Inflammopharmacology最新文献

The neurobiology of Alzheimer's disease (AD) is unclear due to its multifactorial nature. Although a wide range of studies revealed several pathomechanisms of AD, dementia is yet unmanageable with current pharmacotherapies. The recent growing literature illustrates the role of microglia-mediated neuroinflammation in the pathogenesis of AD. Indeed, microglia serve as predominant sentinels of the brain, which diligently monitor the neuroimmune axis by phagocytosis and releasing soluble factors. In the case of AD, microglial cells are involved in synaptic pruning and remodeling by producing inflammatory mediators. The conditional inter-transformation of classical activation (proinflammatory) or alternative activation (anti-inflammatory) microglia is responsible for most brain disorders. In this review, we discussed the role of microglia in neuroinflammatory processes in AD following the accumulation of amyloid-β and tau proteins. We also described the prominent phenotypes of microglia, such as disease-associated microglia (DAM), dark microglia, interferon-responsive microglia (IRMs), human AD microglia (HAMs), and microglial neurodegenerative phenotype (MGnD), which are closely associated with AD incidence. Considering the key role of microglia in AD progression, microglial-based therapeutics may hold promise in mitigating cognitive deficits by addressing the neuroinflammatory responses.

Background: The neutrophil-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) are emerging inflammatory markers related to cardiovascular outcomes. This study investigated their relationships with cardiovascular disease (CVD) and mortality among individuals with prediabetes or diabetes and assessed their predictive roles.

Methods: A cohort of 6871 individuals with diabetes or prediabetes from the NHANES (2001-2018) was included. Weighted multivariate logistic regression models assessed NLR and SII associations with CVD risk, while survey-weighted Cox proportional hazards models evaluated their links to mortality. The predictive accuracy of the biomarkers for mortality was quantified by receiver-operating characteristic (ROC) curve analysis.

Results: Individuals in the higher NLR and SII groups exhibited a high incidence of CVD. A total of 1146 deaths occurred throughout an average follow-up duration of 191 months, of which 382 were caused by CVD. Participants with higher NLR markedly increased the risk of all-cause (HR = 1.82) and cardiovascular mortality (HR = 2.07). A similar result was observed in the higher SII group. RCS analysis identified a linear correlation between NLR and CVD risk and mortality (p > 0.05), while SII showed a nonlinear correlation (p < 0.05). ROC results demonstrated that NLR exhibited a higher predictive ability in mortality than SII.

Conclusions: Elevated levels of NLR and SII correlated with an increased risk of CVD and both all-cause and cardiovascular mortality in individuals with diabetes or prediabetes. The NLR appears to be particularly valuable for assessing risk and predicting outcomes in these patients.

Alzheimer's disease (AD) is a most prevalent neurologic disorder characterized by cognitive dysfunction, amyloid-β (Aβ) protein accumulation, and excessive neuroinflammation. It affects various life tasks and reduces thinking, memory, capability, reasoning and orientation ability, decision, and language. The major parts responsible for these abnormalities are the cerebral cortex, amygdala, and hippocampus. Excessive inflammatory markers release, and microglial activation affect post-synaptic neurotransmission. Various mechanisms of AD pathogenesis have been explored, but still, there is a need to debate the role of NF-κB, Nrf2, inflammatory markers, CREB signaling, etc. In this review, we have briefly discussed the signaling mechanisms and function of the NF-ĸB signaling pathway, inflammatory mediators, microglia activation, and alteration of autophagy. NF-κB inhibition is a current strategy to counter neuroinflammation and neurodegeneration in the brain of individuals with AD. In clinical trials, numbers of NF-κB modulators are being examined. Recent reports revealed that molecular and cellular pathways initiate complex pathological competencies that cause AD. Moreover, this review will provide extensive knowledge of the cAMP response element binding protein (CREB) and how these nuclear proteins affect neuronal plasticity.

Background: Previous observational studies have indicated a complex association between gut microbiota (GM) and neuropathic pain (NP). Nonetheless, the precise biological mechanisms underlying this association remain unclear. Therefore, we adopted a Mendelian randomization (MR) approach to investigate the causal relationship between GM and neuropathic pain including post-herpetic neuralgia (PHN), painful diabetic peripheral neuropathy (PDPN), and trigeminal neuralgia (TN), as well as to explore the potential mediation effects of immune cells.

Methods: We performed a two-step, two-sample Mendelian randomization study with an inverse variance-weighted (IVW) approach to investigate the causal role of GM on three major kinds of NP and the mediation effect of immune cells between the association of GM and NP. In addition, we determine the strongest causal associations using Bayesian weighted Mendelian randomization (BWMR) analysis. Furthermore, we will investigate the mediating role of immune cells through a two-step Mendelian randomization design.

Results: We identified 53 taxonomies and pathways of gut microbiota that had significant causal associations with NP. In addition, we also discovered 120 immune cells that exhibited significant causal associations with NP. According to the BWMR and two-step Mendelian randomization analysis, we identified the following results CD4 on CM CD4 + (maturation stages of T cell) mediated 6.7% of the risk reduction for PHN through the pathway of fucose degradation (FUCCAT.PWY). CD28 + DN (CD4-CD8-) AC (Treg) mediated 12.5% of the risk reduction for PHN through the influence on Roseburia inulinivorans. CD45 on lymphocyte (Myeloid cell) mediated 11.9% of the risk increase for TN through the superpathway of acetyl-CoA biosynthesis (PWY.5173). HLA DR + CD8br %T cell (TBNK) mediated 3.2% of the risk reduction for TN through the superpathway of GDP-mannose-derived O-antigen building blocks biosynthesis (PWY.7323). IgD-CD38-AC (B cell) mediated 7.5% of the risk reduction for DPN through the pathway of thiazole biosynthesis I in E. coli (PWY.6892).

Discussion: These findings provided evidence supporting the causal effect of GM with NP, with immune cells playing a mediating role. These findings may inform prevention strategies and interventions directed toward NP. Future studies should explore other plausible biological mechanisms.

Since the early 1990s, when Robert's and Szabo's cytoprotection concept had already been more than one decade old, but still not implemented in therapy, we suggest the stable gastric pentadecapeptide BPC 157 as the most relevant mediator of the cytoprotection concept. Consequently, it can translate stomach and gastrointestinal mucosal maintenance, epithelium, and endothelium cell protection to the therapy of other tissue healing (organoprotection), easily applicable, as native and stable in human gastric juice for more than 24 h. These overwhelm current clinical evidence (i.e., ulcerative colitis, phase II, no side effects, and no lethal dose (LD1) in toxicology studies), as BPC 157 therapy effectively combined various tissue healing and lesions counteraction. BPC 157 cytoprotection relevance and vascular recovery, activation of collateral pathways, membrane stabilizer, eye therapy, wound healing capability, brain-gut and gut-brain functioning, tumor cachexia counteraction, muscle, tendon, ligament, and bone disturbances counteraction, and the heart disturbances, myocardial infarction, heart failure, pulmonary hypertension, arrhythmias, and thrombosis counteraction appeared in the recent reviews. Here, as concept resolution, we review the counteraction of advanced Virchow triad circumstances by activation of the collateral rescuing pathways, depending on injury, activated azygos vein direct blood flow delivery, to counteract occlusion/occlusion-like syndromes starting with the context of alcohol-stomach lesions. Counteraction of major vessel failure (congested inferior caval vein and superior mesenteric vein, collapsed azygos vein, collapsed abdominal aorta) includes counteraction of the brain (intracerebral and intraventricular hemorrhage), heart (congestion, severe arrhythmias), lung (hemorrhage), and congestion and lesions in the liver, kidney, and gastrointestinal tract, intracranial (superior sagittal sinus), portal and caval hypertension, aortal hypotension, and thrombosis, peripherally and centrally.

Introduction: Inflammatory bowel disease (IBD), consists of two primary types: Ulcerative Colitis (UC) and Crohn's Disease (CD). Infliximab (IFX) and Adalimumab (ADA) are frequently utilized in the management of moderate to severe cases of IBD.

Aim: This study aimed to assess the efficacy and safety of IFX and ADA in individuals diagnosed with moderate to severe IBD.

Method: This study is a prospective open-labeled randomized parallel study that included moderate to severe IBD patients treated with either IFX or ADA. A total of 56 patients participated, with 34 patients received IFX and 22 patients received ADA. Various measures, including Crohn's Disease Activity Index (CDAI), Mayo Score/ Disease Activity Index (DAI), and C-reactive protein (CRP) levels, were taken at baseline and week 14 to assess the efficacy of the treatments. In addition, the levels of drugs and sTREM-1 were measured at 14 weeks. Patient safety was monitored throughout the study period.

Results: In the group received IFX, there was a notable decrease in CDAI (P = 0.045), DAI (P = 0.026), and CRP (P = 0.023 for CD, and P = 0.021 for UC) levels. In addition, the group received ADA experienced a significant reduction in CDAI (P = 0.001), DAI (P = 0.032), and CRP (P < 0.018 for CD and P = 0.003 for UC) levels. Responders had higher drug concentrations than non-responders, notably IFX concentration was higher in responders with CD (P = 0.001) and UC (P < 0.001). ADA concentration was higher in UC (P <= 0.001) and all CD patients responded to the treatment. The same trend was observed for sTREM-1 levels in CD and UC patients (P = 0.042, and P = 0.015, respectively) in the IFX group. In UC patients treated with ADA, the level of sTREM-1 was significantly low (P = 0.002).

Conclusion: Both IFX and ADA have a good safety profile and deliver a beneficial clinical and laboratory response in moderate-severe IBD patients.

Clinical trial registration: This study is registered on ClinicalTrials.gov under the identifier NCT05291039. (You can access the study at https://clinicaltrials.gov/study/NCT05291039 (First Posted: March 22, 2022).

The present study aims to investigate the anti-inflammatory potential of the leaf hydroalcoholic extract of Piper betleoides C. DC., also known as "Jangli Paan" in Northeast India, using lipopolysaccharide (LPS)-treated both cell culture (RAW264.7, macrophage cells) and animal (albino rat) model of inflammation. Treatment with leaf hydroalcoholic extract of Piper betleoides (PBtE) dose-dependently (5, 10, and 20 µg/mL) decreased the secretion of pro-inflammatory (TNF-α, IL-6, and MCP-1) and increased anti-inflammatory (IL-4 and IL-10) cytokines in LPS-treated macrophages. Similarly, treatment with PBtE also prevented the alternation in mRNA expression of inflammatory markers (TNF-α, CCL-2, IL-6, and IL-10) in LPS-treated macrophages. Dose-dependent supplementation with PBtE further reduced the production of intracellular ROS and increased the phagocytosis efficacies in LPS-treated cells. Further in vivo studies demonstrated that treatment with PBtE dose-dependently (50, 100, and 200 mg/kg body weight) prevented the dysregulation of the secretion of inflammatory cytokines (TNF-α, IL-4, IL-6, and IL-10) and reduced the circulatory levels of prostaglandin (PGE2) and nitric oxide products (nitrite) in LPS-treated animals. In addition, alternation of blood cell profiling and the liver as well as kidney dysfunctions were also prevented by the treatment with PBtE in LPS-treated rats. The anti-inflammatory potential of PBtE was comparable to those seen in sodium diclofenac (positive control) treated group. LC-MS analyses showed piperine, piperlongumine, piperolactam-A, and dehydropipernonaline and GC-MS analyses demonstrated phytol, caryophyllene, and falcarinol as the phytochemicals present in Piper betleoides, which might play an important role in preventing inflammation and associated pathophysiology. Different treatments didn't cause any toxicity in cell culture and animal models. This study for the first time demonstrated the promising anti-inflammatory potential of the leaf hydroalcoholic extract of Piper betleoides.

Fridericia chica is an Amazonian plant used to treat stomach disorders. However, the pharmacological activity of flavonoids in the extract has yet to be investigated. Therefore, we considered that a flavonoid-rich F. chica subfraction (FRS) has gastroprotective functions. For this, before the induction of gastric ulcers with ethanol or piroxicam, the rats received vehicle (water), omeprazole (30 mg/kg), or FRS (30 mg/kg), and the ulcer area was measured macro and microscopically, and the antisecretory action was investigated in pylorus-ligated rats. In addition, the roles of nitric oxide (NO) and nonprotein sulfhydryl compounds (NP-SH) in the gastroprotective effects of FRS were studied. FRS reduced ethanol- and piroxicam-induced ulcerations by 81% and 77%, respectively, as confirmed histologically. Antioxidant effects were observed for FRS through the maintenance of GSH and LPO levels, and the SOD and CAT activity similar to those found in the nonulcerated group. Moreover, FRS avoided the increase in MPO activity and TNF, IL-6, IL-4 and IL-10 levels. Moreover, mucin staining increased in ulcerated rats receiving FRS, and the pharmacological mechanism gastroprotective seems to involve the NO and NP-SH in addition to antisecretory actions. The chemical study by mass spectrometry confirmed the presence of flavonoids in FRS, and molecular docking studies have shown that these compounds interact with cyclooxygenase-1 and NO synthase. Furthermore, there was no indication that FRS had cytotoxic effects. Our results support the popular use of F. chica, and we conclude that the gastroprotection effect promoted by FRS can be attributed to the combined effect of the flavonoids.

Mammalian zinc ectopeptidases have significant functions in deactivating neurological and hormonal peptide signals on the cell surface. The identification of Opiorphin, a physiological inhibitor of zinc ectopeptidases that inactivate enkephalin, has revealed its strong analgesic effects in both chemical and mechanical pain models. Opiorphin achieves this by increasing the transmission of endogenous opioids, which are dependent on the body's own opioid system. The function of opiorphin is closely linked to the rat sialorphin peptide, which inhibits pain perception by enhancing the activity of naturally occurring enkephalinergic pathways that depend on μ- and δ-opioid receptors. Opiorphin is highly intriguing in terms of its physiological implications within the endogenous opioidergic pathways, particularly in its ability to regulate mood-related states and pain perception. Opiorphin can induce antidepressant-like effects by influencing the levels of naturally occurring enkephalin, which are released in response to specific physical and/or psychological stimuli. This effect is achieved through the modulation of delta-opioid receptor-dependent pathways. Furthermore, research has demonstrated that opiorphin's impact on the cardiovascular system is facilitated by the renin-angiotensin system (RAS), sympathetic ganglia, and adrenal medulla, rather than the opioid system. Hence, opiorphin shows great potential as a solitary candidate for the treatment of several illnesses such as neurodegeneration, pain, and mood disorders.

Background: Epilepsy ranks among the most prevalent neurological conditions worldwide. Cannabidiol (CBD) has received authorization for epilepsy treatment, yet utilizing CBD is linked to a variety of adverse events (AEs). This umbrella review aims to explore risk and frequency of AEs in epilepsy patients undergoing treatment with CBD.

Methods: International electronic databases comprising Scopus, PubMed, and Web of Science were extensively searched from the most ancient data accessible until May 2024. In line with fundamental principle of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA), this umbrella review was executed. RStudio software version 2023.03.1 along with R software 4.3.2 was used for our statistical analyses.

Results: Thirteen meta-analyses and systematic reviews were included. CBD use in epileptic patients compared to controls can be meaningfully linked with 10.87% becoming seizure-free (RD: 10.87%, 95%CI: 2.39%, 19.34%; I² = 80%). Compared to controls, a meaningful 73% increase in 50% or greater reduction in seizure frequency was observed (RR: 1.73, 95%CI: 1.47, 2.03; I² = 0%). In epileptic individuals who using CBD with the dosage of 20 mg/kg/d, a higher incidence of treatment withdrawal was detected (RR: 4.39, 95%CI: 2.46, 7.83; I² = 0%).

Conclusion: In this umbrella review of meta-analyses and systematic reviews, CBD use in epileptic patients was linked to an increased risk of ample AEs. Further research, specifically targeting various epilepsy categories, is essential to fully understand the effectiveness and potential side effects of CBD across different epilepsy forms.