In-vitro and in-vivo anti-breast cancer activity of synergistic effect of berberine and exercise through promoting the apoptosis and immunomodulatory effects

PurposeBreast cancer is the most common reason of cancer death in women. Berberine (BBR), a main alkaloid in Coptis chinensis, exerted anti-cancer activities. Exercise is a new immunotherapy treatment against cancer. However, it is unclear whether exercise has effects on breast cancer and whether exercise has synergistic anti-cancer effect when co-treated with BBR. Thus, it is assumed that exercise might exert an anti-cancer effect through the immune way.MethodThe anti-tumor effect of exercise and BBR in vivo was studied in mice. The MTT method, hoechst staining and cell morphology were performed to determine the synergistic effect of exercise and BBR on breast cancer in vitro. At the same time, Western blotting, intestinal microbial and SCFA detection, Q-PCR and other methods were used to study the anti-cancer molecular mechanism.ResultsThe study found that exercise and BBR co-treatment significantly slowed the progression of breast cancer in 4T1 tumor-bearing mice (p < 0.01). Compared with the TC group, the infiltration of NK cells increased in the combined group of BBR and exercise (p < 0.01), and the expression of immune factors and cytokines was also regulated. At the same time, the synergistic effect significantly increased the level of short chain fatty acids (SCFA). SCFA can promote apoptosis of 4T1 cells and change the inflammatory factors in vitro. The expression of bcl-2 and XIAP was reduced in tumor tissues, and the expression of Fas, Fadd, Bid, Cyto-C, and Caspase-3/8/9 was also increased in vitro experiments (p < 0.05).ConclusionsThese results indicate that the synergistic treatment of exercise and BBR can improve the immune system, regulate intestinal microbial metabolite (SCFA), activate the mitochondrial apoptosis pathway and Fas death receptor apoptosis pathway, and thus play an anticancer role. This may provide a new method for the treatment of breast cancer.     

2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione,isolated from the root of Averrhoa carambola L., protects against diabetic kidney disease by inhibiting TLR4/TGFβ signaling pathway

ObjectiveDiabetic kidney disease (DKD) is the leading cause of death and disability of diabetes mellitus. However, there is still a lack of specific drugs for the treatment of DKD. The chief aim of this research is to investigate the role and mechanism of 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) for DKD.MethodsWild type and TLR4 knockout mice were induced to diabetes. After 4-week treatment with DMDD, blood sugar, renal function, blood lipid and pathological changes were assessed. Real-time PCR, western blotting, and immunohistochemistry were employed to detect the expressions of TLR4, TGFβ1 and Smad2/3 in the renal tissue.ResultsDMDD improved the serum lipid and decreased fasting blood glucose levels in diabetic mice. CysC and urinary albumin levels increased markedly in the diabetic group, and they were obviously decreased after 4 weeks of DMDD treatment. Compared with the WT diabetic mice, the urinary albumin and CysC in the TLR4^-/- mice were expressed at lower levels. HE and Masson’s staining revealed that DMDD clearly ameliorated pathological changes and renal fibrosis. When TLR4 gene was knock out, the pathological was improved. Mechanistically, TLR4, TGF-β1 and Smad2/3 were obvious up-regulation in the renal tissues of diabetic mice. The expressions of these proteins were significantly down-regulated after DMDD treatment (p < 0.05). In the TLR4^-/- mice, mRNA and protein levels of TGF-β1 and Smad2/3 were obviously lower than those in the WT mice. In addition, IHC revealed that a strong in situ expressions of TLR4, TGF-β1 and Smad2/3 were seen in the kidney tissues of diabetic mice, which were distinctly weakened in the DMDD-treated mice. In the TLR4^-/- mice, however, expressions of TGF-β1 and Smad2/3 were not remarkable increase in the diabetic mice compared with normal mice.ConclusionsThese results strongly indicate that TLR4 is essential for DMDD protection against renal dysfunction in diabetic mice. Its hypoglycemic and anti-fibrosis effects were likely mediated by the TLR4/TGFβ signaling pathway.     

Identification of the collagen family as prognostic biomarkers and immune-associated targets in gastric cancer

BackgroundGastric cancer has extremely high morbidity and mortality. Currently, it is lack of effective biomarkers and therapeutic targets for guiding clinical treatment. In this study, we aimed to identify novel biomarkers and therapeutic targets for gastric cancer.MethodsDifferentially expressed genes (DEGs) between gastric cancer and normal tissues were obtained from Gene Expression Omnibus (GEO). Core genes were identified by constructing protein-protein interaction network of DEGs. The expression of core genes was verified in Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN and clinical samples. Further, the mutation, DNA methylation, prognostic value, and immune infiltration of core genes were validated by cBioPortal, MethSurv, Kaplan-Meier plotter, and Tumor Immune Estimation Resource (TIMER) databases. Additionally, drug response analysis was performed by Cancer Therapy Response Portal (CTRP).ResultsA total of seven collagen family members were identified as core genes among upregulated genes. And copy number amplification may be involved in the upregulation of COL1A1 and COL1A2. Importantly, the collagen family was associated with the poor prognosis of patients with metastasis. Among them, COL1A1 had a higher hazard ratio (HR) for overall survival than other members (HR = 2.33). The correlation between DNA methylation levels at CpG sites of collagen family members and the prognosis was verified in gastric cancer. Besides, collagen family expression was positively correlated with macrophages infiltration and the expression of M2 macrophages markers. Further, collagen expression was related to the sensitivity and resistance of gastric cancer cell lines to certain drugs.ConclusionsThe collagen family, especially COL1A1, COL1A2, and COL12A1, may act as potential prognostic biomarkers and immune-associated therapeutic targets in gastric cancer.     

Therapeutic monitoring of amiodarone and desethylamiodarone after surgical ablation of atrial fibrillation-evaluation of the relationship between clinical effect and the serum concentration

BackgroundAssociation between clinical effect and serum concentration of amiodarone (AMI) and its active metabolite desethylamidarone (DEA) in patients after surgical ablation (SA) of atrial fibrillation (AF) has not yet been studied.AimsWe wanted to find a correlation between AMI and DEA serum concentration and maintaining sinus rhythm (SR) after SA of AF.MethodsSixty eight patients with AF who had undergone surgical ablation between 2014 and 2017 were included in a single-centre, prospective, observational study. Maintaining of SR was evaluated by standard 12-lead ECG and 24-hour Holter ECG monitoring at months 1, 3, 6 and 12 following surgery. Therapeutic monitoring of AMI and DEA concentrations was done to optimize therapy and adverse effects were followed up.ResultsWe have noticed a high success rate in maintaining of SR (overall 83%). The median of serum concentration of AMI was 0.81 mg/L (range 0.16–2.35 mg/L) and DEA 0.70 mg/l (range 0.19–2.63 mg/L). No significant differences were found in the serum concentratration of AMI, DEA or DEA/AMI concentratration ratios between patients with SR and persistent supraventricular tachyarrhythmia except on the second outpatient visit. We observed significant correlation between serum concentration of DEA and thyroid-stimulating hormone elevation.ConclusionWe confirmed the efficacy of AMI and DEA at the measured serum concentrations. However, analysis of these concentrations alone cannot replace assessment of the clinical response for treatment. Establishment of individual AMI (and DEA) concentrations at which the optimal therapeutic response is achieved seems to be advantageous. Therapeutic monitoring of AMI and DEA is helpful in personalised pharmacotherapy after SA of AF.     

Effects of sildenafil on inflammatory injury of the lung in sodium taurocholate-induced severe acute pancreatitis rats

BackgroundInflammatory response and acute lung injury (ALI) occur in sodium taurocholate-induced severe acute pancreatitis (SAP). Because sildenafil has anti-inflammatory, anti-oxidant and immune-modulating effects, we investigated its effect on inflammatory and lung injury in sodium taurocholate-induced SAP-associated ALI rat lung.MethodsSodium taurocholate-induced SAP rats received sildenafil (100 mg/kg) or not and were compared to age-matched normal control animals. We evaluated inflammatory response by detecting the expression of inflammatory factors including IL-1β, IL-6 and TNF-α, and detected the level of lung injury through histopathological evaluation. Moreover, we also tested the protein expression of PCNA, P21, Bcl-2 and Bax in the lung.ResultsSildenafil administration rats had a low level of lung injury and inflammation. In addition, sildenafil significantly increased the expression of proliferation-related markers and decreased the expression of apoptosis-related markers in lung tissue.ConclusionsSildenafil administration may attenuate inflammation and lung injury by promoting proliferation and suppressing apoptosis in SAP rats.     

Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.     

Interacting with α7 nAChR is a new mechanism for AChE to enhance the inflammatory response in macrophages

Acetylcholine (ACh) regulates inflammation via α7 nicotinic acetylcholine receptor (α7 nAChR). Acetylcholinesterase (AChE), an enzyme hydrolyzing ACh, is expressed in immune cells suggesting non-classical function in inflammatory responses. Here, the expression of PRiMA-linked G4 AChE was identified on the surface of macrophages. In lipopolysaccharide-induced inflammatory processes, AChE was upregulated by the binding of NF-κB onto the ACHE promotor. Conversely, the overexpression of G4 AChE inhibited ACh-suppressed cytokine release and cell migration, which was in contrast to that of applied AChE inhibitors. AChEmt, a DNA construct without enzymatic activity, was adopted to identify the protein role of AChE in immune system. Overexpression of G4 AChEmt induced cell migration and inhibited ACh-suppressed cell migration. The co-localization of α7 nAChR and AChE was found in macrophages, suggesting the potential interaction of α7 nAChR and AChE. Besides, immunoprecipitation showed a close association of α7 nAChR and AChE protein in cell membrane. Hence, the novel function of AChE in macrophage by interacting with α7 nAChR was determined. Together with hydrolysis of ACh, AChE plays a direct role in the regulation of inflammatory response. As such, AChE could serve as a novel target to treat age-related diseases by anti-inflammatory responses.     

Alterations in peripheral blood B cells in systemic lupus erythematosus patients with renal insufficiency

ObjectiveSystemic lupus erythematosus (SLE) is one of the autoimmune diseases, believed to be closely related to hyperactivity of B cells, overproduction of autoantibodies and immune complex formation and deposition in affected tissue. The autoreactive inflammation leads to multiorgan damage with kidney dysfunction in the forefront. Studies on lupus nephritis (LN), affecting the majority of SLE patients, are mainly focused on cells causing local inflammation. The aim of our work was to detect alterations in more accessible peripheral blood B cells in the course of SLE focusing on the influence of renal insufficiency (RI) on those parameters.MethodsWe performed a comprehensive flow cytometry analysis of B cell subpopulations, analyzed gene expression patterns with qPCR, and examined serum cytokine levels with multiplex cytokine/chemokine assay.ResultsWe discovered distribution of specific B cell subsets, especially CD38⁺ cells, plasmablasts, associated with the presence and severity of the disease. Changes in expression of MBD2, DNMT1 and APRIL genes were not only associated with activity of SLE but also were significantly changed in patients with RI.ConclusionsAll these results shed new light on the role of circulating B cells, their subpopulations, function, and activity in the SLE with kidney manifestation.     

Influence of anti-thymocyte globulin plasma levels on outcome parameters in stem cell transplanted children

IntroductionAllogenic hematopoietic stem cell transplantation is a curative option for malignant and non-malignant pediatric diseases. Serotherapy is often employed to avoid graft-versus-host disease (GvHD) on one hand and graft rejection on the other hand. Therapeutic drug monitoring is increasingly used to allow for more precise dosing especially in pediatric patients due to their specific pharmacological characteristics. Application of T-cell directed antibodies is not routinely monitored, but may benefit from more precise dosing regimens.MethodsTwo different preparations of rabbit anti-thymocyte globulin (rATG), Thymoglobuline® and ATG-F (Grafalon®), are frequently used to prevent GvHD in pediatric patients by in vivo T-cell depletion. Total rATG levels and active rATG levels were analyzed prospectively in pediatric patients undergoing HSCT. Clinical and laboratory outcome parameters were recorded.ResultsrATG levels were measured in 32 patients, 22 received thymoglobuline and 10 received ATG-F. The median total peak plasma level was 419.0 µg/ml for ATG-F and 60.4 µg/ml for thymoglobuline. For ATG-F, exposure could be predicted from the calculated dose more precisely than for thymoglobuline. Active peak plasma levels neither of ATG-F, nor of thymoglobuline correlated significantly with the number of lymphocytes prior to serotherapy. There was no significant difference in incidence of aGvHD, cGvHD, rejection, mixed chimerism or viral infections in the two cohorts. However, in our cohort, patients with high thymoglobuline exposure showed a compromised reconstitution of T cells.ConclusionsATG-F and thymoglobuline show different pharmacological and immunological impact in children, whose clinical significance needs to be investigated in larger cohorts.     

Efficacy of clotrimazole for the management of oral candidiasis: A meta-analysis of randomized clinical trials

PurposeTo assess the efficacy and safety of topical application of clotrimazole versus others in the treatment of oropharyngeal candidiasis (OPC).MethodFour electronic databases, registries of ongoing trials, and manual search were used to identify randomized controlled trials (RCTs) that compared the efficacy of clotrimazole to other antifungal agents in patients who were clinically diagnosed with oral candidiasis up to November 1st, 2019. Primary outcomes were clinical response and mycological cure rates. Secondary outcomes include relapse rate, incidence of systemic infections, and compliance. Adverse effects were also evaluated.ResultsSixteen RCTs with a total of 1685 patients were included. Half of the eligible studies were considered at high risk of performance bias and more than a third, at high risk of reporting bias. Our analysis showed no significant difference in clinical response between clotrimazole and all other antifungal agents. However, clotrimazole was less effective in terms of mycologic cure and relapse rate. Sensitivity analysis comparing clotrimazole to other topical antifungal agents only showed no differences in clinical response, microbiologic cure or relapse. Further sensitivity analysis showed significant efficacy of fluconazole over clotrimazole.ConclusionThis meta-analysis indicated that clotrimazole is less effective than fluconazole but as effective as other topical therapies in treating OPC. Well-designed high-quality RCT is needed to validate these findings.     

BICC1 as a novel prognostic biomarker in gastric cancer correlating with immune infiltrates

AimBicC family RNA-binding protein 1 (BICC1) codes an RNA-binding protein that regulates gene expression and modulates cell proliferation and apoptosis. We aim at investigating the role of BICC1 in gastric carcinogenesis.MethodsBICC1 mRNA expression in gastric cancer (GC) was examined using the Tumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Correlations between BICC1 expression and clinicopathological parameters were analyzed. The Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier plotter databases were used to examine the clinical prognostic significance of BICC1 in GC. Signaling pathways related to BICC1 expression were identified by gene set enrichment analysis (GSEA).TIMER and CIBERSORT were used to analyze the correlations among BICC1, BICC1-coexpressed genes and tumor-infiltrating immune cells.ResultsBICC1 was highly expressed in GC and significantly correlated with grade (P = 0.002), TNM stage (P = 0.033), invasion depth (P = 0.001) and vital status (P = 0.009) of GC patients. High BICC1 expression correlated with poor overall survival. The GSEA results showed that cell adhesion-, tumor- and immune- related pathways were significantly enriched in samples with high BICC1 expression. BICC1 and its coexpressed genes were positively related to tumor-infiltrating immune cells and were strongly correlated with tumor-infiltrating macrophages (all r ≥ 0.582, P < 0.0001). The CIBERSORT database revealed that BICC1 correlated with M2 macrophages (P < 0.0001), regulatory T cells (P < 0.0001), resting mast cells (P < 0.0001), activated memory CD4+ T cells (P = 0.002), resting NK cells (P = 0.002), activated dendritic cells (P = 0.002), and follicular helper T cells (P = 0.016). The results from TIMER database confirmed that BICC1 is closely associated with the markers of M2 macrophages and tumor-associated macrophages (all r ≥ 0.5, P < 0.0001).ConclusionBICC1 may be a potential prognostic biomarker in GC and correlates with immune infiltrates.     

Amlodipine alleviates cisplatin-induced nephrotoxicity in rats through gamma-glutamyl transpeptidase (GGT) enzyme inhibition,associated with regulation of Nrf2/HO-1, MAPK/NF-κB,and Bax/Bcl-2 signaling

BackgroundThe therapeutic utility of the effective chemotherapeutic agent cisplatin is hampered by its nephrotoxic effect. We aimed from the current study to examine the possible protective effects of amlodipine through gamma-glutamyl transpeptidase (GGT) enzyme inhibition against cisplatin nephrotoxicity.MethodsAmlodipine (5 mg/kg, po) was administered to rats for 14 successive days. On the 10^th day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ip). On the last day, blood samples were collected for estimation of kidney function, while kidney samples were used for determination of GGT activity, oxidative stress, inflammatory, and apoptotic markers, along with histopathological evaluation.ResultsAmlodipine alleviated renal injury that was manifested by significantly diminished serum creatinine and blood urea nitrogen levels, compared to cisplatin group. Amlodipine inhibited GGT enzyme, which participates in the metabolism of extracellular glutathione (GSH) and platinum-GSH-conjugates to a reactive toxic thiol. Besides, amlodipine diminished mRNA expression of NADPH oxidase in the kidney, while enhanced the anti-oxidant defense by activating Nrf2/HO-1 signaling. Additionally, it showed marked anti-inflammatory response by reducing expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB), with subsequent down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, amlodipine reduced Bax/Bcl-2 ratio and elevated hepatocyte growth factor (HGF), thus favoring renal cell survival.ConclusionsEffective GGT inhibition by amlodipine associated with enhancement of anti-oxidant defense and suppression of inflammatory signaling and apoptosis support our suggestion that amlodipine could replace toxic GGT inhibitors in protection against cisplatin nephrotoxicity.     

Safety and tolerability of Empagliflozin use during the holy month of Ramadan by fasting patients with type 2 diabetes: A prospective cohort study

BackgroundType 2 Diabetes Mellitus (T2DM) patients are exposed to a 7.5 times higher risk of hypoglycemia while fasting during Ramadan. Relevant diabetes guidelines prioritize the use of SGLT2 inhibitors over other classes. There is a great need to enrich data on their safe and effective use by fasting patients at greater risk of hypoglycemia. Therefore, this study aims to assess the safety and tolerability of Empagliflozin in T2DM Muslim patients during Ramadan.MethodologyA prospective cohort study was conducted for adult Muslim T2DM patients. Patients who met the inclusion criteria were categorized into two sub-cohorts based on Empagliflozin use during Ramadan (Control versus Empagliflozin). The primary outcomes were the incidence of hypoglycemia symptoms and confirmed hypoglycemia. Other outcomes were secondary. All patients were followed up to eight weeks post-Ramadan. A propensity score (PS) matching and Risk Ratio (RR) were used to report the outcomes.ResultsAmong 1104 patients with T2DM who were screened, 220 patients were included, and Empagliflozin was given to 89 patients as an add-on to OHDs. After matching with PS (1:1 ratio), the two groups were comparable. The use of other OHDs, such as sulfonylurea, DPP4 inhibitors, and Biguanides, was not statistically different between the two groups. The risk of hypoglycemia symptoms during Ramadan was lower in patients who received Empagliflozin than in the control group (RR 0.48 CI 0.26, 0.89; p-value = 0.02). Additionally, the risk of confirmed hypoglycemia was not statistically significant between the two groups (RR 1.09 CI 0.37, 3.22; p-value = 0.89).ConclusionEmpagliflozin use during Ramadan fasting was associated with a lower risk of hypoglycemia symptoms and higher tolerability. Further randomized control trials are required to confirm these findings.     

Therapeutic effects of AdipoRon on liver inflammation and fibrosis induced by CCl4 in mice

ObjectiveThe present work aimed to investigate the effects of AdipoRon against acute hepatitis and liver fibrosis induced by carbon tetrachloride (CCl₄) in mice.MethodsC57BL/6 mice were randomly divided into five groups: control, model, AdipoRon groups (three different dosages), CCl₄ was administered to induce acute hepatitis or liver fibrosis except for control group. The liver function, inflammatory and fibrotic profiles were evaluated by histology, immunohistochemistry and expression analysis, respectively.ResultsAdipoRon pretreatment effectively attenuated oxidative stress and hepatocellular damage in acute CCl₄ intoxication, demonstrated by marked reduction in peroxidation indexes [hepatic malonaldehyde (MDA), total nitric oxide synthase (tNOS), inducible nitric oxide synthase (iNOS)] and serum transaminases [alanine aminotransferase (ALT), aspartate transaminase (AST)]. Moreover, AdipoRon attenuated the severity of fibrosis induced by sustaining CCl₄ challenge, with the alleviation of fibrous deposit and architecture distortion. The levels of canonical fibrosis markers (aminotransferases, hydroxyproline, hyaluronic acid, laminin) were also dose-dependently modulated by AdipoRon. Immunochemistry and expression analysis showed AdipoRon restrained the proinflammatory and profibrotic cytokines (TNF-α, TGF-β1, α-SMA, COL1A1), which somehow, ascribed the anti-fibrotic action to inhibiting hepatic stellate cells (HSCs) activation and quenching specific inflammation-fibrogenesis pathways.ConclusionsAdipoRon demonstrates a remedial capacity against hepatitis and fibrosis induced by CCl₄, potentially by inflammation restraint and HSC deactivation, which might pave the way for its therapeutical application in hepatic fibrosis.     

Preclinical study for the ameliorating effect of l-ascorbic acid for the oxidative stress of chronic administration of organic nitrates on myocardial tissue in high sucrose/fat rat model

BackgroundThe therapeutic activity of Glyceryl trinitrate (GTN) is mainly regulated by liberating nitric oxide (NO) and reactive nitrogen species (RNS). During this biotransformation, oxidative stress and lipid peroxidation inside the red blood cells (RBCs) occur. Hemoglobin tightly binds to NO forming methemoglobin altering the erythrocytic antioxidant defense system.AimThe principal objective of our research is to show the ameliorating effect of l-ascorbic acid for the deleterious effects of chronic administration of nitrovasodilator drugs used in cardiovascular diseases such as oxidative stresses and tolerance.MethodWe studied some biochemical parameters for the oxidative stress using groups of high sucrose/fat (HSF) diet Wistar male rats chronically orally administered different concentrations of Isosorbide-5-mononitrate (ISMN) 0.3 mg/kg, 0.6 mg/kg and 1.2 mg/kg. Afterwards, we evaluated the role of l-ascorbic acid against these biochemical changes in cardiac tissues.ResultsChronic treatment with organic nitrates caused elevated serum levels of lipid peroxidation, hemoglobin derivatives as methemoglobin and carboxyhemoglobin, rate of hemoglobin autoxidation, the cellular levels of the pro-inflammatory cytokines marker (NF-κB) and apoptosis markers (caspase-3) in the myocardium muscles in a dose-dependent manner. Meanwhile, such exposure caused a decline in the enzymatic effect of SOD, GSH and CAT accompanied by a decrease in the level of mitochondrial oxidative stress marker (nrf2) in the myocardium muscles and a decrease in the serum iron and total iron-binding capacity (TIBC) in a dose-dependent manner. Concomitant treatment with l-ascorbic acid significantly diminished these changes for all examined parameters.ConclusionChronic administration of organic nitrates leads to the alteration of the level of oxidative stress factors in the myocardium tissue due to the generation of reactive oxygen species. Using l-ascorbic acid can effectively ameliorate such intoxication to overcome nitrate tolerance.     

Efficacy of lidocaine versus mepivacaine in the management of myofascial pain

ObjectivesThere are many treatment modalities for myofascial pain, and recent findings reported in the literature highlight the superiority of using local anesthetics as the treatment of choice. The objective of the present study was to compare the effectiveness of two of the most used local anesthetic agents—lidocaine and mepivacaine—in the management of myofascial pain.Materials and methodsThirty patients (20 females, 10 males) were randomly assigned to one of two groups: 50% received lidocaine and 50% received mepivacaine. Trigger point injections in the orofacial region were administered 4 times, 10 days between each injection, with 4 weeks of follow-up after the end of the treatment course. Pain levels were recorded using a visual analog scale (VAS) at the time of follow-up and 30 min after injection.ResultsAll patients exhibited statistically significant improvement when comparing pre- and post-treatment mean values. Both local anesthetics (i.e., lidocaine and mepivacaine) were similarly effective for the management of myofascial pain (p = 0.875). The mepivacaine-treated group exhibited significantly lower post-injection tenderness than the lidocaine group (p = 0.038). There was no relationship between sex and treatment response. Female and male patients both reported similar responses in terms of VAS scores (p = 0.818).ConclusionNo drug was superior in the long term; thus, the clinician’s choice can be based on drug availability and patient medical history.     

Cardioprotective effects of sinomenine in myocardial ischemia/reperfusion injury in a rat model

BackgroundIschemia reperfusion (I/R) play an imperative role in the expansion of cardiovascular disease. Sinomenine (SM) has been exhibited to possess antioxidant, anticancer, anti-inflammatory, antiviral and anticarcinogenic properties. The aim of the study was scrutinized the cardioprotective effect of SM against I/R injury in rat.MethodsRat were randomly divided into normal control (NC), I/R control and I/R + SM (5, 10 and 20 mg/kg), respectively. Ventricular arrhythmias, body weight and heart weight were estimated. Antioxidant, inflammatory cytokines, inflammatory mediators and plasmin system indicator were accessed.ResultsPre-treated SM group rats exhibited the reduction in the duration and incidence of ventricular fibrillation, ventricular ectopic beat (VEB) and ventricular tachycardia along with suppression of arrhythmia score during the ischemia (30 and 120 min). SM treated rats significantly (P < 0.001) altered the level of antioxidant parameters. SM treatment significantly (P < 0.001) repressed the level of creatine kinase MB (CK-MB), creatine kinase (CK) and troponin I (Tnl). SM treated rats significantly (P < 0.001) repressed the tissue factor (TF), thromboxane B2 (TXB2), plasminogen activator inhibitor 1 (PAI-1) and plasma fibrinogen (Fbg) and inflammatory cytokines and inflammatory mediators.ConclusionOur result clearly indicated that SM plays anti-arrhythmia effect in I/R injury in the rats via alteration of oxidative stress and inflammatory reaction.