A booming field of large animal model research

Animal models are integral to the study of fundamental biological processes and the etiology of human diseases.Small animal models,especially those involving mice,have yielded abundant and significant insights,greatly enhancing our understanding of biological phenomena and disease mechanisms.

Alcohol promotes epithelial mesenchymal transformation-mediated premetastatic niche formation of colorectal cancer by activating interaction between laminin-γ2 and integrin-β1

BACKGROUND Colorectal cancer(CRC) is a common malignant tumor. Alcohol consumption is positively correlated with CRC malignant metastasis;however, the mechanism is unclear. The interaction between laminin-γ2(LAMC2) and integrin-β1(ITGB1) plays a role in premetastatic niche signaling, which may induce epithelial mesenchymal transformation(EMT) and lead to metastasis.AIM To investigate the effects of alcohol on CRC metastasis from the molecular mechanism of the premetastatic niche.METHODS The interaction between LAMC2 and ITGB1 was measured by Duolink assay, and the expression levels of LAMC2, ITGB1 and focal adhesion kinase(FAK), snail, fibronectin, N-cadherin and special AT-rich sequence binding protein 1(SATB1) were measured by quantitative real-time polymerase chain reaction, immunohistochemistry and western blotting. Interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α) and IL-6 levels were measured via enzyme-linked immunosorbent assay, histopathological assessment via hematoxylin eosin staining, and determination of aberrant crypt foci via methylene blue.RESULTS The lymph node metastasis rate was higher in the alcohol group than non-alcohol group. There was a significant increase in interaction signals between LAMC2 and ITGB1, and an increase in phosphorylate-FAK/FAK, snail, fibronectin, N-cadherin and SATB1, whereas E-cadherin was reduced in the alcohol group compared to the non-alcohol group in both animal and clinical samples. Serum IL-1β, TNF-α and IL-6 were higher in alcohol group than in non-alcohol group. Alcohol may promote CRC metastasis by influencing the molecular mechanism of the premetastatic niche.CONCLUSION Our study suggests that alcohol promotes EMT-mediated premetastatic niche formation of CRC by activating the early interaction between LAMC2 and ITGB1 and lead to CRC metastasis.

Evaluation of hypoglycemic and hypolipidemic activities of aqueous extract of Cistus ladaniferus in streptozotocin-induced diabetic rats

Objective:To evaluate the effect of aqueous leaf extract of Cistus ladaniferus(C.ladaniferus) on glycemic and lipidemic status in diabetic rats.Methods:Overnight fasted rats were injected intraperitoneally with streptozotocin(45 mg/kg) to induce experimental diabetes.The aqueous extract of the leaves of C.ladaniferus was administered orally at the dose of 500 mg/kg body weight to diabetic rats for a period of 28 days.Hypoglycemic effect,body weight,oral glucose tolerance,change in lipid parameters,urea,creatinine,aspartate aminotransferase and alanine aminotransferase levels of diabetic rats treated with aqueous extract were evaluated in experimental animals.Results:Administration of 500 mg/kg of C.ladaniferus extract to diabetic rats for 28 days resulted in a significant reduction in the levels of blood glucose,alanine aminotransferase,aspartate aminotransferase,urea and creatinine.Furthermore,the extract of C.ladaniferus improved glucose tolerance in diabetic rats,and its antidiabetic effect was similar to the one obtained with glibenclamide.The hypolipidemic effect was demonstrated by an important decrease in plasma total cholesterol,triglycerides and low density lipoprotein-cholesterol levels.Conclusions:It is concluded that C.ladaniferus leaf extract showed an antidiabetic activity in experimental diabetes which was similar to the one obtained with glibenclamide.

Assessment of Heavy Metals Content in Sewage Discharges from Health Structure in Mauritania

This study was carried to assess the quality of liquid waste produced by the Nouakchott Friendship Hospital in Mauritania,the aim is to quantify different heavy metals obtained from discharge of the hospital waste six heavy metals(arsenic,lead,cobalt,chromium,cadmium and copper)were object of evaluation.Analysis was carried using inductively coupled plasma-optical emission spectrometry(ICP-OES)method and the standards used are those of the WHO.The average content of heavy metals in different samples is different:Arsenic(4.625μg/L),Lead(3.800μg/L),Cyanide(0.05μg/L),Chromium(0.013μg/L),Cadmium(<LD(0.000000012μg/L)and Copper(60μg/L).Results showed that the samples of liquid waste from the Nouakchott Friendship Hospital were very loaded with pollutants,this may constitute a threat to the environment and a potential health risk for human,since the continuous introduction of these heavy metals into aquatic medium could be harmful through bioaccumulation and biomagnifications.

Mimotope peptide modified pompon mum-like magnetic microparticles for precise recognition,capture and biotransformation analysis of rituximab in biological fluids

Due to low immobilized ligand density,limited binding capacity,and severe interference from serum proteins,developing ideal peptide-based biomaterials for precise recognition and in vivo analysis of biopharmaceuticals remains a huge challenge.In this study,mimotope peptide modified pompon mum-like biomimetic magnetic microparticles(MMPs,3.8μm)that mimic the specific functionalities of CD20 on malignant B cells were developed for the first time.Benefit from the numerous ligand binding sites(Ni^(2+))on the pompon mum-like MMPs,these novel materials achieved≥10 times higher peptide ligand densities(>2300 mg/g)and antibody binding capacities(1380 mg/g)compared to previous reported biomaterials.Leveraging the high specificity of the mimotope peptide,rituximab can be precisely recognized and enriched from cell culture media or serum samples.We also established an LC-MS/MS method using the MMPs for tracking rituximab biotransformation in patient serum.Intriguingly,deamidation of Asn55 and Asn33,as well as oxidation of Met81 and Met34 were observed at the key complementarity determining regions of rituximab,which could potentially influence antibody function and require careful monitoring.Overall,these versatile biomimetic MMPs demonstrate superior recognition and enrichment capabilities for target antibodies,offering interesting possibilities for biotransformation analysis of biopharmaceuticals in patient serum.

GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer

Glutamate-ammonia ligase(GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.

Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of death.Ginkgo biloba,a well-known traditional Chinese medicine with notable cardiovascular actions,has been used as a cardio-and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries.Preclinical studies have shown that ginkgolide B,a bioactive component in Ginkgo biloba,can ameliorate atherosclerosis in cultured vascular cells and disease models.Of clinical relevance,several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases,such as ischemia stroke.Here,we present a comprehensive review of the pharmacological activities,pharmacokinetic characteristics,and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy.We highlight new molecular targets of ginkgolide B,including nicotinamide adenine dinucleotide phosphate oxidases(NADPH oxidase),lectin-like oxidized LDL receptor-1(LOX-1),sirtuin 1(SIRT1),platelet-activating factor(PAF),proprotein convertase subtilisin/kexin type 9(PCSK9)and others.Finally,we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

The evolution and significance of medicine and food homology

Historical insights into medicine and food homology(MFH)Evolution of the MFH theory MFH,a basic concept in traditional Chinese medicine(TCM),suggests that many materials function as both food and medicine,providing nourishment and simultaneously treating ailments.This concept has evolved significantly throughout TCM history^([1]).Integral to this evolution was the discovery of certain materials with dual purposes during early searches for food.These materials not only offer sustenance and nutrition but are also capable of treating simple illnesses^([2]).

Marsdenia tenacissima injection induces the apoptosis of prostate cancer by regulating the AKT/GSK3β/STAT3 signaling axis

Marsdenia tenacissima injection,a standard Marsdenia tenacissima extract(MTE),has been approved as an adjuvant therapeutic agent for various cancers.Our previous study showed that MTE inhibited the proliferation and metastasis of prostate cancer(PCa)cells.However,the underlying mechanisms and active ingredients of MTE against PCa were not completely understood.This study revealed that MTE induced significant decreases in cell viability and clonal growth in PCa cells.In addition,MTE induced the apoptosis of DU145 cells by reducing the mitochondrial membrane potential and increasing the expression of Cleaved Caspase 3/7,Cyt c,and Bax.In vivo,DU145 xenografted NOD-SCID mice treated with MTE showed significantly decreased tumor size.TUNEL staining and Western blot confirmed the pro-apoptotic effects of MTE.Network pharmacology analysis collected 196 ingredients of MTE linked to 655 potential targets,and 709 PCa-associated targets were retrieved,from which 149 overlapped targets were screened out.Pathway enrichment analysis showed that the HIF-1,PI3K-AKT,and ErbB signaling pathways were closely related to tumor apoptosis.Western blot results confirmed that MTE increased the expression of p-AKT^(Ser473) and p-GSK3β^(Ser9),and decreased the expression of p-STAT3^(Tyr705) in vitro and in vivo.A total of 13 compounds in MTE were identified by HPLC-CAD-QTOF-MS/MS and UPLCQTOF-MS/MS.Molecular docking analysis indicated that six compounds may interact with AKT,GSK3β,and STAT3.In conclusion,MTE induces the endogenous mitochondrial apoptosis of PCa by regulating the AKT/GSK3β/STAT3 signaling axis,resulting in inhibition of PCa growth in vitro and in vivo.

Scutellaria baicalensis:a promising natural source of antiviral compounds for the treatment of viral diseases

Viruses,the smallest microorganisms,continue to present an escalating threat to human health,being the leading cause of mortality worldwide.Over the decades,although significant progress has been made in the development of therapies and vaccines against viral diseases,the need for effective antiviral interventions remains urgent.This urgency stems from the lack of effective vaccines,the severe side effects associated with current drugs,and the emergence of drug-resistant viral strains.Natural plants,particularly traditionally-used herbs,are often considered an excellent source of medicinal drugs with potent antiviral efficacy,as well as a substantial safety profile.Scutellaria baicalensis,a traditional Chinese medicine,has garnered considerable attention due to its extensive investigation across diverse therapeutic areas and its demonstrated efficacy in both preclinical and clinical trials.In this review,we mainly focused on the potential antiviral activities of ingredients in Scutellaria baicalensis,shedding light on their underlying mechanisms of action and therapeutic applications in the treatment of viral infections.

Six new coumarins from the roots of Toddalia asiatica and their anti-inflammatory activities

We reported the discovery of six novel coumarins, toddasirins A–F ( 1 – 6 ), each endowed with modified isoprenyl or geranyl side chains, derived from the roots of Toddalia asiatica. Comprehensive structural elucidation was achieved through multispectroscopic analyses, single-crystal X-ray diffraction experiments, and advanced quantum mechanical electronic circular dichroism (ECD) calculations. Furthermore, the anti-inflammatory activity of these compounds was assessed. Notably, compounds 1 – 3 and 6 demonstrated notable inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cells, with 50% inhibitory concentration (IC50) values of 3.22, 4.78, 8.90, and 4.31 μmol·L^(−1), respectively.

Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer(LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha(FAPα) expression in LNM-CRC cells. Gain-or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis(CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

Neuron navigator 2 is a novel mediator of rheumatoid arthritis

Rheumatoid arthritis(RA)is a systemic autoimmune disease mainly characterized by synovial tumor-like hyperplasia,synovial inflammation,and damage to adjacent cartilage and bones.^(1) Our previous study provided evidence that cystathionine-γ-lyase(CSE)and the histone demethylase JMJD3 are significantly increased in RA,and CSE was found to negatively regulate the inflammatory response in fibroblast-like synoviocytes(FLSs),which was mainly attributed to JMJD3 inhibition,in RA.

Effects of iodoacetic acid drinking water disinfection byproduct on the gut microbiota and its metabolism in rats

Iodoacetic acid(IAA) is an unregulated disinfection byproduct in drinking water and has been shown to exert cytotoxicity, genotoxicity, tumorigenicity, and reproductive and developmental toxicity. However, the effects of IAA on gut microbiota and its metabolism are still unknown, especially the association between gut microbiota and the metabolism and toxicity of IAA. In this study, female and male Sprague–Dawley rats were exposed to IAA at 0 and 16 mg/kg bw/day daily for 8 weeks by oral gavage. Results of 16S r RNA gene sequencing showed that IAA could alter the diversity, relative abundance and function of gut microbiota in female and male rats. IAA also increased the abundance of genes related to steroid hormone biosynthesis in the gut microbiota of male rats. Moreover, metabolomics profiling revealed that IAA could significantly disturb 6 and 13 metabolites in the feces of female and male rats, respectively. In female rats, the level of androstanediol increased in the IAA treatment group. These results were consistent with our previous findings, where IAA was identified as an androgen disruptor. Additionally, the perturbed gut microbiota and altered metabolites were correlated with each other. The results of this study indicated that IAA could disturb gut microbiota and its metabolism. These changes in gut microbiota and its metabolism were associated with the reproductive and developmental toxicity of IAA.

A general principle enabling the design of ultrastable metal nanocatalysts

The design and the development of catalysts with high activity,high selectivity and high stability are of great significance for improving the efficiency of catalytic reactions,saving energy and reducing consumption,which is particularly important for achieving the dual-carbon goal.The development and the guidance of advanced catalytic theories are urgently needed[1].The Sabatier’s principle of catalyst activity states that the interaction between the reactants and the catalyst should not be too strong or too weak.As one of the basic theories of heterogeneous catalysis developed on this basis in the past century,it has profoundly affected the design of modern catalysts[2].

STAT3-NAV2 axis as a new therapeutic target for rheumatoid arthritis via activating SSH1L/Cofilin-1 signaling pathway

Dear Editor,Rheumatoid arthritis(RA),which is the most common inflammatory arthritis disease,as well as a kind of most prevalent autoimmune disease,affects 1–3%population all over the world.1 Currently available treatments can reduce the disability rate of patients with RA to some extent,but they cannot completely block the inflammatory joint destruction and relieve the pain that comes with it.Our previous study found that Neuron Navigator 2(NAV2)increased significantly in RA and was regulated by transcription factor E2F1.2 However,it is still unclear why NAV2 is elevated at the genetic level in RA fibroblast-like synoviocytes(FLS).Additionally,RA’s exact pathological mechanisms and therapeutic targets are also not fully understood.Hence,an indepth study of the pathogenesis of RA is urgently needed.

Accurate Description of Catalytic Selectivity:Challenges and Opportunities for the Development of Density Functional Approximations

An accurate description of catalytic selectivity poses an enormous challenge for theoretical simulations.Due to the absence of a well-defined benchmark set on the catalytic selectivity,the performance of even the widely used density functional approximations(DFAs)is yet to be validated.This work reports a test set based on the selective hydrogenation ofα,β-unsaturated aldehydes catalyzed by ruthenium(Ru)hydride complexes.Special attention is paid to benchmark the regioselectivity of aldehydes to either unsaturated alcohols or saturated aldehydes.Accurate reference data were calculated by the massive parallel implementation of the coupled-cluster single,double,and perturbative triple excitations[CCSD(T)]approach,based completely on set limits.Furthermore,we performed the microkinetic simulation based on the CCSD(T)energy profiles,serving the most direct criteria for the performance of DFAs on catalytic selectivity of hydrogenation reactions.Using this test set,we uncovered the intrinsic difficulty of semilocal and hybrid functionals for such a purpose.In the context of the XYG3-type double hybrid(xDH)framework,we showed that this particular challenge could be addressed by the top rung functionals only when the many-body nondynamic correlation effect was accounted for adequately.A recently proposed xDH,namely scsRPA,showed unprecedented accuracy with only 5%error on average.The predicted kinetic selectivity by scsRPA is in close agreement with the reference value,revealing a unique versatility of the top rung DFAs for a reliable description of catalytic selectivity of hydrogenation reactions.

Signaling pathways in rheumatoid arthritis:implications for targeted therapy

Rheumatoid arthritis(RA)is an incurable systemic autoimmune disease.Disease progression leads to joint deformity and associated loss of function,which significantly impacts the quality of life for sufferers and adds to losses in the labor force.In the past few decades,RA has attracted increased attention from researchers,the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA,which provides important evidence for understanding this complex disease and developing novel RA-linked intervention targets.The current review intends to provide a comprehensive overview of RA,including a general introduction to the disease,historical events,epidemiology,risk factors,and pathological process,highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms,including genetic factors,epigenetic factors,summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating RA.therapeutic interventions including approved drugs,clinical drugs,pre-clinical drugs,and cutting-edge therapeutic technologies.These developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future.

基于高凝集素亲和性载体的抗生素吸入粉雾剂用于高效治疗细菌生物膜相关肺部感染

多重耐药细菌引发的肺部感染对人类健康构成了严重威胁.细菌生物膜加剧了肺部感染的持续和复发,限制了抗生素的可及性和有效性.基于凝集素竞争策略和颗粒表面修饰策略,本研究设计了一种硫酸多粘菌素B(PMBS)的吸入粉雾剂(DPI)用于治疗肺部感染.该制剂的载体是具有高凝集素亲和性(HLA)的小分子糖(如棉子糖),可靶向细菌凝集素,限制生物膜的扩展.该制剂的粒径约为3μm,其表面褶皱程度和药物与载体的比例有关.处方F_(5)(PMBS:棉子糖=10:90)表现出最高的微细粒子分数(FPF=64.86%),表明其具备显著增强的肺部药物递送效率.通过添加棉子糖,制剂在抑制生物膜形成和清除成熟生物膜方面的效果显著提高.在急性和慢性肺部感染的大鼠模型中,相较于喷雾干燥的PMBS,处方F_(5)表现出更强的抗菌效果,并引起更低炎症反应.综上,基于HLA载体的抗生素DPI具有治疗细菌生物膜相关肺部感染的良好前景.

Leonurine: From Gynecologic Medicine to Pleiotropic Agent

Leonurus japonicus Houtt,a Chinese traditional herbal medicine,has been widely used to cure gynecological diseases,such as incomplete abortion and menoxenia.Leonurine,a major active alkaloid compound only be found in Leonurus japonicus Houtt,has been successfully extracted and purified.Recent evidence has shown that leonurine can regulate a variety of pathologic processes including oxidative stress,inflammation,fibrosis,apoptosis,and multiple metabolic disorders.Here,we have reviewed the pharmacological actions and biological functions of leonurine,with a focus on the role of leonurine in the amelioration of various pathological processes.Insights into the related signaling pathways and molecular mechanisms have strengthened our understanding on the function of leonurine in the alleviation of multiple pathological states.Our summary of the existing researches should help direct future research into the basic science and clinical applications in related diseases.