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Objectives: Osteoporosis is the most prevalent metabolic bone disorderworldwide. This review was undertaken to compare the efficacies of bisphosphonatestherapies for patient persistence and compliance for the treatment of osteoporosis. Methods: A systematic review was performed in accordance with the available reportingitems. MEDLINE and Cochrane library databases were applied for literature searched up toJanuary 2020. All major studies such as prospective, retrospective and review articles thatexamined patient persistence or compliance to bisphosphonates for osteoporosis wereincluded. Results: The literature search found 656 relevant published reports, out of which 87 wereincluded. The 10, 712, 176 osteoporotic patients were studied for patient persistence and5, 875, 718 patients were studied for patient compliances. Analysis of all studiedbisphosphonates showed almost similar patterns for patient persistence rates as it wasdecreased over the time following initial prescription, but persistence length was found tobe significantly higher for alendronate therapy as compared to the other studiedbisphosphonates (p<0.001), whereas the length of persistence of all otherbisphosphonates (other than alendronate) were almost same (p>0.05). Analysis of patientcompliances with etidronate therapy showed the highest percent medication possessionratio (MRP) at 12 months, followed by the MRPs of ibandronate, alendronate, risedronate,and clodronate. Conclusion: This is the first systematic review that shows the comparison of theefficiencies of bisphosphonates for patient persistence and compliance for the treatment ofosteoporosis. The data showed that the length of patient persistence was highest foralendronate therapy, whereas patient compliance was highest for etidronate therapy for thetreatment of osteoporosis.

Streptomycesis a genus with known biocontrol activity, producing a broad range of biologically active substances. Our goal was to isolate local Streptomycesspecies, evaluate their capacity to biocontrol the selected phytopathogens, and promote the plant growth via siderophore and indole acetic acid (IAA) production and phosphate solubilization. Eleven isolates were obtained from local soil samples in Saudi Arabia via the standard serial dilution method and identified morphologically by scanning electron microscope (SEM) and 16S rRNA amplicon sequencing. The biocontrol of phytopathogens was screened against known soil-borne fungi and bacteria. Plant growth promotion capacity was evaluated based on siderophore and IAA production and phosphate solubilization capacity. From eleven isolates obtained, one showed 99.77% homology with the type strain Streptomyces tricolorAS 4.1867, and was designated S. tricolorstrain HM10. It showed aerial hyphae in SEM, growth inhibition of ten known phytopathogens in in vitroexperiments, and the production of plant growth promoting compounds such as siderophores, IAA, and phosphate solubilization capacity. S. tricolorstrain HM10 exhibited high antagonism against the fungi tested (i.e., Colletotrichum gloeosporideswith an inhibition zone exceeding 18 mm), whereas the lowest antagonistic effect was against Alternaria solani(an inhibition zone equal to 8 mm). Furthermore, the most efficient siderophore production was recorded to strain HM8, followed by strain HM10 with 64 and 22.56 h/c (halo zone area/colony area), respectively. Concerning IAA production, Streptomycesstrain HM10 was the most effective producer with a value of 273.02 µg/ml. An autochthonous strain S. tricolorHM10 should be an important biological agent to control phytopathogens and promote plant growth.

Background: Myoglobin is an oxygen binding protein and its dysfunction has been associated with the pathology of several human disorders. This study was undertaken to investigation the role of hydrogen peroxide (H2O2) in the formation of met-myoglobin and the protective potential of four different reductants such as uric acid, folic acid, glutathione and ascorbic acid were also tested against met-myoglobin formation. Methods: Human myoglobin was treated with H2O2in-vitro in order to prepare met-myoglobin. The generation of met-myoglobin was confirmed by UV-visible spectroscopy and its stability was analysed by the treatment of human myoglobin with H2O2at varying pH or time. High performance liquid chromatography (HPLC) was used to determine the oxidatively modified heme products in met-myoglobin. Spectroscopic analysis was used to identify the protective potential of uric acid, folic acid, glutathione and ascorbic acid against the formation of met-myoglobin. Results: The novel data of this study showed that H2O2induced extensive damage of myoglobin but the treatment with uric acid, folic acid, glutathione or ascorbic acid provides protection of myoglobin against H2O2induced oxidative damaged. The study apparently proved the protective potential of all these compounds against the toxicity produced by H2O2. Conclusion: This is the first study that shows uric acid, folic acid, glutathione and ascorbic acid provide protection against the generation of toxic met-myoglobin and might be used therapeutically to modify the blood conditions in order to prevent the progression of human disorders associated with myoglobin dysfunction.

This study quantified the effect of cold or heat exposure of ambient temperature on the alteration of well-known cardiac markers. A meta-analysis was performed using the PRISMA guidelines. Peer-reviewed studies on ambient temperature and cardiac biomarkers were retrieved from MEDLINE, ScienceDirect and Google Scholar from January 2000 to February 2022. The pooled effect sizes of ambient temperature on cardiac biomarkers c-reactive protein, soluble-cell adhesion-molecule-1, soluble-intercellular-adhesion-molecule-1, total cholesterol, low-densitylipoprotein, interleukin-6, B-type-Natriuretic-Peptide; systolic/diastolic blood pressure were quantified using a random-effects meta-analysis. A total of 26 articles were included in the metaanalysis after screening the titles, abstracts and full texts. The pooled results for a 1°C decrease of ambient temperature showed an increase of 0.31% (95% CI= 0.26 to 0.38) in cardiac biomarkers (p=0.00; I-squared=99.2%; Cochran’s Q=5636.8). In contrast, the pooled results for a 1°C increase in ambient temperature showed an increase of 2.03% (95% CI= 1.08 to 3.82) in cardiac biomarkers (p=0.00; I-squared=95.7%; Cochran’s Q=235.2). In the cardiovascular (CV) population, the percent increase in cardiac biomarkers levels due to a decrease/increase in ambient temperature was greater. This study showed the decrease/increase in ambient temperature has a direct correlation with the alterations in cardiac biomarkers. These findings are useful for managing temperatureassociated cardiovascular mortality.

Toll-like receptors (TLRs) are pattern-recognition-receptors that sense a variety of pathogens and initiation of innate and adaptive immune responses. This study was undertaken to investigate the expression of TLRs in peripheral blood-mononuclear cells (PBMCs) of AA patients and to determine whether TLR-mediated inflammatory signals are important for the perspective of AA management.

Objectives Honey total polyphenolic fraction (HTPF) is reported to have anti-disease potential, however the role of HTPF in the regulation of microRNAs (miRNAs) has never been investigated. This study was undertaken to investigate the potential of HTPF against inflammation via regulation of miRNAs in pancreatic islets of Langerhans.Methods Pancreatic islets were isolated from C57BL/6 mice and HTPF was purified from honey. Bioinformatics algorithms were used to determine miRNA target genes. Expression of miRNA and mRNA was determined using their specific taqman assays. Pairing between miRNA and 3′untranslated region (3′UTR) of mRNA was confirmed using luciferase reporter clone containing the 3′UTR of mRNA sequences and results were verified by transfection of mouse pancreatic β-cell line Min6 with miRNA inhibitors.Results The data showed that mmu-miR-26a-5p is a direct regulator of cyclooxygenase-2 (COX-2) expression and HTPF inhibits COX-2 expression or prostaglandin E2(PGE2) production via up-regulating mmu-miR-26a-5p expression. Transfection of islets with anti-miR-26a-5p significantly enhanced COX-2 expression and PGE2production (p< .01), while HTPF treatment significantly inhibited anti-miR-26a-5p transfection-induced COX-2 expression or PGE2production (p< .05). These findings were further verified in pancreatic β-cells Min6. Moreover, the data also determined that HTPF also inhibits glucose-induced nuclear transcription factor (NF)-κB activity.Conclusion HTPF suppresses glucose-induced PGE2production and activation of NF-κB via negative regulation of COX-2 and mmu-miR26a-5p. These novel pharmacological actions of HTPF on glucose-stimulated pancreatic islets provide new suggestions that HTPF or HTPF-derived compounds inhibit glucose induced inflammation in pancreas by up-regulating the expression of microRNAs.

Activation of mast cells in rheumatoid synovial tissue has often been associated with tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 production and disease pathogenesis by adjacent cell types. Butea monosperma (BM) is a well known medicinal plant in India and the tropics. The aim of this study was to examine whether a standardized extract of BM flower (BME) could inhibit inflammatory reactions in human mast cells (HMC) using activated HMC-1 cells as a model. Four previously characterized polyphenols--butrin, isobutrin, isocoreopsin, and butein--were isolated from BME by preparative thin layer chromatography, and their purity and molecular weights were determined by liquid chromatography/mass spectrometry analysis. Our results showed that butrin, isobutrin, and butein significantly reduced the phorbol 12-myristate 13-acetate and calcium ionophore A23187-induced inflammatory gene expression and production of TNF-alpha, IL-6, and IL-8 in HMC-1 cells by inhibiting the activation of NF-kappaB. In addition, isobutrin was most potent in suppressing the NF-kappaB p65 activation by inhibiting IkappaBalpha degradation, whereas butrin and butein were relatively less effective. In vitro kinase activity assay revealed that isobutrin was a potent inhibitor of IkappaB kinase complex activity. This is the first report identifying the molecular basis of the reported anti-inflammatory effects of BME and its constituents butrin, isobutrin, and butein. The novel pharmacological actions of these polyphenolic compounds indicate potential therapeutic value for the treatment of inflammatory and other diseases in which activated mast cells play a role.

The role of advanced glycation end products (AGEs)–damaged immunoglobulin G (AGE-IgG) in type 1 diabetes has been investigated in the present study. IgG was isolated from the normal humans and was subjected to in vitro glycation with glucose. The AGEs caused extensive damaged to IgG. The AGE-IgG was found to be highly immunogenic in rabbits as compared to native IgG. The binding characteristics of circulating autoantibodies in type 1 diabetes mellitus (DM) patients against native and AGE-IgG were assessed. Type 1 DM patients (n=31) were examined by ELISA and their results were compared with healthy age-matched human controls (n=22). High degree of specific binding by 61.3 % of DM sera autoantibodies towards AGE-IgG was observed, in comparison to its native analog (p< 0.05). Sera from those type 1 DM patients having smoking history, high aging with high degree of disease showed substantially stronger binding to AGE-IgG over native IgG in particular. IgG from type 1 DM patients (DM-IgG) contained higher levels of carbonyls as compared to normal human subjects (normal-IgG) (p<0.001). Collectively, the AGEs modification of IgG causes perturbations, resulting in the generation of neo-epitopes, and making it a potential immunogen. The IgG modified with AGEs may be one of the factors for the induction of circulating type 1 diabetes autoantibodies.

Introduction: Pomegranate has been revered throughout history for its medicinal properties. p38-MAPK is a major signal-transducing pathway in osteoarthritis (OA) and its activation by interleukin-1β (IL-1β) plays a critical role in the expression and production of several mediators of cartilage catabolism in OA. In this study we determined the effect of a standardized pomegranate extract (PE) on the IL-1β-induced activation of MKK3/6, p38-MAPK isoforms and the activation of transcription factor RUNX-2 in primary human OA chondrocytes. Methods: Human chondrocytes were derived from OA cartilage by enzymatic digestion, treated with PE and then stimulated with IL-1β. Gene expression of p38-MAPK isoforms was measured by RT-PCR. Western immunoblotting was used to analyze the activation of MAPKs. Immunoprecipitation was used to determine the activation of p38-MAPK isoforms. DNA binding activity of RUNX-2 was determined using a highly sensitive and specific ELISA. Pharmacological studies to elucidate the involved pathways were executed using transfection with siRNAs. Results: Human OA chondrocytes expressed p38-MAPK isoforms p38α, -γ and -δ, but not p38β. IL-1β enhances the phosphorylation of the p38α-MAPK and p38γ-MAPK isoforms but not of p38δ-MAPK isoform in human OA chondrocytes. Activation of p38-MAPK in human OA chondrocytes was preferentially mediated via activation of MKK3. In addition, we also demonstrate that polyphenol rich PE inhibited the IL-1β-induced activation of MKK3, p38α-MAPK isoform and DNA binding activity of the transcription factor RUNX-2. Conclusions: Our results provide an important insight into the molecular basis of the reported cartilage protective and arthritis inhibitory effects of pomegranate extract. These novel pharmacological actions of PE on IL-1β stimulated human OA chondrocytes impart a new suggestion that PE or PE-derived compounds may be developed as MKK and p38-MAPK inhibitors for the treatment of OA and other degenerative/inflammatory diseases.

The major risk factor for osteoarthritis (OA) is aging, but the mechanisms underlying this risk are only partly understood. Age-related accumulation of advanced glycation end products (AGEs) can activate chondrocytes and induce the production of proinflammatory cytokines and matrix metalloproteinases (MMPs). In the present study, we examined the effect of epigallocatechin-3-gallate (EGCG) on AGE-modified-BSA (AGE-BSA)-induced activation and production of TNFα and MMP-13 in human OA chondrocytes.