognostic role of this miRNA in CRC will support the identification of a novel therapeutic target for CRC. Therefore, in the present meta-analysis, we evaluated the diagnostic value of miR-451 in CRC patients. MATERIALS AND METHODS: The electronic databases of Embase, PubMed, ISI Web of Science, and Scopus systematically searched for relevant studies. The odds ratio (OR) with a 95% confidence interval (CI) was calculated to evaluate the association between miR-451 family expression and diagnosis of colorectal cancer. The parameters including sensitivity, specificity, and area under the curve (AUC) were obtained. The quality of evidence was evaluated using the Newcastle-Ottava Scale (NOS). RESULTS: This study involved 510 patients (45% female and 55% male) with CRC. The pooled analysis of the studies showed a significant association between low expression levels of miR-451 in patients with CRC (OR = 7.59; 95% CI 2.39 - 24.07; p = 0.001). The overall sensitivity and specificity were 0.95 (0.61 - 1) and 0.83 (0.43 - 0.99), respectively. The pooled AUC was 0.97 (0.88 - 1; p < 0.006). Results showed if the pre-test probability is 50% for a patient, the post-test probability will be 85%. The indices demonstrated the high potency of miR-451 as a diagnostic biomarker in patients with CRC. No publication bias was observed using the Begg's (p=0.85) and Egger's tests (p=0.45). CONCLUSION: A strong relationship between the low expression levels of miR-451 and CRC progression was observed. This finding suggests the miR-451 family may be helpful as a potential biomarker for the earlier diagnosis of colorectal cancer.

Screening the critical protein subnetwork to delineate potential mechanisms and protective agents associated with arsenic-induced cutaneous squamous cell carcinoma: A toxicogenomic study.

Recent studies show that complex mechanisms are involved in arsenic-induced malignant transformation of cells. This study aimed to decipher molecular mechanisms associated with arsenic-induced cutaneous squamous cell carcinoma (cSCC) and suggest potential protective factors. RNA-seq-based differentially expressed genes between arsenic-exposed human keratinocytes (HaCaT) and controls were used to construct a protein-protein interaction (PPI) network and discover critical subnetwork-based mechanisms. Protective compounds against arsenic toxicity were determined and their target interactions in the core sub-network were identified by the comparative toxicogenomic database (CTD). The binding affinity between the effective factor and target was calculated by molecular docking. A total of 15 key proteins were screened out as critical arsenic-responsive subnetwork (FN1, IL-1A, CCN2, PECAM1, FGF5, EDN1, FGF1, PXDN, DNAJB9, XBP1, ERN1, PDIA4, DNAJB11, FOS, PDIA6) and 7 effective protective agents were identified (folic acid, quercetin, zinc, acetylcysteine, methionine, catechin, selenium). The GeneMANIA predicted detailed interactions of the subnetwork and revealed terms related to unfolded protein response as the main processes. FN1, IL1A and CCN2, as top significant genes, had good docking affinity with folic acid and quercetin, as selected key compounds. Integration of gene expression and protein-protein interaction related to arsenic exposure in cSCC explored the potential mechanisms and protective agents.

Potential role of resveratrol in prevention and therapy of diabetic complications: a critical review.

Background: Diabetes mellitus (DM) is a category of metabolic conditions affecting about 5% of people worldwide. High mortality associated with DM is mostly due to its severe clinical complications, including diabetic nephropathy, retinopathy, neuropathy, and cardiomyopathy. Resveratrol (RSV) is a natural, biologically active polyphenol known to have various health-promoting effects in animal models and humans. Objective: In this review, we have reviewed the preventive and therapeutic role of RSV on diabetes complications with emphasis on its molecular mechanisms of action. Methods: To prepare this review, all the basic and clinical available literatures regarding this topic were gathered through electronic databases, including PubMed, Web of Science, Scopus, and Google Scholar. Therefore, we summarized previous studies that have evaluated the effects of RSV on diabetic complications and their mechanisms. Only English language studies published up to January 2023 were included in this review. Results: RSV improves glucose homeostasis, decreases insulin resistance, induces autophagy, regulates lipid metabolism, protects pancreatic ß-cells, ameliorates metabolic disorders, and increases the GLUT4 expression. These effects induced by RSV are strongly associated with ability of this polyphenol agent to elevation expression/activity of AMP-activated protein kinase and Sirtuin 1 in various organs of diabetic subjects, which leads to prevention and therapy of diabetic complications. In addition, antioxidant and anti-inflammatory properties of RSV were reported to be involved in its action in diabetic complications, such as retinopathy and nephropathy. Conclusion: RSV is a promising compound for improving diabetic complications. However, the exact antidiabetic mechanisms of RSV need to be further investigated.

Mass Spectrometry-Based Proteomics Research to Fight COVID-19: An Expert Review on Hopes and Challenges.

The COVID-19 pandemic caused by the severe acute respiratory syndrome (SARS)-CoV-2 infection is a systemic disease and a major planetary health burden. While SARS-CoV-2 impacts host biology extensively, our knowledge of these alterations from a systems perspective remains incomplete. Moreover, there is currently only a limited description of this systemic disease. For precision diagnosis and treatment of SARS-CoV-2, multiomics technologies and systems science research offer significant prospects. This expert review offers a critical analysis of the prospects and challenges of the emerging mass spectrometry-based proteomics approaches to the study of COVID-19 as seen through a systems medicine lens. We also discuss the ways in which proteomics is poised to offer hope for diagnostics and therapeutics innovation on SARS-CoV-2 infection as the disease transitions from a pandemic to an endemic disease, and thus further challenging the health systems and services worldwide in the coming decade. Proteomics is an important high-throughput technology platform to achieve a functional overview of the ways in which COVID-19 changes host biology, and hence, can help identify possible points of entry for innovation in medicines and vaccines, among others.

Identification of protein profile in metacyclic and amastigote-like stages of Leishmania tropica: a proteomic approach.

Leishmaniasis is a tropical disease that leads to various clinical phenotypes. This study aimed to investigate protein expression changes in metacyclic and amastigote-like stages of L. tropica isolated from Iranian cutaneous leishmaniasis patients. Isolated samples were cultured and species type identified using PCR-RFLP technique. The promastigotes were grown in RPMI1640 media and differentiated to metacyclic and amastigote-like forms, followed by the extracted proteins of both successive stages carried out for proteomics and bioinformatics analysis. Using SWATH-MS quantitative proteomics technique, a total 176 and 155 distinct proteins were identified in metacyclic and axenic amastigote stages, respectively. Of these, 65 proteins were altered significantly (p-value < 0.05 and fold change ≥ 2) between studied stages. Several gene ontology (GO) categories were enriched for biological process during conversion of metacyclic promastigotes into amastigote-like, which "metabolic process" (GO: 0044281, P-Value: 6.52e-5), and "translation" (GO: 0006412, p-value: 5.01e-14) were disclosed as the top category in up and down-regulated proteins, respectively. Also, the KEGG pathway analysis indicated "metabolic pathways" and "ribosome" term as the most important pathways in up and down-regulated proteins, respectively. According to protein interaction network analysis, enolase (ENOL) has been detected as main hub proteins during differentiation, followed by Putative NADH-dependent fumarate reductase (LmjF.35.1180) and 40S ribosomal protein S2 (LmjF.32.0450). Overall, protein changes possibly play important roles in L. tropica biology. Anabolic pathways were down-regulated, whereas catabolic pathways were up-regulated during L. tropica differentiation. These protein expression changes could provide parasite survival in host macrophages, and could use as novel potential drug and vaccine targets for leishmaniasis.

Serum cortisol concentration and COVID-19 severity: a systematic review and meta-analysis.

The novel COVID-19 outbreak is a major health threat to human beings with multiorgan injuries. However, its endocrine system manifestations are much less studied. In this study, we aimed to reassess the available findings on the association between cortisol level and severity of COVID-19 infection. We conducted a systematic search on Medline/PubMed, Scopus, Web of Science, and Cochrane Library databases. To pool data, a random-effects model was performed depending on the heterogeneity among studies. Sensitivity analysis was also carried out by removing each study systematically. In addition, subgroup and meta-regression analyses were performed depending on the presence of the variables of sex and age. Subsequently, 11 studies (5 observational studies and 6 case reports) were included in the meta-analysis. Pooled analysis on the observational studies showed significantly higher levels of cortisol in patients with severe COVID-19 in comparison with those with mild-to-moderate COVID-19 (standardized mean difference: 1.48 µg/dL; 95% CI (0.51 to 2.46); p=0.003). Assessment of the results of case reports revealed that the patients with severe COVID-19 demonstrated higher cortisol levels than the patients with mild-to-moderate COVID-19. No publication bias was observed using the Begg's (p=0.08) and Egger's tests (p=0.09). Meta-regression illustrated a significant correlation between cortisol levels with sex. The serum cortisol level seems to be higher in patients with severe COVID-19 infection. This finding could be helpful to detect patients with poor prognosis at early stages of the disease, although age and sex may modify this level.

Association between circulating visfatin and pre-eclampsia: a systematic review and meta-analysis.

OBJECTIVE: Pre-eclampsia (PE) is a serious pregnancy status characterized by high blood pressure. Although visfatin is usually associated with PE. Observational studies evaluating the relationship between circulating visfatin and pre-eclampsia have reported inconsistent results. We conducted this systematic review and meta-analysis to summarize published data on the association between visfatin and pre-eclampsia. METHODS: Electronic databases PubMed, ISI web of science, EMBASE, Scopus and the Cochrane library were comprehensively searched for selection of eligible studies until January 5, 2020. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. The assessment of study quality was performed using the e Newcastle-Ottawa scale and the Agency for Healthcare Research and Quality. Sensitivity analyses and prespecified subgroup were conducted to evaluate potential heterogeneity. Random-effects meta-regression was conducted to assess the impact of potential confounders on the estimated effect sizes. The protocol for this study was registered in PROSPERO (No. CRD42018105861) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Thirteen studies comprising a total of 536 subjects were included in this meta-analysis. We observed that the pre-eclampsia risk is associated with a statistically significant elevation of visfatin level [SMD (1.33 µg/l) (95% CI 0.37, 2.2) p = .007]. No significant publication bias was observed in the meta-analysis. Subgroup and sensitivity analyses indicated that the pooled effects size were affected by systolic blood pressure [SMD (1.82 µg/l) 95% CI (0.94, 2.7), p < .05], gestational age [SMD (2.01 µg/l) 95% CI (0.57, 3.4), p = .006], body mass index [SMD (1.6 µg/l) 95% CI (0.37, 3), p < .05] and pregnancy trimesters[SMD (2.3 µg/l) 95% CI (0.95, 3.7), p = .001]. Random-effects meta-regression showed a significant association of visfatin level with potential confounders including systolic blood pressure, gestational age and birth weight at delivery of pre-eclampsia patients. CONCLUSIONS: Collectively, our data revealed that the increase of visfatin level can be associated with the risk of pre-eclampsia. However, further studies on pre-eclampsia populations are warranted for corroboration of our findings.

Metabolomic study of serum in patients with invasive ductal breast carcinoma with LC-MS/MS approach.

BACKGROUND: Invasive ductal carcinoma (IDC) is the most common type of breast cancer so its early detection can lead to a significant decrease in mortality rate. However, prognostic factors for IDC are not adequate and we need novel markers for the treatment of different individuals. Although positron emission tomography and magnetic resonance imaging techniques are available, they are based on morphological features that do not provide any clue for molecular events accompanying cancer progression. In recent years, "omics" approaches have been extensively developed to propose novel molecular signatures of cancers as putative biomarkers, especially in biofluids. Therefore, a mass spectrometry-based metabolomics investigation was performed to find some putative metabolite markers of IDC and potential metabolites with prognostic value related to the estrogen receptor, progesterone receptor, lymphovascular invasion, and human epidermal growth factor receptor 2. METHODS: An untargeted metabolomics study of IDC patients was performed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The multivariate principal component analysis by XCMS online built a model that could separate the study groups and define the significantly altered m/z parameters. The most important biological pathways were also identified by pathway enrichment analysis. RESULTS: The results showed that the significantly altered metabolites in IDC serum samples mostly belonged to amino acids and lipids. The most important involved pathways included arginine and proline metabolism, glycerophospholipid metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. CONCLUSIONS: Significantly altered metabolites in IDC serum samples compared to healthy controls could lead to the development of metabolite-based potential biomarkers after confirmation with other methods and in large cohorts.

Molecular pathways involved in COVID-19 and potential pathway-based therapeutic targets.

Deciphering the molecular downstream consequences of severe acute respiratory syndrome coronavirus (SARS-CoV)- 2 infection is important for a greater understanding of the disease and treatment planning. Furthermore, greater understanding of the underlying mechanisms of diagnostic and therapeutic strategies can help in the development of vaccines and drugs against COVID-19. At present, the molecular mechanisms of SARS-CoV-2 in the host cells are not sufficiently comprehended. Some of the mechanisms are proposed considering the existing similarities between SARS-CoV-2 and the other members of the ß-CoVs, and others are explained based on studies advanced in the structure and function of SARS-CoV-2. In this review, we endeavored to map the possible mechanisms of the host response following SARS-CoV-2 infection and surveyed current research conducted by in vitro, in vivo and human observations, as well as existing suggestions. We addressed the specific signaling events that can cause cytokine storm and demonstrated three forms of cell death signaling following virus infection, including apoptosis, pyroptosis, and necroptosis. Given the elicited signaling pathways, we introduced possible pathway-based therapeutic targets; ADAM17 was especially highlighted as one of the most important elements of several signaling pathways involved in the immunopathogenesis of COVID-19. We also provided the possible drug candidates against these targets. Moreover, the cytokine-cytokine receptor interaction pathway was found as one of the important cross-talk pathways through a pathway-pathway interaction analysis for SARS-CoV-2 infection.

Identification of differential protein expression and putative drug target in metacyclic stage of Leishmania major and Leishmania tropica: A quantitative proteomics and computational view.

Cutaneous leishmaniasis (CL) is an infectious disease that commonly caused by Leishmania (L.) major and L.tropica. Recently there has been a growing interest in proteomics analysis on Leishmania for drug target discovery. Therefore, we aimed to distinguish proteins which might be characteristic for each of the species from those shared by both to the detection of drug targets, which may become helpful for designing new drugs for CL. To identify differences in protein profiles of L. major and L. tropica, we conducted a Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) analysis. Totally 67 differentially expressed proteins (DEPs) (fold change> 2 and p < 0.05) were identified between species. Of these, 42 and 25 proteins were up-regulated in L. major and L. tropica, respectively. Several enriched GO terms were identified via biological process of up-regulated proteins. Furthermore, the small molecule metabolic process and translation were detected as significant biological processes for up-regulated proteins in L. major, while translation was identified for L. tropica. Also, KEGG analysis has revealed glycolysis/gluconeogenesis and translation as the top pathways in the proteins up-regulated in L. major and L. tropica, respectively. Finally glycosomal malate dehydrogenase was identified as putative drug target using network and homology analyses. The DEPs between the species are essential in host-pathogen interactions and parasite survival in the macrophage. Furthermore, L. major and L. tropica possibly uses different pathogenicity mechanisms that leads to anthroponotic or zoonotic CL. Our results may help in the drug discovery and chemotherapeutic interventions.

Prognostic value of microRNA-125a/b family in patients with gastric cancer: a meta-analysis.

AIM: This meta-analysis was designed to reassess the prognostic and clinicopathologic values of the microRNA-125 family in GC patients. BACKGROUND: The miR-125 family (including miR-125a, miR-125b) has been reported as being pivotal prognostic biomarkers of gastric cancer (GC). However, there is controversy about the role of the miR-125 family in predicting the progression of GC. METHODS: The miR-125 family (including miR-125a, miR-125b) has been reported as being pivotal prognostic biomarkers of gastric cancer (GC). However, there is controversy about the role of the miR-125 family in predicting the progression of GC. RESULTS: The electronic databases of PubMed, ISI Web of Science, Scopus, and Cochrane Library were systematically searched for relevant studies. Overall survival (OS) rate as the primary outcome from each study was extracted. The overall hazard ratio (HR or survival rate in patients with GC) and odds ratio (OR) with 95% confidence interval (CI) was calculated to evaluate the association between miR-125 family expression and prognosis and susceptibility to gastric cancer. The quality of evidence was evaluated using the Newcastle-Ottava Scale (NOS). The extracted data was combined based on the random-effects model. CONCLUSION: The low expression of miR-125 family predicts poor OS in GC patients. Thus, the miR-125 family may be helpful as a potential biomarker for the prognosis of gastric cancer.

Effect of rosiglitazone on circulating malondialdehyde (MDA) level in diabetes based on a systematic review and meta-analysis of eight clinical trials.

Patients with type 2 diabetes have high levels of malondialdehyde (MDA), and clinical data suggest a reducing effect of rosiglitazone (RSG) on the level of MDA in these patients. However, the results of available studies on the level of MDA in RSG-treated patients are not univocal. This meta-analysis aimed to assess the impact of RSG on the level of MDA. We performed a comprehensive search of PubMed, the Institute for Scientific Information Web of Science, Embase, Scopus, and Cochrane Library for related controlled trials until July 2020. Eligible studies were selected based on the inclusion criteria. Extracted data from each study were combined using a random-effects model. Sensitivity and subgroup analyses were conducted to explore potential heterogeneity. Eight trials with 456 subjects met the inclusion criteria. The results significantly showed the reducing effect of RSG on circulating MDA level (-0.47 µmol/mL; 95% CI -0.93 to -0.01; p=0.04; I2=82.1%; p heterogeneity=0.00) in individuals with T2D. No publication bias was observed with Begg's rank correlation (p=0.71) and Egger's linear regression (p=0.52) tests. Subgroup analyses showed that an intervention dose of 8 mg/day in serum samples was found to have a reducing effect on the level of MDA (-0.56 µmol/mL; 95% CI -0.98 to -0.14; p=0.008; I2=11.4%; p heterogeneity=0.32). Random-effects meta-regression did not show any significant association between the level of MDA and potential confounders including RSG dose, treatment duration, and sex. In conclusion, we found a significant reduction in MDA concentration in subjects with T2D who received a dose of 8 mg of RSG daily.

Discovery of Novel Pyruvate Kinase Inhibitors Against Leishmania major Among FDA Approved Drugs Through System Biology and Molecular Docking Approach.

OBJECTIVES: Leishmaniasis is one of the common forms of neglected parasitic diseases that cause a worldwide disease burden without any effective therapeutic strategy. Control of the disease currently relies on chemotherapy because most of the available drugs have toxic side-effects and drug-resistant strains have emerged. Therefore, the development of new therapeutic strategies to treat patients for leishmaniasis has become a priority. The first step in drug discovery is to identify an effective drug target by methods such as system biology. Protein kinases are a promising drug target for different diseases. Due to lack of a functional krebs cycle in Leishmania species, they use glycolysis as the only source of ATP generation. Pyruvate kinase is the enzyme involved in the last step of glycolysis and considered as essential enzyme for the Leishmania survival. MATERIALS AND METHODS: This study sought to discover FDA approved compounds against the leishmanial pyruvate kinase protein. Our approach involved using quantitative proteomics, protein interaction networks and docking to detect new drug targets and potent inhibitors. RESULTS: Pyruvate kinase was determined as the potential drug target based on protein network analysis. The docking studies suggested trametinib and irinotecan with high binding energies of -10.4 and -10.3 kcal/mol, respectively, as the potential chemotherapeutic agents against L. major. CONCLUSION: This study demonstrated the importance of integrating protein network analysis and molecular docking to identify new anti-leishmanial drugs. These potential inhibitors constitute novel drug candidates that should be tested in vitro and in vivo to determine their potential as an alternative chemotherapy in the treatment of leishmaniasis.

A quantitative proteomic and bioinformatics analysis of proteins in metacyclogenesis of Leishmania tropica.

Recently there has a growing interest in MS-based analysis on Leishmania for biology study, host-parasite interaction and drug target discovery. The aims of this study were to analyzed protein profiles in the procyclic and metacyclic stages of L. tropica, and investigate their potential role in metacyclogenesis molecular mechanisms. Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) analysis was used to analyze protein profiles in each of procyclic and metacyclic stages. Proteins with a fold change>2 or <0.5 and p < 0.05 were considered to be significantly differentially expressed proteins (DEPs). The DEPs were subjected to gene ontology (GO), KEGG pathway and network analysis using PANTHER and STRING database, respectively. Quantitative real-time PCR of six selected genes validated the proteomic data. We quantified a total of 352 proteins in procyclic and metacyclic cells and 56 differentially expressed proteins (27 up/ 29down-regulated in metacyclic compared to procyclic). On the basis of biological processes in GO, the DEPs were primarily involved in ``metabolic process'' (GO: 0008152) and ``cellular process'' (GO: 0009987). In addition, several enriched GO terms were identified via molecular function, which among them ``catalytic activity'' (GO: 0003824) and ``binding'' (GO: 0005488) were disclosed as top category. The KEGG pathway analysis indicated ``metabolic pathways'' (p-value: 3.80E-08) including 17 genes term as the top pathway in DEPs. These findings bring a new insight in our understanding of the molecular characterization of metacyclogenesis and infective form in L. tropica. Comparative analysis of the proteome of both developmental stages of the L. tropica would help to the identification of proteins candidates for the development of new potential drug targets and vaccines.

Comparison of gene expression of pyruvate kinase and tryparedoxin peroxidase in metacyclic promastigote forms of Leishmania (L.) tropica and L. major by real-time PCR

Two predominant forms of cutaneous leishmaniosis are anthroponotic CL (ACL) and zoonotic CL (ZCL) caused by Leishmania (L.) tropica and L. major in Iran and many countries, respectively. Since differential gene expression play an important role in outcome of the infection, we compared relative gene expression value of pyruvate kinase (PyrK) and tryparedoxin peroxidase (TryP) in metacyclic forms of Iranian isolates of L. major and L. tropica. Clinical isolates of CL patients were sampled in endemic foci of Iran and identified by PCR-RFLP. Then, we employed real-time PCR to evaluation of the expression level of PyrK and Tryp genes in L. major and L. tropica. By this comparison, up-regulation of PyrK and Tryp genes was observed in metacyclic stage. Moreover, the average mRNA expression of PyrK and Tryp genes in L. major was 1.69 and 3.72 folds of its expression in L. tropica isolates. The results of this study could open the new window for further investigations of the correspondence between parasite gene expression level and disease pathology. Species-specific parasite factors contributing to virulence and pathogenicity in the host may be mostly due to the some of the differential regulation of conserved genes between species.