Protective Effect Research Articles

Inhibition of NLRP3 inflammasome by MCC950 under hypoxia alleviates photoreceptor apoptosis via inducing autophagy in Müller glia.

NLRP3 inflammasome activation has emerged as a critical initiator of inflammatory response in ischemic retinopathy. Here, we identified the effect of a potent, selective NLRP3 inhibitor, MCC950, on autophagy and apoptosis under hypoxia. Neonatal mice were exposed to hyperoxia for 5 days to establish oxygen-induced retinopathy (OIR) model. Intravitreal injection of MCC950 was given, and then autophagy and apoptosis markers were assessed. Retinal autophagy, apoptosis, and related pathways were evaluated by western blot, immunofluorescent labeling, transmission electron microscopy, and TUNEL assay. Autophagic activity in Müller glia after NLRP3 inflammasome inhibition, together with its influence on photoreceptor death, was studied using western blot, immunofluorescence staining, mRFP-GFP-LC3 adenovirus transfection, cell viability, proliferation, and apoptosis assays. Results showed that activation of NLRP3 inflammasome in Müller glia was detected in OIR model. MCC950 could improve impaired retinal autophagic flux and attenuate retinal apoptosis while it regulated the retinal AMPK/mTOR/ULK-1 pathway. Suppressed autophagy and depressed proliferation capacity resulting from hypoxia was promoted after MCC950 treatment in Müller glia. Inhibition of AMPK and ULK-1 pathway significantly interfered with the MCC950-induced autophagy activity, indicating MCC950 positively modulated autophagy through AMPK/mTOR/ULK-1 pathway in Müller cells. Furthermore, blockage of autophagy in Müller glia significantly induced apoptosis in the cocultured 661W photoreceptor cells, whereas MCC950 markedly preserved the density of photoreceptor cells. These findings substantiated the therapeutic potential of MCC950 against impaired autophagy and subsequent apoptosis under hypoxia. Such protective effect might involve the modulation of AMPK/mTOR/ULK-1 pathway. Targeting NLRP3 inflammasome in Müller glia could be beneficial for photoreceptor survival under hypoxic conditions.

Complanatuside A ameliorates 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice by regulating the Th17/Treg balance via the JAK2/STAT3 signaling pathway.

Immunity imbalance of T helper 17 (Th17)/regulatory T (Treg) cells is involved in the pathogenesis of Crohn's disease (CD). Complanatuside A (CA), a flavonol glycoside, exerts anti-inflammatory activities and our study aimed to identify its effect on TNBS-induced colitis and the possible mechanisms. We found that CA alleviated the symptoms of colitis in TNBS mice, as demonstrated by prevented weight loss and colon length shortening, as well as decreased disease activity index scores, inflammatory scores, and levels of proinflammatory factors. Flow cytometry analysis showed that CA markedly reduced the percentage of Th17 cells while increasing the percentage of Treg cells in TNBS mice. Under Th17 cell polarizing conditions, CA inhibited the differentiation of Th17 cells while the Treg cell differentiation was elevated under Treg cell polarizing conditions. Furthermore, it was observed that JAK2 interacted with CA through six hydrogen bonds via molecular docking. The phosphorylation of JAK2/STAT3 was reduced by CA, which might be correlated with the protective effect of CA on colitis. In conclusion, CA reduced the imbalance of Th17/Treg cells by inhibiting the JAK2/STAT3 signaling pathway in TNBS-induced colitis, which may provide novel strategies for CD treatment.

GEOGRAPHICAL DESCRIPTION AND PHARMACOLOGICAL PROPERTIES OF DICHANTHIUM ANNULATUM: A REVIEW

Dichanthium annulatum herb belongs to Poaceae family; also referred to as marvel grass. It grows to a height of about 25cm. Due to its straightforward and affordable development from seed, it is used as forage. The present review was based on the geographical description and pharmacological properties of dichanthium annulatum. It is indigenous to regions of Africa, the Middle East, and tropical Asia. It has been brought to many different regions of the world for cultivation, and in some, like Australia, it has established itself as a native species. This pasture grass is well-liked in various regions. It can be harvested for hay and silage and used in fields to graze livestock. It can grow in a wide range of soil types, including those with a lot of clay and sand, poor drainage, and a little saline and alkaline soil. It creates turf that can withstand pressure from grazing animals. It can bounce back from fire and drought, but it can't stand frost and shade as well. Although it doesn't need fertiliser, it does benefit from a little more nitrogen. It concluded that D. annulatum is versatile herb having diverse pharmacological activities including antioxidant, antioxidant activity index, DNA damage protection assay, antimicrobial assay, and cytotoxic activity. It also reported for protective effect against DNA damage. These biological properties are reported due to numerous phytochemicals present in the D. annulatum herb.

The antioxidant ergothioneine alleviates cisplatin-induced hearing loss through the Nrf2 pathway.

Cisplatin (CDDP) is a commonly used chemotherapeutic agent for treating head and neck tumors. However, there is high incidence of ototoxicity in patients treated with CDDP, which may be caused by the excessive reactive oxygen species generation (ROS) in the inner ear. Many studies have demonstrated the strong antioxidant effects of ergothioneine (EGT). Therefore, we assumed that EGT could also attenuate CIHL as well. However, the protective effect and mechanism of EGT on CIHL have not been elucidated as so far. In this study, we investigated whether EGT could treat CIHL and the mechanism. In our study, we confirmed the protective effect of EGT on preventing cisplatin induced toxicity both in vitro and in vivo. The auditory brainstem response (ABR) threshold shift in the EGT + CDDP treatment mice was 30 dB less than that in the CDDP treatment mice. EGT suppressed production of ROS and pro-apoptotic proteins both in tissue and cells. By silencing Nrf2, we confirmed that EGT protected against CIHL via the Nrf2 pathway. We also found that SLC22A4 (OCTN1), an important molecule involved in transporting EGT, was expressed in the cochlea. Our results revealed the role of EGT in the prevention of CIHL by activating Nrf2/HO-1/NQO-1 pathway, and broadened a new perspective therapeutic target of EGT. EGT decreased ROS production and promoted the expression of antioxidative enzymes to maintain redox homeostasis in sensory hair cells (HCs). Overall, our results indicated that EGT may serve as a novel treatment drug to attenuate CIHL.

Pathogenesis of chronic enteropathy associated with the SLCO2A1 gene: Hypotheses and conundrums

Chronic enteropathy associated with the SLCO2A1 gene (CEAS) is a complex gastroenterological condition characterized by multiple ulcers in the small intestine with chronic bleeding and protein loss. This review explores the potential mechanisms underlying the pathogenesis of CEAS, focusing on the role of SLCO2A1 -encoded prostaglandin transporter OATP2A1 and its impact on prostaglandin E2 (PGE2) levels. Studies have suggested that elevated PGE2 levels contribute to mucosal damage, inflammation, and disruption of the intestinal barrier. The effects of PGE2 on macrophage activation and Maxi-Cl channel functionality, as well as its interaction with nonsteroidal anti-inflammatory drugs play crucial roles in the progression of CEAS. Understanding the balance between its protective and pro-inflammatory effects and the complex interactions within the gastrointestinal tract can shed light on potential therapeutic targets for CEAS and guide the development of novel, targeted therapies.

Inhibition of miR-199b-5p reduces pathological alterations in osteoarthritis by potentially targeting Fzd6 and Gcnt2.

Osteoarthritis (OA) is a degenerative disease with a high prevalence in the elderly population, but our understanding of its mechanisms remains incomplete. Analysis of serum exosomal small RNA sequencing data from clinical patients and gene expression data from OA patient serum and cartilage obtained from the GEO database revealed a common dysregulated miRNA, miR-199b-5p. In vitro cell experiments demonstrated that miR-199b-5p inhibits chondrocyte vitality and promotes extracellular matrix degradation. Conversely, inhibition of miR-199b-5p under inflammatory conditions exhibited protective effects against damage. Local viral injection of miR-199b-5p into mice induced a decrease in pain threshold and OA-like changes. In an OA model, inhibition of miR-199b-5p alleviated the pathological progression of OA. Furthermore, bioinformatics analysis and experimental validation identified Gcnt2 and Fzd6 as potential target genes of MiR-199b-5p. Thus, these results indicated that MiR-199b-5p/Gcnt2 and Fzd6 axis might be a novel therapeutic target for the treatment of OA.

Exploring animal protein sources against prevent age-related short-term memory decline in mice: Dietary fish (Alaska Pollock) protein exhibits superior protective effects.

Dietary factors, particularly proteins, have been extensively explored to combat cognitive impairment. We have previously reported that dietary fish (Alaska Pollock) protein (APP) is more effective than casein (CAS) or fish oil in maintaining short-term memory in senescence-accelerated mice prone 10 (SAMP10). To examine the specificity of the protective effect of APP intakes against short-term memory decline, we assessed the impact of various dietary animal proteins, including APP, CAS, chicken breast protein (CP), and whey protein (WP), against age-related cognitive function in SAMP10 mice. After feeding the experimental diets for 5 months, memory was assessed using the Y-maze. The APP group exhibited a significant increase in spontaneous alternation behavior as an indicator of working memory when group compared with groups fed with other protein source. Additionally, the APP group displayed significantly higher neurofilament heavy chain positivity than the CAS and CP groups, as evidenced immunohistochemical analysis. Gut microbiota analysis indicated that dietary APP significantly enhanced the relative abundance of Lactobacillus, which positively correlated with spontaneous alternation behavior. Collectively, these findings suggest that dietary APP is more effective than CAS, CP, or WP in preventing age-related short-term memory decline and morphological abnormalities in the hippocampal axons of SAMP10 mice. Moreover, APP-mediated improvements in cognitive deficits may be associated with changes in microbiota diversity. PRACTICAL APPLICATION: This research suggests that dietary fish protein from Alaska Pollock may be more efficient in prevention short-term memory decline in mice, compared to other animal proteins. This finding has practical implications for nutritional optimization, developing the new health food products, and elucidating the relationship between the impact of specific proteins on gut microbiota and prevention of age-related cognitive decline.

Protective Mechanisms of SGLTi in Ischemic Heart Disease.

Ischemic heart disease (IHD) is a common clinical cardiovascular disease with high morbidity and mortality. Sodium glucose cotransporter protein inhibitor (SGLTi) is a novel hypoglycemic drug. To date, both clinical trials and animal experiments have shown that SGLTi play a protective role in IHD, including myocardial infarction (MI) and ischemia/reperfusion (I/R). The protective effects may be involved in mechanisms of energy metabolic conversion, anti-inflammation, anti-fibrosis, ionic homeostasis improvement, immune cell development, angiogenesis and functional regulation, gut microbiota regulation, and epicardial lipids. Thus, this review summarizes the above mechanisms and aims to provide theoretical evidence for therapeutic strategies for IHD.

Aspergillus awamori: potential antioxidant, anti-inflammatory, and anti-apoptotic activities in acetic acid-induced ulcerative colitis in rats.

Ulcerative colitis (UC) is a chronic colonic inflammation with a significant health hazard. Aspergillus awamori (A. awamori) is a microorganism with various bioactive compounds with natural antioxidant and anti-inflammatory properties. The present work aimed to elucidate the protective and therapeutic effects of varying concentrations of A. awamori against acetic acid (AA)-induced ulcerative colitis (UC) in rats. Nine groups of albino male rats were established: a control negative group (G1), a control positive group (G2,AA), and preventive protocol groups (including G3A, G4A, and G5A) that received 100mg, 50mg, and 25mg/kg b.w, respectively, of A. awamori orally and daily from the 1st day of the experiment and for 7 consecutive days. Then, they were subjected to one dose of AA intrarectally on day 8th. G3B, G4B, and G5B were termed as curative protocol groups that received one dose of AA on day 8th and then administered 100mg, 50mg, and 25mg/kg b.w. of A. awamori, respectively, on day 9th and continued receiving these doses daily until day 16th. Rats in the AA group exhibited marked histopathological alterations of the distal colon, with an exaggeration of the DAI. In addition, a remarkable increase in oxidative stress was represented by the elevation of MDA and NO levels with a decline in SOD and GPx activities. In addition, upregulation of TNF-α, IL-6, and IL-1β mRNA expressions and downregulation of Muc2 and Nrf2 levels were detected. Unambiguously, a remarkable anti-inflammatory effect was noticed either in A. awamori prevented or treated groups expounded by reducing and regulating TNF-α, IL-6, and IL-1β with improved pathological lesion scoring. The Muc2, Nrf2, and bcl-2 gene levels were upregulated and restored also. In summary, the findings in this work reveal that A. awamori supplementation successfully alleviated the UC induced by AA, which had a better effect when administered before colitis induction.

Alleviative effect of betaine against copper oxide nanoparticles-induced hepatotoxicity in adult male albino rats: histopathological, biochemical, and molecular studies

BackgroundCopper oxide nanoparticles (CuO-NPs) have gained interest due to their availability, efficiency, and their cost-effectiveness. Betaine is an essential methyl donor and takes part in various physiological activities inside the body; it is found to have protective and curative effects against various liver diseases. The present study aimed to evaluate the hepatotoxic effect of CuO-NPs on adult male albino rats and the ability of betaine to alleviate such hepatotoxicity.MethodsForty adult male albino Wister rats were grouped into 4 groups (10 rats/group): group I a negative control, group II (CuO-NPs) injected with CuO-NPs intra peritoneal by insulin needle (0.5 mg/kg/day), group III (betaine + CuO-NPs) administered betaine orally by gavage needle (250 mg/kg/day 1 h before CuO-NPs) and CuO-NPs (0.5 mg/kg/day) finally, group IV (betaine) administered betaine orally by gavage needle (250 mg/kg/day) for consecutive 28 days. Blood and liver samples were gathered and processed for biochemical, molecular, histopathological, and immunohistochemical investigations.ResultsGroup II displayed a marked rise in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malondialdehyde (MDA) levels. Furthermore, there is an excessive upregulation of the inflammatory biomarkers interleukin1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). On the other hand, substantial reduction in glutathione (GSH) levels and significant downregulation at glutathione peroxidase (GPx) mRNA gene expression. Regarding the histopathological deviations, there were severe congestion, dilatation and hyalinization of blood vessels, steatosis, hydropic degeneration, hepatocytic necrosis, increased binucleation, degenerated bile ducts, hyperplasia of ducts epithelial lining, and inflammatory cells infiltration. Immunohistochemically, there was a pronounced immunoreactivity toward IL-1β. Luckily, the pre-administration of betaine was able to mitigate these changes. MDA was dramatically reduced, resulting in the downregulation of IL-1β and TNF-α. Additionally, there was a considerable rise in GSH levels and an upregulation of GPx. Histopathological deviations were substantially improved as diminished dilatation, hyalinization and congestion of blood vessels, hepatocytes, and bile ducts are normal to some extent. In addition, IL-1β immunohistochemical analysis revealed marked decreased intensity.ConclusionBetaine can effectively reduce the hepatotoxicity caused by CuO-NPs via its antioxidant properties and its ability to stimulate the cell redox system.

Shexiang tongxin dropping pill alleviates myocardial injury induced by coronary microembolization by down-regulating APOC1 to inhibit STAT3 signaling pathway.

This study determines to validate the mechanism of Shexiang Tongxin dropping pill (STDP) in attenuating coronary microembolization (CME) induced myocardial injury. CME rat models were established and underwent corresponding treating. Gene chip analysis was performed in rat myocardial tissues for GO and KEGG enrichment analysis. The differentially expressed genes were detected by qRT-PCR. H&E staining and ELISA were used for pathological analysis and detection of troponin (cTnI) and Creatine Kinase Isoenzyme (CK-MB). Lipopolysaccharide (LPS) treated primary cardiomyocytes were used to mimic inflammatory in vitro models. Cell viability and apoptosis of cardiomyocytes were determined by MTT and flow cytometry. The expressions of inflammatory cytokines, apoptotic proteins and proteins related to the STAT3 signal pathway were detected by western blot. APOC1 mRNA expression was detected by qRT-PCR. Immunofluorescence (IF) was used for subcellular localization of p-STAT3 and the binding of APOC1 with STAT3 was verified using Co-IP. STDP can attenuate myocardial injury in CME rat models, and lead to decreased expression of APOC1 and suppressed STAT3 signal pathway. In vitro models found STDP can suppress the cell viability and cell apoptosis of primary cardiomyocytes, in addition to suppressing the secretions of IL-6, IL-1β and TNF-α, while the protective effect of STDP can be reversed by overexpression of APOC1. Co-IP found that APOC1 can bind STAT3 directly. APOC1 can increase p-STAT3 expression in the nucleus to activate the STAT3 signal pathway. STDP can suppress APOC1 and STAT3 signal pathway to inhibit inflammation and cell apoptosis of cardiomyocytes. APOC1 may be one of the key regulatory factors in CME-induced myocardial injury.

Adjunctive Chinese medicine therapy reduces relapse of psoriasis vulgaris after discontinuation of biologics: a prospective registry-based cohort study

Background Biologics have revolutionized psoriasis treatment; however, relapse of psoriasis after discontinuation of biologics remains unresolved. Objective To assess the impact of adjunctive Chinese medicine (CM) therapy on relapse of psoriasis vulgaris (PV) after discontinuation of biologics. Methods We constructed a prospective cohort study through a psoriasis case registry platform that enrolled patients treated with biologics (in combination with or without CM). The endpoint event was relapse, defined as loss of psoriasis area and severity index (PASI) 75. Results A total of 391 patients completed the study and were included in the analysis, of whom 169 (43.2%) experienced relapse during follow-up. To minimize the bias, a 1:1 propensity score matching (PSM) was performed, generating matched cohorts of 156 individuals per group. Adjuvant CM therapy significantly associated with reduced incidence of relapse (HR =0.418, 95% CI = 0.289 ∼ 0.604, p < 0.001), and the protective effect of CM in the subgroup analysis was significant. In addition, PASI 90 response and disease duration were associated with relapse (p < 0.05). Conclusion Adjunctive CM therapy is associated with reduced relapse incidence in PV after discontinuation of biologics.

Bio-nanoparticles loaded with synovial-derived exosomes ameliorate osteoarthritis progression by modifying the oxidative microenvironment

Background and aimsOsteoarthritis (OA) is a prevalent degenerative joint disorder, marked by the progressive degeneration of joint cartilage, synovial inflammation, and subchondral bone hyperplasia. The synovial tissue plays a pivotal role in cartilage regulation. Exosomes (EXOs), small membrane-bound vesicles released by cells into the extracellular space, are crucial in mediating intercellular communication and facilitating the exchange of information between tissues. Our study aimed to devise a hydrogel microsphere infused with SOD3-enriched exosomes (S-EXOs) to protect cartilage and introduce a novel, effective approach for OA treatment.Materials and methodsWe analyzed single-cell sequencing data from 4247 cells obtained from the GEO database. Techniques such as PCR, Western Blot, immunofluorescence (IF), and assays to measure oxidative stress levels were employed to validate the cartilage-protective properties of the identified key protein, SOD3. In vivo, OA mice received intra-articular injections of S-EXOs bearing hydrogel microspheres, and the effectiveness was assessed using safranine O (S.O) staining and IF.ResultsSingle-cell sequencing data analysis suggested that the synovium influences cartilage via the exocrine release of SOD3. Our findings revealed that purified S-EXOs enhanced antioxidant capacity of chondrocytes, and maintained extracellular matrix metabolism stability. The S-EXO group showed a significant reduction in mitoROS and ROS levels by 164.2% (P < 0.0001) and 142.7% (P < 0.0001), respectively, compared to the IL-1β group. Furthermore, the S-EXO group exhibited increased COL II and ACAN levels, with increments of 2.1-fold (P < 0.0001) and 3.1-fold (P < 0.0001), respectively, over the IL-1β group. Additionally, the S-EXO group showed a decrease in MMP13 and ADAMTS5 protein expression by 42.3% (P < 0.0001) and 44.4% (P < 0.0001), respectively. It was found that S-EXO-containing hydrogel microspheres could effectively deliver SOD3 to cartilage and significantly mitigate OA progression. The OARSI score in the S-EXO microsphere group markedly decreased (P < 0.0001) compared to the OA group.ConclusionThe study demonstrated that the S-EXOs secreted by synovial fibroblasts exert a protective effect on chondrocytes, and microspheres laden with S-EXOs offer a promising therapeutic alternative for OA treatment.

4-Octyl itaconate alleviates dextran sulfate sodium-induced ulcerative colitis in mice via activating the KEAP1-NRF2 pathway.

Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease with a relapsing-remitting course. Although its etiology remains unknown, excessive oxidative stress in colon is a major intermediate factor that can promote the progression of UC. In the present study, we investigated the effect and the underlying mechanisms of 4-Octyl itaconate (OI) on dextran sulfate sodium (DSS)-induced UC in mice. Our work identified that OI alleviated the colitis by reducing the oxidative stress and the apoptosis in colon tissue, then increasing the tight junction proteins expression and in turn enhancing the intestinal barrier function, thereby creating less severe inflammatory responses. Moreover, our results demonstrated that OI reduced the Kelch-like ECH-associated protein 1 (KEAP1) expression and subsequent upregulated nuclear factor E2-related factor (NRF2) expression and its nuclear translocation which in turn induced the expression of glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition, ML385, a NRF2 antagonist, can inhibit the protective effects of OI on UC, indicating that the role of OI in this colitis model could be dependent on the activation of KEAP1-NRF2 pathway. Notably, OI co-administration significantly enhanced the therapeutic effects of mesalazine or 1400W on UC. Collectively, itaconate may have a great potential for use in the treatment of IBD.

Causal effect of blood osteocalcin on the risk of Alzheimer’s disease and the mediating role of energy metabolism

Growing evidence suggests an association between osteocalcin (OCN), a peptide derived from bone and involved in regulating glucose and lipid metabolism, and the risk of Alzheimer’s disease (AD). However, the causality of these associations and the underlying mechanisms remain uncertain. We utilized a Mendelian randomization (MR) approach to investigate the causal effects of blood OCN levels on AD and to assess the potential involvement of glucose and lipid metabolism. Independent instrumental variables strongly associated (P < 5E-08) with blood OCN levels were obtained from three independent genome-wide association studies (GWAS) on the human blood proteome (N = 3301 to 35,892). Two distinct summary statistics datasets on AD from the International Genomics of Alzheimer’s Project (IGAP, N = 63,926) and a recent study including familial-proxy AD patients (FPAD, N = 472,868) were used. Summary-level data for fasting glucose (FG), 2h-glucose post-challenge, fasting insulin, HbA1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol (TC), and triglycerides were incorporated to evaluate the potential role of glucose and lipid metabolism in mediating the impact of OCN on AD risk. Our findings consistently demonstrate a significantly negative correlation between genetically determined blood OCN levels and the risk of AD (IGAP: odds ratio [OR, 95%CI] = 0.83[0.72–0.96], P = 0.013; FPAD: OR = 0.81 [0.70–0.93], P = 0.002). Similar estimates with the same trend direction were obtained using other statistical approaches. Furthermore, employing multivariable MR analysis, we found that the causal relationship between OCN levels and AD was disappeared after adjustment of FG and TC (IGAP: OR = 0.97[0.80–1.17], P = 0.753; FPAD: OR = 0.98 [0.84–1.15], P = 0.831). There were no apparent instances of horizontal pleiotropy, and leave-one-out analysis showed good stability of the estimates. Our study provides evidence supporting a protective effect of blood OCN levels on AD, which is primarily mediated through regulating FG and TC levels. Further studies are warranted to elucidate the underlying physio-pathological mechanisms.

Preparation of the new peptide drug ACTY116-loaded in situ forming implants and evaluation of its efficacy in pulmonary arterial hypertension and right ventricular hypertrophy induced by SU5416/hypoxia in mice.

There is a lack of effective therapeutic drugs for pulmonary arterial hypertension. Previous studies have demonstrated the positive cardiovascular system protective effects of the new peptide ACTY116. However, its stability in ordinary aqueous solution injections is poor and its half-life in the body is short, which has hindered the development of preparations. This study aimed to prepare in situ forming implants (ISFIs) of the peptide ACTY116 and investigate its impact on pulmonary arterial hypertension. We prepared ISFIs using NMP/TA as a solvent and PLGA as a polymer. These ISFIs exhibited low viscosity, low toxicity and sustained release properties. In a mouse model of pulmonary hypertension induced by SU5416/hypoxia, both ISFIs and ACTY116 peptides effectively reduced pulmonary hypertension, cardiac hypertrophy and pulmonary blood vessel wall thickness. In conclusion, this study highlights the potential of ACTY116 as a treatment for pulmonary arterial hypertension and suggests that incorporating it into an in-situ gel implant could be a promising option.

Human Plasma‐Derived Extracellular Vesicles Protect Against Cerebral Ischemia‐Reperfusion Injury via HSP27 Phosphorylation

AbstractIschemic stroke (IS) has become a serious public health problem, with patients undergoing endovascular treatment experiencing ischemia‐reperfusion (I/R) injury, which exacerbates cerebrovascular diseases. Circulating extracellular vesicles (EVs) have shown potential for treating cerebral I/R injury. In this study, the therapeutic effect of human plasma‐derived EVs and protective mechanisms in cerebral I/R injury is explored. An oxygen‐glucose deprivation/reperfusion (OGD/R) model is used to treat SH‐SY5Y cells in vitro, and an I/R injury model is constructed by transient middle cerebral artery occlusion (tMCAO) in mice. Human plasma‐derived EVs are extracted by size exclusion chromatography. Western blot, Immunofluorescence Staining, and 2,3,5‐Triphenyltetrazolium Chloride (TTC) Staining are employed to observe the effects of EVs on the neuroinflammatory response and infarct volumes in tMCAO mice, while TUNEL Staining, Flow Cytometry, and Western Blot are employed to assess cell apoptosis. Human plasma‐derived EVs alleviated apoptosis in SH‐SY5Y cells under OGD/R stress and exerted a protective effect against brain I/R injury in tMCAO mice. Mechanistically, EVs protected against cerebral I/R injury via HSP27 phosphorylation, and the HSP27 phosphorylation inhibitor KRIBB3 attenuated the anti‐apoptotic effects of EVs. Human plasma‐derived EVs activated the phosphorylation of HSP27, thereby inhibiting cell apoptosis and protecting against cerebral I/R injury.

Risk/benefit trade-off of habitual physical activity and air pollution on mortality: A large-scale prospective analysis in the UK Biobank

BackgroundPrevious observational studies have indicated associations of physical activity (PA) and air pollution with mortality. A few studies have evaluated air pollution and PA interactions for health. Still, the trade-off between the harmful effects of air pollution exposure and the protective effects of PA remains controversial and unclear. ObjectiveThis study aimed to investigate the joint association of air pollution and PA with mortality risks. MethodsThis prospective cohort study included 322,092 participants from 2006 to 2010 and followed up to 2021 in the UK Biobank study. The concentrations of air pollutants (2006–2010), including particulate matter (PM) with diameters <=2.5 mm (PM2.5), <=10 mm (PM10), and between 2.5 and 10 mm (PM2.5–10), and nitrogen oxides (NO2 and NOx) were obtained. Information on PA measured by the International Physical Activity Questionnaire short form (2006–2010) and wrist-worn accelerometer (2013–2015) were collected. All-cause and cause-specific mortalities were recorded. Cox proportional hazard models were used to investigate the associations of air pollution exposure and PA with mortality risks. The additive and multiplicative interactions were also examined. ResultsDuring a mean follow-up of 11.83 years, 16629 deaths were recorded. Compared with participants reporting low PA, higher PA was negatively associated with all-cause [hazard ratio (HR), 0.74; 95% CI, 0.71–0.78], cancer (HR, 0.85; 95% CI, 0.80–0.90), CVD (HR, 0.79; 95% CI, 0.71–0.87), and respiratory disease-specific mortality (HR, 0.51; 95% CI, 0.44–0.60). Exposure to PM2.5 (HR, 1.05; 95% CI, 1.00–1.09) and NOx (HR, 1.06; 95% CI, 1.02–1.10) was connected with increased all-cause mortality risk, and significant PM2.5-associated elevated risks for CVD mortality and NOx-associated elevated risks for respiratory disease mortality were observed. No obvious interaction between PA and PM2.5 or NOx exposure was detected. ConclusionsOur study provides additional evidence that higher PA and lower air pollutant levels are independently connected with reduced mortality risk. The benefits of PA are not significantly affected by long-term air pollution exposure, indicating PA can be recommended to prevent mortality regardless of air pollution levels. Our findings highlight the importance of public health policies and interventions facilitating PA and reducing air pollution in reducing mortality risks and maximizing health benefits. Future investigation is urgently needed to identify these findings in areas with severe air pollution conditions.

Challenging the safety and efficacy of topically applied chlorogenic acid, apigenin, kaempferol, and naringenin by HET-CAM, HPLC-TBARS-EVSC, and laser Doppler flowmetry

The integumentary system, a vital organ, constitutes a multifaceted barrier against pathogens and environmental factors, crucial for maintaining homeostasis. Intrinsic and extrinsic factors can accelerate skin aging and compromise its homeostatic functions and solar rays, particularly ultraviolet (UV) radiation, pose a significant risk for skin cancer. Polyphenols are molecules that donate hydrogen or electrons, preventing the oxidation of substances, such as lipids, or the formation of inflammatory mediators by cyclooxygenase enzymes. This study explored the in vitro safety, by HET-CAM (hen’s egg test on chorioallantoic membrane), and protective effects of polyphenols (chlorogenic acid, apigenin, kaempferol, and naringenin) against stratum corneum UV-induced lipid peroxidation using an innovative method, the HPLC-TBARS-EVSC (high-performance liquid chromatography–thiobarbituric acid reactive substances–ex vivo stratum corneum), and a stress test using methyl nicotinate and laser Doppler flowmetry to establish in vivo the samples’ topical anti-inflammatory ability. An aqueous gel containing 0.1% w/w of each polyphenol was formulated using ammonium acryloyldimethyltaurate/VP copolymer. Through the utilization of the HET-CAM assay for in vitro safety assessment, chlorogenic acid, apigenin, kaempferol, and naringenin were classified as non-irritating active ingredients. This classification was based on their lack of adverse reactions within the vascularization of the chorioallantoic membrane. To assess the protective capabilities of four polyphenols against lipid peroxidation in the stratum corneum, the HPLC-TBARS-EVSC protocol was conducted. It was observed that only naringenin exhibited a significant reduction in epidermal lipoperoxidation, indicating superior anti-radical potential. Conversely, chlorogenic acid, apigenin, and kaempferol displayed a pro-oxidant profile under the specified test conditions. The laser Doppler flowmetry suggested the anti-inflammatory potential of naringenin, kaempferol, and chlorogenic acid, with naringenin showing superior efficacy involving all parameters quantified. Naringenin emerged as the only polyphenol capable of reducing the intensity of the inflammatory response induced by methyl nicotinate solution in the participants, compared to the blank gel and the untreated area. This comprehensive investigation underscores the diverse protective roles of polyphenols in skin health, emphasizing naringenin’s notable anti-radical and anti-inflammatory properties.

Dexmedetomidine use during orthotopic liver transplantation surgery on early allograft dysfunction: A randomized controlled trial.

Previous studies have shown a protective effect of dexmedetomidine use in kidney transplantation. In contrast, it is not known whether intraoperative administration of dexmedetomidine can reduce early allograft dysfunction incidence following liver transplantation. To investigate the effect of dexmedetomidine use during surgery on early allograft dysfunction following orthotopic liver transplantation (OLT). This is a single-center, double-blinded, placebo-controlled randomized clinical trial. 330 adult patients undergoing orthotopic liver transplantation were enrolled from Jan 14th, 2019 to May 22nd, 2022. Patients received dexmedetomidine or normal saline during surgery. 1 year follow-ups were recorded. Patients were randomized to two groups receiving either dexmedetomidine or normal saline intraoperatively. For patients in the dexmedetomidine group, a loading dose (1μg/kg over 10 min) of dexmedetomidine was given after induction of anesthesia followed by a continuous infusion (0.5μg/kg /h) until the end of surgery. For patients in the normal saline group, an equal volume loading dose of 0.9% saline was given after the induction of anesthesia followed by an equal volume continuous infusion until the end of surgery. The primary outcome was early allograft dysfunction. Secondary outcomes included primary graft non-function, acute kidney injury and acute lung injury/ acute respiratory distress syndrome. Of 330 patients included in the intention-to-treat analysis, 165 were in the dexmedetomidine group (mean [SD] age, 49 [10] years; 117 [70.9%] men), and 165 were in the normal saline group (mean SD age, 49 [9] years; 118 [74%] men). 39 (24.4%) patients in the dexmedetomidine group and 31 (19.4%) in normal saline group developed early allograft dysfunction and the difference was statistically insignificant (P=0.28). Secondary outcomes including primary graft non-function and acute kidney injury was similar between the two groups. Intraoperative administration of dexmedetomidine did not reduce early allograft dysfunction rate after orthotopic liver transplantation.