Beneficial Effects Research Articles

A Novel One-Pot Three-Component Approach to Orthoaminocarbonitrile Tetrahydronaphthalenes Using Triethylamine (Et_3N) as a Highly Efficient and Homogeneous Catalyst Under Mild Conditions and Investigating Its Anti-cancer Properties Through Molecular Docking Studies and Calculations

An efficient and environmentally friendly method for the one-pot synthesis of ortho-aminocarbonitrile tetrahydronaphthalenes has been developed in the presence of triethylamine (Et3N) as a homogeneous catalyst. The multicomponent reactions of benzaldehydes, cyclohexanone and malononitrile were carried out under mild conditions to obtain some ortho-aminocarbonitrile tetrahydronaphthalene derivatives. A broad range of structurally diverse benzaldehydes were applied successfully, and corresponding products (4A-L) were obtained in good to excellent yields (87-98%) in very short times (10-25 minutes). The present approach provides several advantages including simple workup, high yields, very mild reaction conditions, short reaction times, little catalyst loading and not requiring specialized equipment. Furthermore, with the help of computational chemistry and drug design methods, the anti-cancer properties of these compounds were studied and investigated. All the synthesized compounds bind to an agonist at the active site of the 3A8P protein, which leads to the inactivation of this protein and produces beneficial effects during cancer treatment. In synthesized compounds, the ligands establish hydrogen bonds with leucine A:728 residues through nitrogen, which has a very special and vital role in biological sciences and pharmaceutical connections. In this study, it was found that these compounds have the potential to become an oral anti-cancer drug.

Knowledge and Consumption Practice of Energy Drinks among Medical University Students in Mosul, Iraq

Objective: Energy drinks are gaining popularity, and their consumption is associated with adverse effects. This study aims to explore the level of knowledge regarding energy drinks among medical students and the practices of those students who consume these products. Methods: A cross-sectional, questionnaire-based study design was adopted for this work. The survey was distributed among students of medical colleges at the University of Mosul to assess their knowledge and practices regarding energy drinks. Results: A total of 1298 students participated in the study, with 60% being females. Most of the students (89%) knew what energy drinks are, but only 42% knew their ingredients. Almost all the students (95%) were aware that energy drinks have adverse effects, but only a few knew about any beneficial effects these products might have. Only 30% of the participants admitted to consuming energy drinks, with more than half of those students drinking less than five cans monthly. Sugar-containing products were more favored than sugar-free ones, and Tiger™ was the most preferred brand of energy drinks among students. Forty-one percent of the energy drink-consuming students reported experiencing side effects. The knowledge of the side effects of energy drinks was the most commonly reported reason for not consuming these beverages. Older male students in their last two years of study and those living within the city were found to be more knowledgeable about energy drinks. Conclusions: The level of knowledge regarding energy drinks was low, which should be a cause for concern, especially given the increasing popularity of energy drinks and the marketing campaigns targeting youth.

Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons.

Alzheimer's disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. To investigate the potential therapeutic benefit of sildenafil on AD. We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil's mechanism-of-action. We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32- 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49- 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.

Flavonoids from Liriodendron chinense Leaves Alleviate Oxidative Activity in Vitro and D-galactose-induced Brain Injury via AMPK/SIRT1 Pathway in Vivo

The exploration of active ingredients and new activities of industrial crops could expand their scope of applications. Liriodendron chinense (L. chinense), an important ornamental and economic forest tree in China, has been widely used in timber, medicine and landscape. Flavonoids are major constituents of L. chinense leaves, while their effects of preventing brain damage are still unclear. In this study, flavonoids from L. chinense leaves (LCLF) were obtained through AB-8 resin chromatography and UPLC-MS/MS assay indicated that 16 compounds were identified from LCLF. LCLF treatment showed significant scavenging activities against DPPH•, ABTS•+, •OH, FRAP and total reducing power. D-galactose-impaired exploratory behaviors, cognitive functions and histopathological alterations in hippocampus of mice were obviously recovered by LCLF administration. Network pharmacology results demonstrated that LCLF could produce the healing efficacy through multiple pathways, mostly related to oxidative stress and inflammation. Further in vivo experiments revealed that LCLF treatment could regulated MDA content, SOD, CAT and GSH-Px activity, as well as the production of inflammatory factors (NO, IL-1β and IL-6). The underlying mechanisms of LCLF were probably related to Nrf2/HO-1, NF-κB and AMPK/SIRT1 pathways. Molecular docking results and surface plasmon resonance analysis validated that especially hesperidin in LCLF had strong binding activities with all 8 genes in the mentioned pathways. Our study revealed the beneficial effects of LCLF on oxidative activity and D-galactose-induced brain injury, offering experimental support for its potential application in pharmaceutical and other industries.

Vaccines and Dementia: Part I. Non-Specific Immune Boosting with BCG: History, Ligands, and Receptors.

Vaccines such as Bacille Calmette-Guérin (BCG) can apparently defer dementia onset with an efficacy better than all drugs known to date, as initially reported by Gofrit et al. (PLoS One14, e0224433), now confirmed by other studies. Understanding how and why is of immense importance because it could represent a sea-change in how we manage patients with mild cognitive impairment through to dementia. Given that infection and/or inflammation are likely to contribute to the development of dementias such as Alzheimer's disease (Part II of this work), we provide a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents. We review early studies in which poxvirus, herpes virus, and tuberculosis (TB) infections afford cross-protection against unrelated pathogens, a concept known as 'trained immunity'. We then focus on the attenuated TB vaccine, BCG, that was introduced to protect against the causative agent of TB, Mycobacterium tuberculosis. We trace the development of BCG in the 1920 s through to the discovery, by Freund and McDermott in the 1940 s, that extracts of mycobacteria can themselves exert potent immunostimulating (adjuvant) activity; Freund's complete adjuvant based on mycobacteria remains the most potent immunopotentiator reported to date. We then discuss whether the beneficial effects of BCG require long-term persistence of live bacteria, before focusing on the specific mycobacterial molecules, notably muramyl dipeptides, that mediate immunopotentiation, as well as the receptors involved. Part II addresses evidence that immunopotentiation by BCG and other vaccines can protect against dementia development.

Electrophysiological Mechanisms of Memory Consolidation in Human Non-rapid Eye Movement Sleep

Abstract Purpose of Review Pioneering work in rodents has shown that the reactivation of recently acquired memories during sleep is a key mechanism underlying the beneficial effect of sleep on memory consolidation. In this review, we consider recent evidence of memory reactivation processes in human sleep. Recent Findings The precise temporal coupling of sleep spindles to slow oscillations during non-rapid eye movement sleep plays a central role in sleep-associated memory consolidation. Both correlational studies and studies directly manipulating oscillatory activity in the sleeping brain have confirmed that spindles coupled to slow oscillations are better predictors of memory than uncoupled spindles and that the greatest memory benefit comes when spindles are tightly coupled to the up-state of the slow oscillation. Recent evidence suggests that memory content is reactivated during sleep, with a functional benefit for memory performance after sleep. Reactivation events are time-locked around slow oscillation-spindle coupling events, as well as sharp-wave ripples in hippocampus. Summary Memory reactivation, which is facilitated by slow oscillation-spindle coupling events, can be observed during human sleep and shows promise as a prime mechanism underlying sleep’s beneficial effects on memory.

O72: Machine perfusion in deceased-donor kidney transplantation: Cochrane review and meta-analysis

Abstract Background Several novel machine perfusion technologies have been developed which aim to improve kidney transplant outcomes compared with ice-box static cold storage (SCS). These machine perfusion technologies can be applied “continuous” from donor centre, or only at the recipient centre (“end-ischaemic”). We aimed to compare machine perfusion technologies with each other and with SCS. Methods We searched the Cochrane Kidney and Transplant Register of Studies to 20 June 2023. Two independent authors screened articles and extracted data. Pairwise random-effects meta-analysis was performed, with additional indirect comparisons performed. Main results 22 studies (4007 participants) were included. “Continuous” non-oxygenated hypothermic machine perfusion (HMP) versus SCS improves graft-survival (follow-up=1-10 years, HR=0.55, 95% confidence interval=0.40-0.77, P=0.0005, GRADE: high-certainty evidence), reduces delayed graft function (RR 0.78, 0.64-0.96, P=0.02; high-certainty evidence) and is cost-saving. Beneficial effects persist when cold ischaemic times were short, but were only seen when HMP was “continuous”; End-ischaemic oxygenated HMP (median 4.6hours) does not improve outcomes. Addition of oxygen to continuous HMP further improves graft-survival in DCD donors. End-ischaemic normothermic machine perfusion (NMP) does not improve outcomes versus SCS; indirect comparison revealed that continuous non-oxygenated HMP was associated with improved graft survival compared with end-ischaemic NMP (HR=0.31, 0.11-0.92, P=0.03). Conclusions Continuous HMP (initiated in donor hospital) is superior to SCS in deceased-donor kidney transplantation. Timing of HMP is important, and benefits have not been demonstrated with end-ischaemic HMP. Whilst end-ischaemic NMP is inferior to continuous HMP on indirect comparisons, further studies assessing NMP for viability assessment and therapeutic delivery are in progress.

Effect of Gracilaria vermiculophylla Macroalga on Non-Alcoholic Fatty Liver Disease in Obese Rats.

Marine algae are valuable sources of bioactive compounds that have the potential to be used in the management of various pathologies. Despite the increasing prevalence of NAFLD, the absence of an approved effective pharmacological treatment with demonstrable effectiveness persists. In this context, the aim of the present study is to assess the effect of Gracilaria vermiculophylla red seaweed dietary supplementation on hepatic lipid accumulation, as well as on oxidative stress, inflammation and fibrosis- related markers on obese fa/fa Zucker rats fed with a standard diet, supplemented or not with 2.5% or 5% dehydrated Gracilaria vermiculophylla. After a six-week supplementation with the macroalga, no significant reduction in hepatic total lipid content or hepatic triglyceride content was observed. However, both doses were able to diminish hepatic NEFA concentration by reducing de novo lipogenesis and increasing mitochondrial biogenesis. Moreover, supplementation with the dose of 2.5% improved some oxidative stress and inflammation-related markers. Supplementation with the dose of 5% did not exert these clear beneficial effects. Thus, this study demonstrates that while Gracilaria vermiculophylla may not mitigate hepatic steatosis, it could exert protective effects on the liver by reducing NEFA content and enhancing oxidative stress and inflammation parameters.

Immunomodulatory and Anti-Inflammatory Effects of Vitamin A and Tryptophan on Monocyte-Derived Dendritic Cells Stimulated with Gliadin in Celiac Disease Patients.

Celiac Disease (CeD) is an autoimmune disorder with various symptoms upon gluten exposure. Dendritic cells (DCs) play a crucial role in gliadin-induced inflammation. Vitamin A (retinol; Ret) and its metabolite, retinoic acid (RA), along with tryptophan (Trp) and its metabolite, kynurenic acid (KYNA), are known to influence the immune function of DCs and enhance their tolerogenicity. This research aims to assess the impact of gliadin on DC maturation and the potential of vitamin A and tryptophan to induce immune tolerance in DCs. The monocyte cells obtained from peripheral blood mononuclear cells (PBMCs) of celiac disease patients were differentiated into DCs in the absence or presence of Ret, RA, Trp, KYNA, and then stimulated with peptic and tryptic (PT) digested of gliadin. We used flow cytometry to analyze CD11c, CD14, HLA-DR, CD83, CD86, and CD103 expression. ELISA was carried out to measure TGF-β, IL-10, IL-12, and TNF-α levels. qRT-PCR was used to assess the mRNA expression of retinaldehyde dehydrogenase 2 (RALDH2) and integrin αE (CD103). The mRNA and protein levels of Indoleamine 2, 3-dioxygenase (IDO) was analyzed by qRT-PCR and Western blot assays, respectively. Our findings demonstrate that PT-gliadin enhances the expression of maturation markers, i.e. CD83, CD86 and HLA-DR and promote the secretion of TNF-α and IL-12 in DCs. Interestingly, vitamin A, tryptophan, and their metabolites increase the expression of CD103, while limiting the expression of HLA-DR, CD83, and CD86. They also enhance RALDH2 and IDO expression and promote the secretion of TGF-β and IL-10, while limiting IL-12 and TNF-α secretion. These findings suggest that vitamin A and tryptophan have beneficial effects on PT-gliadin-stimulated DCs, highlighting their potential as therapeutic agents for celiac disease. However, further research is needed to fully understand their underlying mechanisms of action in these cells.

Beneficial effect and functional alteration of food proteins in the manufacturing process

Beneficial effect and functional alteration of food proteins in the manufacturing process

Gut microbiota-derived gamma-aminobutyric acid from metformin treatment reduces hepatic ischemia/reperfusion injury through inhibiting ferroptosis.

Hepatic ischemia/reperfusion injury (HIRI) is a common and inevitable factor leading to poor prognosis in various liver diseases, making the outcomes of current treatments in clinic unsatisfactory. Metformin has been demonstrated to be beneficial to alleviate HIRI in recent studies, however, the underpinning mechanism remains unclear. In this study, we found metformin mitigates HIRI-induced ferroptosis through reshaped gut microbiota in mice, which was confirmed by the results of fecal microbiota transplantation treatment but showed the elimination of the beneficial effects when gut bacteria were depleted using antibiotics. Detailedly, through 16S rRNA and metagenomic sequencing, we identified that the metformin-reshaped microbiota was characterized by the increase of gamma-aminobutyric acid (GABA) producing bacteria. This increase was further confirmed by the elevation of GABA synthesis key enzymes, glutamic acid decarboxylase and putrescine aminotransferase, in gut microbes of metformin-treated mice and healthy volunteers. Furthermore, the benefit of GABA against HIRI-induced ferroptosis was demonstrated in GABA-treated mice. Collectively, our data indicate that metformin can mitigate HIRI-induced ferroptosis by reshaped gut microbiota, with GABA identified as a key metabolite.

A Systematic Review of Health-Related Quality of Life in Women with HER2-Positive Metastatic Breast Cancer Treated with Trastuzumab.

Many trials of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer treatment with trastuzumab have provided evidence of improved clinical outcomes. This systematic review examined how a regimen that includes trastuzumab affects patients' health-related quality of life (HRQoL) during and after treatment. A systematic search for articles published up to February 2023 without restrictions of language or publication year was performed using the Pubmed, Embase, and Scopus databases. We included studies of women aged >18 years with metastatic HER2-positive breast cancer treated with a trastuzumab-containing regimen. We assessed the quality of the studies using the Cochrane Risk of Bias (RoB) tool (2.0) for randomized controlled trials (RCTs) and the Risk Of Bias In Non-randomised Studies-of Interventions (ROBINS-I) tool for cross-sectional studies. We used Microsoft Excel to extract and synthesize data, and documented the review procedure following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In total, eight studies compared 1104 trastuzumab-treated patients and 1003 non-trastuzumab-treated patients. Most studies were RCTs (n=7) and one was a prospective observational study. All the included studies used the EORTC-QLQ-C30, EORTC-QLQ-BR23, FACT-B, or FACT-G questionnaires. During treatment, patients taking regimens that included trastuzumab showed clinical improvement in HRQoL, social functioning, and role functioning. After the treatment, patients' HRQoL profiles in the trastuzumab and chemotherapy arms were similar. However, trastuzumab (versus chemotherapy) treatment led to clinically improved functional status, role and physical functioning, and fatigue. The quality assessment revealed some concerns in most RCTs, with the risk of bias being high in two studies, low in one study, and moderate in the cross-sectional study. Trastuzumab-containing regimens administered to HER2-positive breast cancer patients at the metastatic stage evidenced beneficial effects on total HRQoL during and after treatment. Upon therapy cessation, patients' HRQoL scores for both interventions improved. Nevertheless, HRQoL profiles of patients treated with trastuzumab were more favorable, particularly for functional status, role functioning, physical well-being, and fatigue. This review was registered in PROSPERO (registration number: CRD42021259826).

A Traditional Review: The Utilization of Nutraceutical as a Traditional Cure for the Modern World at Current Prospectus for Multiple Health Conditions

Nutraceuticals refer to food products that have a positive impact on the well-being of individuals. This category includes dietary supplements, herbal products, probiotics, and prebiotics, as well as medical foods designed for disease prevention and treatment. The nutraceutical market is witnessing substantial growth worldwide, primarily due to the growing awareness among consumers about the connection between diet and health. Additionally, there is a rising demand for functional foods and dietary supplements. As consumers prioritize preventive healthcare, they are increasingly looking for products that provide targeted health benefits beyond basic nutrition. The rise of this trend can be attributed to various factors, including the aging population, rising healthcare expenses, and a preference for natural and organic ingredients. Nutraceuticals, as a major force in the industry, offer numerous beneficial effects with minimal undesirable impacts, thus attracting more consumer interest. The increasing shift towards preventive treatments, along with the growth in disposable income and a positive market outlook for the pharmaceutical sector, has primarily contributed to the expanding nutraceutical market in India. However, challenges such as the lack of regulation and awareness, high pricing, marketing, and distribution issues need to be addressed. Nutraceutical market is seeing flowing development chiefly in United States, India, and European nations. This review article primarily focuses on providing a concise overview of nutraceuticals, categorizing them, and discussing their significant roles in various health conditions. Additionally, it delves into the present and future status of nutraceuticals on a global scale.
 Keywords: traditional cure; nutraceuticals; remedy; prebiotics; probiotics; regulatory compliance; supplementary diets; nutraceutical ingredients.

Smartphone use and its association with body image distortion and weight loss behaviours among adolescents in Saudi Arabia.

Concerns about the harmful effects of smartphone use on teenage development have been raised as the use of cell phones among adolescents has risen. This study aimed to examine the associations of smartphone usage patterns with Body Image Distortion (BID) and weight loss behaviors among adolescent smartphone users in Saudi Arabia. This population-based, cross-sectional study was conducted from July to October 2022. We assessed the mean daily length of smartphone use and classified it into quartiles using data from a self-reported survey and data on weekday and weekend use. Self-reported body weight and height were collected via an online survey. Out of the 11384 adolescents, the majority was females (65.7%) and was secondary school students (68.9%). The prolonged smartphone use (301 min/d) was found in 36.4% of adolescents, 181-300 min/d in 27.6% of respondents, 121-180 min/d in 22.4% of respondents, while the modest smartphone use (1-120 min/d) was found only in 13.6% of participants. The duration of smartphone use was significantly associated with BID (P= 0.000); students with middle perceived stress levels (51.4%) and no depressive symptoms (68.9%) used smartphones 121-180 min/d sparingly. However, prolonged smartphone use was significantly associated with the presence of depressive symptoms (42.6%) and high perceived stress levels (21.5%). Weight loss behaviors were significantly associated with smartphone use duration. Modest smartphone use was significantly found in students with normal weight (P= 0.00, 71.9%); however, aerobic physical activity weight loss strategy (P= 0.00, 30.9%) was correlated with prolonged smartphone use. Adequate parental advice is required to assist teenagers in developing healthy smartphone usage practices. Digital platform companies may increase their social responsibility for the information generated and delivered on their networks, boosting its beneficial effect.

Nonspecific Effects of the Bacillus Calmette-Guérin Vaccine in Portuguese Children Under 5 Years of Age: Protocol for a Population-Based Historical Birth Cohort Study.

The Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis (TB) shows beneficial nonspecific effects, which are likely related to innate immune training. Until 2016, a single BCG dose was administered to all newborns in Portugal. In July 2016, a clinical guideline established that only children under 6 years belonging to high-risk groups should receive BCG. This might have prevented nonvaccinated children from developing trained immunological responses as effectively as BCG-vaccinated children. This study aims to investigate if there is variation in TB-related and all-cause mortality, and severe, moderate, or mild morbidity in children under 5 years of age, and whether such variation might be explained by the BCG vaccination policy change in 2016. This population-based historical birth cohort study includes children under 5 years of age born in Portugal between July 1, 2010, and June 30, 2021. Newborns with low birth weight, premature status, or known or suspected HIV infection are excluded. The follow-up period is until the completion of 5 years of age or the end of follow-up (June 30, 2021). The study will use secondary data from the National Health Service user registry, death certificate database, vaccination registry, communicable diseases surveillance system, TB surveillance system, diagnosis-related group information system for hospital admissions and emergency department visits, and primary health care information system. The data will be linked. Primary outcomes include person-time incidence rates of death (all causes and TB), TB diagnosis, and all causes and some specific causes of severe, moderate, or mild morbidity, and the incidence rate ratio of nonvaccinated to BCG-vaccinated children. We will compare the probability of surviving the first and fifth years of life or of not having severe, moderate, or mild morbidity during the follow-up period according to exposure (BCG vaccinated or nonvaccinated, number of doses, and time from birth until the first dose), using the log-rank test for assessing differences in survival rates between exposed and nonexposed children and hazard ratios for quantifying the differences. Moreover, we will perform a proportional hazards regression analysis. Ethics approval has been obtained. In March 2022, database owners were contacted to present the project and discuss the request for data. A unique identifier will be used. In July 2023, a process of redefinition of the variables per database was initiated. Data were received in October and November 2023. In November 2023, further work was conducted. By April 2024, we expect to start analyzing the full data set. The results will contribute to the accumulating body of knowledge and might have relevance to guide global BCG vaccination policy. Data linkage can contribute to a swifter mechanism to use available health data to conduct population-based studies and inform policy decision-making. ClinicalTrials.gov NCT05471167; https://clinicaltrials.gov/study/NCT05471167. DERR1-10.2196/55332.

Postbiotic butyrate: role and its effects for being a potential drug and biomarker to pancreatic cancer.

Postbiotics are produced by microbes and have recently gained importance in the field of oncology due to their beneficial effects to the host, effectiveness against cancer cells, and their ability to suppress inflammation. In particular, butyrate dominates over all other postbiotics both in quantity and anticancer properties. Pancreatic cancer (PC), being one of the most malignant and lethal cancers, reported a decreased 5-year survival rate in less than 10% of the patients. PC causes an increased mortality rate due to its inability to be detected at an early stage but still a promising strategy for its diagnosis has not been achieved yet. It is necessary to diagnose Pancreatic cancer before the metastatic progression stage. The available blood biomarkers lack accurate and proficient diagnostic results. Postbiotic butyrate is produced by gut microbiota such as Rhuminococcus and Faecalibacterium it is involved in cell signalling pathways, autophagy, and cell cycle regulation, and reduction in butyrate concentration is associated with the occurrence of pancreatic cancer. The postbiotic butyrate is a potential biomarker that could detect PC at an early stage, before the metastatic progression stage. Thus, this review focused on the gut microbiota butyrate's role in pancreatic cancer and the immuno-suppressive environment, its effects on histone deacetylase and other immune cells, microbes in major butyrate synthesis pathways, current biomarkers in use for Pancreatic Cancer.

Pregnane X Receptor Activation in Liver Macrophages Protects against Endotoxin-Induced Liver Injury.

Endotoxemia-related acute liver injury has a poor prognosis and high mortality, and macrophage polarization plays a central role in the pathological process. Pregnane X receptor (PXR) serves as a nuclear receptor and xenosensor, safeguarding the liver from toxic stimuli. However, the effect and underlying mechanism of PXR activation on endotoxemic liver injury remain largely unknown. Here, the expression of PXR is reported in human and murine macrophages, and PXR activation modified immunotypes of macrophages. Moreover, PXR activation significantly attenuated endotoxemic liver injury and promoted macrophage M2 polarization. Macrophage depletion by GdCl3 confirmed the essential of macrophages in the beneficial effects observed with PXR activation. The role of PXR in macrophages is further validated using AAV8-F4/80-Pxr shRNA-treated mice; the PXR-mediated hepatoprotection is impaired, and M2 polarization enhancement is blunted. Additionally, treatment with PXR agonists inhibited lipopolysaccharide (LPS)-induced M1 polarization and favored M2 polarization in BMDM, Raw264.7, and THP-1 cells. Further analyses revealed an interaction between PXR and p-STAT6 in vivo and in vitro. Moreover, blocking Pxr or Stat6 abolished the PXR-induced polarization shift. Collectively, macrophage PXR activation attenuated endotoxin-induced liver injury and regulated macrophage polarization through the STAT6 signaling pathway, which provided a potential therapeutic target for managing endotoxemic liver injury.

Alleviating Severe Cytoskeletal Destruction of Spinal Motor Neurons: Another Effect of Docosahexaenoic Acid in Spinal Cord Injury.

Spinal cord injury (SCI) treatment remains a major challenge. Spinal motor neurons (MNs) are seriously injured in the early stage after SCI, but this has not received sufficient attention. Oxidative stress is known to play a crucial role in SCI pathology. Our studies demonstrated that oxidative stress can cause severe damage to the cytoskeleton of spinal MNs. Docosahexaenoic acid (DHA) has been shown to have beneficial effects on SCI, but the mechanism remains unclear, and no study has investigated the effect of DHA on oxidative stress-induced spinal MN injury. Here, we investigated the effect of DHA on spinal MN injury through in vivo and in vitro experiments, focusing on the cytoskeleton. We found that DHA not only promoted spinal MN survival but, more importantly, alleviated the severe cytoskeletal destruction of these neurons induced by oxidative stress in vitro and in mice with SCI in vivo. In addition, the mechanisms involved were investigated and elucidated. These results not only suggested a beneficial role of DHA in spinal MN cytoskeletal destruction caused by oxidative stress and SCI but also indicated the important role of the spinal MN cytoskeleton in the recovery of motor function after SCI. Our study provides new insights for the formulation of SCI treatment.

Effect of laparoscopic sleeve gastrectomy on male reproductive function in chinese men with obesity: A prospective cohort study.

Obesity is a widely recognized global public health issue, and bariatric surgery has emerged as an effective intervention for alleviating obesity associated health complications. However, the impact of bariatric surgery on male reproductive function remains inconclusive in the literature. The current understanding of the impact of laparoscopic sleeve gastrectomy on male reproductive function remains ambiguous, despite its status as the most commonly performed bariatric surgery. This prospective cohort study aimed to investigate the impact of laparoscopic sleeve gastrectomy on erectile function and semen quality. A total of thirty-four obese patients were enrolled in this study and underwent laparoscopic sleeve gastrectomy (LSG). Prior to the operation and at 3, 6, and 12 months postoperation, all participants were required to complete the International Index of Erectile Function-5 (IIEF-5) questionnaire and undergo a nocturnal erectile function test and semen quality analysis. Within 12 months postoperation, body mass index, blood lipids, and insulin resistance showed significant improvement. The IIEF-5 score increased significantly (18.88±5.97 vs. 23.78±3.19, P < 0.05), and the frequency and duration of erections significantly improved compared to baseline. Sperm concentration, total motility, survival rate, and sperm morphology parameters exhibited a significant decline at 3 months but demonstrated a significant improvement at 6 and 12 months post-operation. At 12 months, sperm concentration was shown to be correlated with changes in zinc (r = 0.25, P = 0.033) as well as changes in testosterone (r = 0.43, P = 0.013). LSG has beneficial effects on erectile function, despite a transient decline in semen quality at 3 months postoperatively, followed by a significant improvement at 12 months.

Animal studies on glucagon-like peptide-1 receptor agonists and related polyagonists in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic liver disease closely associated with the epidemics of obesity and type 2 diabetes mellitus (T2DM), but without licensed pharmacological treatment to date. As glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved anti-diabetic and anti-obesity medications, they were also considered a potential therapeutic option for NAFLD. Preclinical studies suggest that GLP-1RAs have a beneficial effect on major NAFLD histological outcomes, i.e., hepatic steatosis and inflammation, through multiple intrahepatic mechanisms, including increased fatty acid β-oxidation, activation of autophagy, suppression of inflammation, and oxidative stress. Data on hepatic fibrosis are limited or inconclusive, although some studies reported improvement in indices of fibrosis or prevention of fibrosis initiation or reduction of collagen deposition. Whether the positive impact of GLP-1RAs on hepatic histology is indirect, i.e., through their action on extrahepatic tissues, or whether their action is direct, i.e., through activating GLP-1R on the hepatocytes, is still a controversial issue. Alongside GLP-1RAs, newly emerging peptide polyagonists (i.e., synthetic molecules that combine the amino acid sequences of more than one peptide, thus having the ability to bind more than one receptor) are now being investigated in NAFLD with high expectations. This review summarizes the existing knowledge derived from animal studies on the effects of GLP-1RAs and GLP-1RA related peptide polyagonists on NAFLD in an attempt to illuminate areas of uncertainty and provide the groundwork for future animal and clinical research in the field.