Serotonin signaling: a new player and therapeutic target beyond Long-haul coronavirus disease.

During the coronavirus disease 2019 (COVID-19) pandemic, a subset of individuals continues to suffer from symptoms including fatigue, post-exertional malaise, dyspnea, bone loss, and memory and neurocognitive dysfunction for months and even years after infection. This clinical phenomenon has been labeled 'Long-haul COVID' or 'post-acute sequelae of COVID-19 (PASC)'; however, the underlying pathophysiological mechanisms remain unclear. In a recent study published in Cell, Wong et al. revealed that viral infection and type I interferon-driven reduction of peripheral serotonin impaired hippocampal responses and short-term memory through vagal neurons in patients with PASC. Therefore, the study provided novel insights into how serotonin links persistent viral inflammation with the neurocognitive symptoms of Long-haul COVID and actionable therapeutic targets for patients with PASC.

Disparities in awareness and utilisation of National Essential Public Health Services between the floating population and the registered residents: a cross-sectional study in China.

OBJECTIVE: There are differences between the floating population and the registered population in the awareness and use of the National Essential Public Health Services (NEPHS) due to the influence of China's household registration system. The Equalization of Basic Public Health and Family Planning Services (EBPHFPS) policy aims to reduce disparities among populations by enhancing the migrant population's access to basic public health services. The aim of this study is to examine the relationship between the EBPHFPS targeted at the floating population and the disparities in access to and utilisation of NEPHS between registered residents and the floating population. DESIGN: A cross-sectional study. SETTING: 8 cities (regions, autonomous prefectures) in China. PARTICIPANTS: 13 998 floating population and 14 000 registered residents in eight cities (regions, autonomous prefectures) were included in the analysis. OUTCOME MEASURES: Three binomial variables, including awareness of NEPHS, acceptance of health education and establishment of health records, were used as outcome indicators to examine the relationship between the EBPHFPS and the disparities between the floating and registered populations. METHODS: A linear regression model, fairness gap calculation and propensity score matching were used to explore the associations. RESULTS: The areas that implemented EBPHFPS exhibited an 8.3% increase in awareness of the NEPHS (p<0.01) and a 4.0% increase (p<0.05) in the likelihood of individuals having received health education within the previous year compared with the areas without the policy implementation. In contrast to registered residents, however, the floating population still faces significant disparities in NEPHS awareness and utilisation. Compared with areas without the equalisation policy, the inequality of opportunity in health education of the floating population in implementation areas is significantly lower (p<0.01), whereas no significant difference is observed in the inequality of opportunity regarding NEPHS awareness among the floating population (p>0.1). The floating population in the pilot areas of the policy encountered greater disparities in the establishment of health records (p<0.01). CONCLUSIONS: Positive associations between the EBPHFPS policy and NEPHS awareness and utilisation among the floating population were demonstrated to some extent; however, the floating population was still confronted with a degree of inequality of opportunity. The government needs to develop target-oriented policies and a guaranteed mechanism to ensure access to NEPHS among the floating population.

Waste treats waste: Facile fabrication of porous adsorbents from recycled PET and sodium alginate for efficient dye removal.

Dye-contaminated water and waste plastic both pose enormous threats to human health and the ecological environment, and simultaneously solving these two issues in a sustainable and resource-saving way is highly important. In this work, a sodium alginate-polyethylene terephthalate-sodium alginate (SA@PET) composite adsorbent for efficient dye removal is fabricated using wasted PET bottle and marine plant-based SA via simple and energy-efficient nonsolvent-induced phase separation (NIPS) method. Benefiting from its porous structure and the abundant binding sites, SA@PET shows an excellent methylene blue (MB) adsorption capacity of 1081 mg g-1. The Redlich-Peterson model more accurately describes the adsorption behavior, suggesting multiple adsorption mechanisms. In addition to the electrostatic attractions of SA to MB, polar interactions between the PET matrix and MB are also identified as adsorption mechanisms. It is worth mentioning that SA@PET could be recycled 7 times without a serious decrease in performance, and the trifluoroacetic acid-dichloromethane solvent involved in the NIPS process has the possibility of reuse and stepwise recovery. Finally, the discarded adsorbent could be completely degraded under mild conditions. This work provides not only a composite adsorbent with excellent cationic dye removal performance for wastewater treatment, but also an upcycling strategy for waste PET.

A promising therapy for fatty liver disease: PCSK9 inhibitors.

BACKGROUND: Fatty liver disease (FLD) poses a significant global health concern worldwide, with its classification into nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) contingent upon the presence or absence of chronic and excessive alcohol consumption. The absence of specific therapeutic interventions tailored to FLD at various stages of the disease renders its treatment exceptionally arduous. Despite the fact that FLD and hyperlipidemia are intimately associated, there is still debate over how lipid-lowering medications affect FLD. Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) is a serine protease predominantly synthesized in the liver, which has a crucial impact on cholesterol homeostasis. Research has confirmed that PCSK9 inhibitors have prominent lipid-lowering properties and substantial clinical effectiveness, thereby justifying the need for additional exploration of their potential role in FLD. PURPOSE: Through a comprehensive literature search, this review is to identify the relationship and related mechanisms between PCSK9, lipid metabolism and FLD. Additionally, it will assess the pharmacological mechanism and applicability of PCSK9 inhibitors (including naturally occurring PCSK9 inhibitors, such as conventional herbal medicines) for the treatment of FLD and serve as a guide for updating the treatment protocol for such conditions. METHODS: A comprehensive literature search was conducted using several electronic databases, including Pubmed, Medline, Embase, CNKI, Wanfang database and ClinicalTrials.gov, from the inception of the database to 30 Jan 2024. Key words used in the literature search were "fatty liver", "hepatic steatosis", "PCSK9", "traditional Chinese medicine", "herb medicine", "botanical medicine", "clinical trial", "vivo", "vitro", linked with AND/OR. Most of the included studies were within five years. RESULTS: PCSK9 participates in the regulation of circulating lipids via both LDLR dependent and independent pathways, and there is a potential association with de novo lipogenesis. Major clinical studies have demonstrated a positive correlation between circulating PCSK9 levels and the severity of NAFLD, with elevated levels of circulating PCSK9 observed in individuals exposed to chronic alcohol. Numerous studies have demonstrated the potential of PCSK9 inhibitors to ameliorate non-alcoholic steatohepatitis (NASH), potentially completely alleviate liver steatosis, and diminish liver impairment. In animal experiments, PCSK9 inhibitors have exhibited efficacy in alleviating alcoholic induced liver lipid accumulation and hepatitis. Traditional Chinese medicine such as berberine, curcumin, resveratrol, piceatannol, sauchinone, lupin, quercetin, salidroside, ginkgolide, tanshinone, lunasin, Capsella bursa-pastoris, gypenosides, and Morus alba leaves are the main natural PCS9 inhibitors. Excitingly, by inhibiting transcription, reducing secretion, direct targeting and other pathways, traditional Chinese medicine exert inhibitory effects on PCSK9, thereby exerting potential FLD therapeutic effects. CONCLUSION: PCSK9 plays an important role in the development of FLD, and PCSK9 inhibitors have demonstrated beneficial effects on lipid regulation and FLD in both preclinical and clinical studies. In addition, some traditional Chinese medicines have improved the disease progression of FLD by inhibiting PCSK9 and anti-inflammatory and antioxidant effects. Consequently, the inhibition of PCSK9 appears to be a promising therapeutic strategy for FLD.

SETDB1: Progress and prospects in cancer treatment potential and inhibitor research.

SET domain bifurcated methyltransferase 1 (SETDB1) serves as a histone lysine methyltransferase, catalyzing the di- and tri-methylation of histone H3K9. Mounting evidence indicates that the abnormal expression or activity of SETDB1, either through amplification or mutation, plays a crucial role in tumorigenesis and progression. This is particularly evident in the context of tumor immune evasion and resistance to immune checkpoint blockade therapy. Furthermore, there is a robust association between SETDB1 dysregulation and an unfavorable prognosis across various types of tumors. The oncogenic role of SETDB1 primarily arises from its methyltransferase function, which contributes to the establishment of a condensed and transcriptionally inactive heterochromatin state. This results in the inactivation of genes that typically hinder cancer development and silencing of retrotransposons that could potentially trigger an immune response. These findings underscore the substantial potential for SETDB1 as an anti-tumor therapeutic target. Nevertheless, despite significant strides in recent years in tumor biology research, challenges persist in SETDB1-targeted therapy. To better facilitate the development of anti-tumor therapy targeting SETDB1, we have conducted a comprehensive review of SETDB1 in this account. We present the structure and function of SETDB1, its role in various tumors and immune regulation, as well as the advancements made in SETDB1 antagonists. Furthermore, we discuss the challenges encountered and provide perspectives for the development of SETDB1-targeted anti-tumor therapy.

Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression.

Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε (SIKE) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-ß-activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.

Collecting duct NCOR1 controls blood pressure by regulating mineralocorticoid receptor.

INTRODUCTION: Nuclear receptor corepressor 1(NCOR1) is reported to play crucial roles in cardiovascular diseases, but its function in the kidney has remained obscure. OBJECTIVE: We aim to elucidate the role of collecting duct NCOR1 in blood pressure (BP) regulation. METHODS AND RESULTS: Collecting duct NCOR1 knockout (KO) mice manifested increased BP and aggravated vascular and renal injury in an angiotensin II (Ang II)-induced hypertensive model. KO mice also showed significantly higher BP than littermate control (LC) mice in deoxycorticosterone acetate (DOCA)-salt model. Further study showed that collecting duct NCOR1 deficiency aggravated volume and sodium retention after saline challenge. Among the sodium transporter in the collecting duct, the expression of the three epithelial sodium channel (ENaC) subunits was markedly increased in the renal medulla of KO mice. Consistently, BP in Ang II-infused KO mice decreased significantly to the similar level as those in LC mice after amiloride treatment. ChIP analysis revealed that NCOR1 deficiency increased the enrichment of mineralocorticoid receptor (MR) on the promoters of the three ENaC genes in primary inner medulla collecting duct (IMCD) cells. Co-IP results showed interaction between NCOR1 and MR, and luciferase reporter results demonstrated that NCOR1 inhibited the transcriptional activity of MR. Knockdown of MR eliminated the increased ENaC expression in primary IMCD cells isolated from KO mice. Finally, BP was significantly decreased in Ang II-infused KO mice after treatment of MR antagonist spironolactone and the difference between LC and KO mice was abolished. CONCLUSIONS: NCOR1 interacts with MR to control ENaC activity in the collecting duct and to regulate sodium reabsorption and ultimately BP. Targeting NCOR1 might be a promising tactic to interrupt the volume and sodium retention of the collecting duct in hypertension.

Predictive value of serum MDA and 4-HNE levels on the occurrence of early neurological deterioration after intravenous thrombolysis with rt-PA IVT in patients with acute ischemic stroke.

OBJECTIVE: This study investigated the predictive value of serum MDA and 4-HNE levels on early neurological deterioration (END) after recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients. METHODS: This study analyzed 287 AIS patients with standard-dose rt-PA IVT. Clinical baseline and pathological data were recorded before rt-PA IVT, and neurologic deficit was assessed by NIHSS. AIS patients were classified into Non-END and END groups. Serum MDA and 4-HNE levels were determined by ELISA and their correlations with NIHSS scores were evaluated. AIS patients were allocated into groups with high and low MDA or 4-HNE expression, and post-IVT END incidence was compared. Independent risk indexes for post-IVT END and the predictive value of serum MDA+4-HNE levels on post-IVT END were assessed. RESULTS: Serum MDA and 4-HNE were higher in AIS patients with post-IVT END. NIHSS score showed a positive correlation with serum MDA and 4-HNE levels. MDA levels were positively correlated with 4-HNE levels in AIS patients. END after IVT was increased in AIS patients with high MDA/4-HNE expression. FBG, lymphocyte percentage, PLR, NIHSS score, serum MDA, and 4-HNE levels were independent risk factors for END after IVT. The diagnostic efficacy of MDA+4-HNE in assessing post-IVT END in AIS patients (sensitivity 92.00 %, specificity 82.70 %) was higher than MDA or 4-HNE alone. CONCLUSION: Serum MDA and 4-HNE levels were higher in AIS patients with post-IVT END than in those with non-END, and MDA+4-HNE possessed a higher predictive value for post-IVT END in AIS patients.

Histone demethylase KDM1A promotes hepatic steatosis and inflammation by increasing chromatin accessibility in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease without specific Food and Drug Administration-approved drugs. Recent advances suggest that chromatin remodeling and epigenetic alteration contribute to the development of NAFLD. The functions of the corresponding molecular modulator in NAFLD, however, are still elusive. KDM1A, commonly known as lysine-specific histone demethylase 1, has been reported to increase glucose uptake in hepatocellular carcinoma. In addition, a recent study suggests that inhibition of KDM1A reduces lipid accumulation in primary brown adipocytes. We here investigated the role of KDM1A, one of the most important histone demethylases, in NAFLD. In this study, we observed a significant upregulation of KDM1A in NAFLD mice, monkeys, and humans compared to the control group. Based on these results, we further found that the KDM1A can exacerbate lipid accumulation and inflammation in hepatocytes and mice. Mechanistically, KDM1A exerted its effects by elevating chromatin accessibility, subsequently promoting the development of NAFLD. Furthermore, the mutation of KDM1A blunted its capability to promote the development of NAFLD. In summary, our study discovered that KDM1A exacerbates hepatic steatosis and inflammation in NAFLD via increasing chromatin accessibility, further indicating the importance of harnessing chromatin remodeling and epigenetic alteration in combating NAFLD. KDM1A might be considered as a potential therapeutic target in this regard.

Integrative Analysis of N6-methyladenosine RNA modifications related genes and their Influences on Immunoreaction or fibrosis in myocardial infarction.

Increasing studies have shown that N6-methyladenosine (m6A) modification plays an important role in cardiovascular diseases. In this study, we systematically investigated the regulatory mode of m6A genes in myocardial infarction (MI) by combining bioinformatics analysis of clinical samples with animal experiments. We utilized gene expression data of clinical samples from public databases to examine the expression of m6A genes in heart tissues and found a large difference between the healthy control group and MI group. Subsequently, we established an MI diagnosis model based on the differentially expressed m6A genes using the random forest method. Next, unsupervised clustering method was used to classify all MI samples into two clusters, and the differences in immune infiltration and gene expression between different clusters were compared. We found LRPPRC to be the predominant gene in m6A clustering, and it was negatively correlated with immunoreaction. Through GO enrichment analysis, we found that most differentially expressed genes between the two clusters were profibrotic. By means of WGCNA, we inferred that GJA4 might be a core molecule in the m6A regulatory network of MI. This study demonstrates that m6A regulators probably affects the immune-inflammatory response and fibrosis to regulate the process of MI, which provides a potential therapeutic target.

Service readiness for the management of non-communicable diseases in publicly financed facilities in Malawi: findings from the 2019 Harmonised Health Facility Assessment census survey.

INTRODUCTION: Non-communicable diseases (NCDs) are rising in low-income and middle-income countries, including Malawi. To inform policy-makers and planners on the preparedness of the Malawian healthcare system to respond to NCDs, we estimated NCD service readiness in publicly financed healthcare facilities in Malawi. METHODS: We analysed data from 564 facilities surveyed in the 2019 Harmonised Health Facility Assessment, including 512 primary healthcare (PHC) and 52 secondary and tertiary care (STC) facilities. To characterise service readiness, applying the law of minimum, we estimated the percentage of facilities with functional equipment and unexpired medicines required to provide NCD services. Further, we estimated permanently unavailable items to identify service readiness bottlenecks. RESULTS: Fewer than 40% of PHC facilities were ready to deliver services for each of the 14 NCDs analysed. Insulin and beclomethasone inhalers had the lowest stock levels at PHC facilities (6% and 8%, respectively). Only 17% of rural and community hospitals (RCHs) have liver and kidney diagnostics. STC facilities had varying service readiness, ranging from 27% for managing acute diabetes complications to 94% for chronic type 2 diabetes management. Only 38% of STC facilities were ready to manage chronic heart failure. Oral pain medicines were widely available at all levels of health facilities; however, only 22% of RCHs and 29% of STCs had injectable morphine or pethidine. Beclomethasone was never available at 74% of PHC and 29% of STC facilities. CONCLUSION: Publicly financed facilities in Malawi are generally unprepared to provide NCD services, especially at the PHC level. Targeted investments in PHC can substantially improve service readiness for chronic NCD conditions in local communities and enable STC to respond to acute NCD complications and more complex NCD cases.

Dual properties of pharmacological activities and preparation excipient: Bletilla striata polysaccharides.

Bletilla striata has been used for thousands of years and shows the functions of stopping bleeding, reducing swelling, and promoting healing in traditional applications. For Bletilla striata, Bletilla striata polysaccharides (BSP) is the main active ingredient, exhibiting biological functions of anti-inflammatory, anti-oxidant, anti-fibrotic, immune modulation, anti-glycation, and so on. In addition, BSP has exhibited the characteristics of excipient such as bio-adhesion, bio-degradability, and bio-safety and has been prepared into a series of preparations such as nanoparticles, microspheres, microneedles, hydrogels, etc. BSP, as both a drug and an excipient, has already aroused more and more attention. In this review, publications in recent years related to the extraction and identification, biological activities, and excipient application of BSP are reviewed. Specifically, we focused on the advances in the application of BSP as a formulation excipient. We hold opinion that BSP not only needed more researches in the mechanisms, but also the development into hydrogels, nano-formulations, tissue engineering, and so on. And we believe that this paper provides a beneficial reference for further BSP innovation and in-depth research and promotes the use of these natural products in pharmaceutical applications.

A comprehensive review of advanced nasal delivery: Specially insulin and calcitonin.

Peptide drugs through nasal mucous membrane, such as insulin and calcitonin have been widely used in the medical field. There are always two sides to a coin. One side, intranasal drug delivery can imitate the secretion pattern in human body, having advantages of physiological structure and convenient use. Another side, the low permeability of nasal mucosa, protease environment and clearance effect of nasal cilia hinder the intranasal absorption of peptide drugs. Researchers have taken multiple means to achieve faster therapeutic concentration, lower management dose, and fewer side effects for better nasal preparations. To improve the peptide drugs absorption, various strategies had been explored via the nasal mucosa route. In this paper, we reviewed the achievements of 18 peptide drugs in the past decade about the perspectives of the efficacy, mechanism of enhancing intranasal absorption and safety. The most studies were insulin and calcitonin. As a result, absorption enhancers, nanoparticles (NPs) and bio-adhesive system are the most widely used. Among them, chitosan (CS), cell penetrating peptides (CPPs), tight junction modulators (TJMs), soft NPs and gel/hydrogel are the most promising strategies. Moreover, two or three strategies can be combined to prepare drug vectors. In addition, spray freeze dried (SFD), self-emulsifying nano-system (SEN), and intelligent glucose reaction drug delivery system are new research directions in the future.

Metabolic profiles of type 2 diabetes and their association with renal complications.

CONTEXT: The components of metabolic syndrome (MetS) are interrelated and associated with renal complications in patients with type 2 diabetes (T2D). AIMS: We aimed to reveal prevalent metabolic profiles in patients with T2D and identify which metabolic profiles were risk markers for renal progression. METHODS: A total of 3556 participants with T2D from a hospital (derivation cohort) and 931 participants with T2D from a community survey (external validation cohort) were included. The primary outcome was the onset of diabetic kidney disease (DKD), and secondary outcomes included eGFR decline, macroalbuminuria, and end-stage renal disease (ESRD). In the derivation cohort, clusters were identified using the five components of MetS, and their relationships with the outcomes were assessed. To validate the findings, participants in the validation cohort were assigned to clusters. Multivariate odds ratios (ORs) of the primary outcome were evaluated in both cohorts, adjusted for multiple covariates at baseline. RESULTS: In the derivation cohort, six clusters were identified as metabolic profiles. Compared with cluster 1, cluster 3 (severe hyperglycemia) had increased risks of DKD (HR [95% CI]: 1.72 [1.39-2.12]), macroalbuminuria (2.74 [1.84-4.08]), ESRD (4.31 [1.16-15.99]), and eGFR decline [P < 0.001]; cluster 4 (moderate dyslipidemia) had increased risks of DKD (1.97 [1.53-2.54]) and macroalbuminuria (2.62 [1.61-4.25]). In the validation cohort, clusters 3 and 4 were replicated to have significantly increased risks of DKD (adjusted ORs: 1.24 [1.07-1.44] and 1.39 [1.03-1.87]). CONCLUSIONS: We identified six prevalent metabolic profiles in patients with T2D. Severe hyperglycemia and moderate dyslipidemia were validated as significant risk markers for DKD.

A CCL2+DPP4+ subset of mesenchymal stem cells expedites aberrant formation of creeping fat in humans.

Creeping fat is a typical feature of Crohn's disease. It refers to the expansion of mesenteric adipose tissue around inflamed and fibrotic intestines and is associated with stricture formation and intestinal obstruction. In this study, we characterize creeping fat as pro-adipogenic and pro-fibrotic. Lipidomics analysis of Crohn's disease patients (sixteen males, six females) and healthy controls (five males, ten females) reveals abnormal lipid metabolism in creeping fat. Through scRNA-seq analysis on mesenteric adipose tissue from patients (five males, one female) and healthy controls (two females), we identify a CCL2+DPP4+ subset of mesenchymal stem cells that expands in creeping fat and expedites adipogenic differentiation into dystrophic adipocytes in response to CCL20+CD14+ monocytes and IL-6, leading to the formation of creeping fat. Ex vivo experiments (tissues from five males, one female) confirm that both CCL20+CD14+ monocytes and IL-6 activate DPP4+ mesenchymal stem cells towards a pro-adipogenic phenotype. This study provides a comprehensive investigation of creeping fat formation and offers a conceptual framework for discovering therapeutic targets for treatment of Crohn's disease.

Advanced oxidation protein products induce Paneth cells defects by endoplasmic reticulum stress in Crohn's disease.

Paneth cells (PC) play a key role in the innate immune response of intestine epithelium, and PC defects contribute to the pathogenesis of Crohn's disease (CD). In this study, we utilized active CD tissues and advanced oxidation protein products (AOPP)-challenged C57BL/6 mouse model to investigate the effect of AOPP on PC defects in CD. We found that AOPP accumulated in active CD tissues and was negatively associated with lysozyme expression, while positively correlated with the presence of ER stress markers. Furthermore, AOPP treatment induced PC defects mainly through excessive ER stress in vivo, and AOPP also caused mitochondria-associated ER membranes formation and mitochondrial dysfunction. In addition, the effects of AOPP could be attenuated by the administration of ER stress inhibitor, TUDCA. These findings suggest a pathogenic role of AOPP contributing to PC defects and may provide the basis for developing new strategies to managing CD.

Advances of the small molecule drugs regulating fibroblast-like synovial proliferation for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a type of chronic autoimmune and inflammatory disease. In the pathological process of RA, the alteration of fibroblast-like synoviocyte (FLS) and its related factors is the main influence in the clinic and fundamental research. In RA, FLS exhibits a uniquely aggressive phenotype, leading to synovial hyperplasia, destruction of the cartilage and bone, and a pro-inflammatory environment in the synovial tissue for perpetuation and progression. Evidently, it is a highly promising way to target the pathological function of FLS for new anti-RA drugs. Based on this, we summed up the pathological mechanism of RA-FLS and reviewed the recent progress of small molecule drugs, including the synthetic small molecule compounds and natural products targeting RA-FLS. In the end, there were some views for further action. Compared with MAPK and NF-κB signaling pathways, the JAK/STAT signaling pathway has great potential for research as targets. A small number of synthetic small molecule compounds have entered the clinic to treat RA and are often used in combination with other drugs. Meanwhile, most natural products are currently in the experimental stage, not the clinical trial stage, such as triptolide. There is an urgent need to unremittingly develop new agents for RA.

Plasma metabolomics identifies metabolic alterations associated with the growth and development of cat.

BACKGROUND: The purpose of our study was to study the composition and content of the feline plasma metabolome revealing the critical metabolites and metabolic pathways associated with age during growth and development. METHODS: Blood samples were collected from juvenile and adult groups for blood routine tests and serum biochemistry tests. Non-targeted metabolomics analyses of plasma were also performed to investigate changes in metabolites and metabolic pathways. RESULTS: In this study, we found that the red blood cell counts, liver function indexes (albumin and gamma-glutamyl transpeptidase), and the concentration of triglyceride and glucose changed significant with growth and development. The metabolomics results revealed that 1427 metabolites were identified in the plasma of young and adult cats. Most of these metabolites belong to major classes of lipids and lipid-like molecules. The most obvious age-related metabolites include reduced levels of chenodeoxycholate, taurocholate, cholate, and taurochenodeoxycholate but increased levels of L-cysteine and taurocyamine in the adult cat's serum. These metabolites are mainly involved in the primary bile acid biosynthesis pathway, the bile secretion pathway, and the taurine and hypotaurine metabolism pathway. CONCLUSION: This study revealed many age-related metabolite alterations in the feline plasma. These age-varying metabolites, especially in the bile acid biosynthesis and secretion metabolism pathways, indicate that the regulation of these pathways is involved in the growth and development of cats. This study promotes our understanding of the mechanism of feline growth and provides new insights into nutrition and medicine for cats of different ages.

Immune-related adverse events of immune checkpoint inhibitors: a review.

Since the first Immune Checkpoint Inhibitor was developed, tumor immunotherapy has entered a new era, and the response rate and survival rate of many cancers have also been improved. Despite the success of immune checkpoint inhibitors, resistance limits the number of patients who can achieve a lasting response, and immune-related adverse events complicate treatment. The mechanism of immune-related adverse events (irAEs) is unclear. We summarize and discuss the mechanisms of action of immune checkpoint inhibitors, the different types of immune-related adverse events and their possible mechanisms, and describe possible strategies and targets for prevention and therapeutic interventions to mitigate them.