Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases

As a ligand-dependent transcription factor,retinoid-associated orphan receptor gt(RORγt)that controls T helper(Th)17 cell differentiation and interleukin(IL)-17 expression plays a critical role in the progression of several inflammatory and autoimmune conditions.An emerging novel approach to the therapy of these diseases thus involves controlling the transcriptional capacity of RORγt to decrease Th17 cell development and IL-17 production.Several RORγt inhibitors including both antagonists and inverse agonists have been discovered to regulate the transcriptional activity of RORγt by binding to orthosteric-or allosteric-binding sites in the ligand-binding domain.Some of small-molecule inhibitors have entered clinical evaluations.Therefore,in current review,the role of RORγt in Th17 regulation and Th17-related inflammatory and autoimmune diseases was highlighted.Notably,the recently developed RORγt inhibitors were summarized,with an emphasis on their optimization from lead compounds,efficacy,toxicity,mechanisms of action,and clinical trials.The limitations of current development in this area were also discussed to facilitate future research.

Combination of Shengmai San and Radix puerariae ameliorates depression-like symptoms in diabetic rats at the nexus of PI3K/BDNF/SYN protein expression

Background:Hyperglycemia is a characteristic feature of diabetes that often results in neuropsychological complications such as depression.Diabetic individuals are more vulnerable to experience depression compared to the normal population.Thus,novel treatment approaches are required to reduce depressive symptoms among diabetic individuals.Traditional Chinese medicines(TCMs)such as Shengmai San(SMS)and Radix puerariae(R)are usually widely used to treat ailments such as neurological com-plications since ancient time.Methods:In this study,SMS was combined with R to prepare an R-SMS formulation and screened for their antidepressant activity in diabetic rats.The antidepressant po-tential of the prepared combination was evaluated behaviorally using open field test,novelty-induced hypophagia,and forced swim test in diabetic rats with biochemical and protein expression(PI3K,BDNF[brain-derived neurotrophic factor],and SYN[pr-esynaptic vesicle protein])analysis.Results:Diabetic rats(streptozotocin,45 mg/kg)showed elevated fasting blood glu-cose(FBG)>12 mM with depressive symptoms throughout the study.Treatment with R-SMS(0.5,1.5,and 4.5 g/kg)significantly reverted depressive symptoms in diabetic rats as evinced by significantly(p<0.05)reduced immobility time with an increased tendency to eat food in a novel environment.Treatment with R-SMS also significantly increased the protein expression of PI3K,BDNF,and SYN protein,which play a crucial role in depression.Conclusion:This study showed that R-SMS formulation antagonized depressive symptoms in diabetic rats;thus,this formulation might be studied further to develop as an antidepressant.

Synergism of calycosin and bone marrow-derived mesenchymal stem cells to combat podocyte apoptosis to alleviate adriamycininduced focal segmental glomerulosclerosis

BACKGROUND Bone marrow-derived mesenchymal stem cells(MSCs)show podocyte-protective effects in chronic kidney disease.Calycosin(CA),a phytoestrogen,is isolated from Astragalus membranaceus with a kidney-tonifying effect.CA preconditioning enhances the protective effect of MSCs against renal fibrosis in mice with unilateral ureteral occlusion.However,the protective effect and underlying mechanism of CA-pretreated MSCs(MSCsCA)on podocytes in adriamycin(ADR)-induced focal segmental glomerulosclerosis(FSGS)mice remain unclear.AIM To investigate whether CA enhances the role of MSCs in protecting against podocyte injury induced by ADR and the possible mechanism involved.METHODS ADR was used to induce FSGS in mice,and MSCs,CA,or MSCsCA were administered to mice.Their protective effect and possible mechanism of action on podocytes were observed by Western blot,immunohistochemistry,immunofluorescence,and real-time polymerase chain reaction.In vitro,ADR was used to stimulate mouse podocytes(MPC5)to induce injury,and the supernatants from MSC-,CA-,or MSCsCA-treated cells were collected to observe their protective effects on podocytes.Subsequently,the apoptosis of podocytes was detected in vivo and in vitro by Western blot,TUNEL assay,and immunofluorescence.Overexpression of Smad3,which is involved in apoptosis,was then induced to evaluate whether the MSCsCA-mediated podocyte protective effect is associated with Smad3 inhibition in MPC5 cells.RESULTS CA-pretreated MSCs enhanced the protective effect of MSCs against podocyte injury and the ability to inhibit podocyte apoptosis in ADR-induced FSGS mice and MPC5 cells.Expression of p-Smad3 was upregulated in mice with ADR-induced FSGS and MPC5 cells,which was reversed by MSCCA treatment more significantly than by MSCs or CA alone.When Smad3 was overexpressed in MPC5 cells,MSCsCA could not fulfill their potential to inhibit podocyte apoptosis.CONCLUSION MSCsCA enhance the protection of MSCs against ADR-induced podocyte apoptosis.The underlying mechanism may be related to MSCsCA-targeted inhibition of p-Smad3 in podocytes.

5’tiRNA-Pro-TGG,a novel tRNA halve,promotes oncogenesis in sessile serrated lesions and serrated pathway of colorectal cancer

BACKGROUND Transfer RNA(tRNA)-derived small RNAs(tsRNAs)are small fragments that form when tRNAs severe.tRNA halves(tiRNAs),a subcategory of tsRNA,are involved in the oncogenic processes of many tumors.However,their specific role in sessile serrated lesions(SSLs),a precancerous lesion often observed in the colon,has not yet been elucidated.AIM To identify SSL-related tiRNAs and their potential role in the development of SSLs and serrated pathway of colorectal cancer(CRC).METHODS Small-RNA sequencing was conducted in paired SSLs and their adjacent normal control(NC)tissues.The expression levels of five SSL-related tiRNAs were validated by q-polymerase chain reaction.Cell counting kit-8 and wound healing assays were performed to detect cell proliferation and migration.The target genes and sites of tiRNA-1:33-Pro-TGG-1(5′tiRNA-Pro-TGG)were predicted by TargetScan and miRanda algorithms.Metabolism-associated and immune-related pathways were analyzed by single-sample gene set enrichment analysis.Functional analyses were performed to establish the roles of 5′tiRNA-Pro-TGG based on the target genes.RESULTS In total,we found 52 upregulated tsRNAs and 28 downregulated tsRNAs in SSLs compared to NC.The expression levels of tiRNA-1:33-Gly-CCC-2,tiRNA-1:33-Pro-TGG-1,and tiRNA-1:34-Thr-TGT-4-M25′tiRNAs were higher in SSLs than those in NC,while that of 5′tiRNA-Pro-TGG was associated with the size of SSLs.It was demonstrated that 5′tiRNAPro-TGG promoted cell proliferation and migration of RKO cell in vitro.Then,heparanase 2(HPSE2)was identified as a potential target gene of 5′tiRNA-Pro-TGG.Its lower expression was associated with a worse prognosis in CRC.Further,lower expression of HPSE2 was observed in SSLs compared to normal controls or conventional adenomas and in BRAF-mutant CRC compared to BRAF-wild CRC.Bioinformatics analyses revealed that its low expression was associated with a low interferonγresponse and also with many metabolic pathways such as riboflavin,retinol,and cytochrome p450 drug metabolism pathways.CONCLUSION tiRNAs may profoundly impact the development of SSLs.5′tiRNA-Pro-TGG potentially promotes the progression of serrated pathway CRC through metabolic and immune pathways by interacting with HPSE2 and regulating its expression in SSLs and BRAF-mutant CRC.In the future,it may be possible to use tiRNAs as novel biomarkers for early diagnosis of SSLs and as potential therapeutic targets in serrated pathway of CRC.

The Effect of TSH Suppression Therapy on the Efficacy and Immune Function of Postoperative Patients with Thyroid Cancer

Objective:To investigate the efficacy and immune function of thyroid stimulating hormone(TSH)suppression therapy in postoperative thyroid cancer patients.Methods:Sixty thyroid cancer patients admitted from July 2020–July 2022 were recruited and randomly divided into two groups.The control group(30 patients)received hormone replacement therapy,while the study group(30 patients)received TSH suppression therapy.The thyroid function,clinical efficacy,immune function,and tumor markers of the two groups were compared.Results:After treatment,the levels of free triiodothyronine(FT3)and thyroxine(FT4)in both groups increased significantly,while TSH levels decreased significantly.Moreover,the magnitude of change in the study group was greater than that in the control group(P<0.05).The total effective rate in the study group was significantly higher as compared to the control group(P<0.05).After treatment,the levels of CD3+and CD4+cells in both groups of patients increased significantly,with the study group showing significantly higher levels than the control group,whereas the level of CD8+cells decreased significantly,with the study group having lower levels than the control group(P<0.05).After treatment,the levels of Tg and CEA in both groups were significantly lowered as compared to before treatment,and the levels of Tg and CEA in the study group were significantly lower than the control group(P<0.05).Conclusion:TSH suppression therapy in postoperative thyroid cancer patients can improve thyroid function,suppress the levels of tumor markers,and enhance immune function,thereby achieving good clinical outcomes.

Methamphetamine:Mechanism of Action and Chinese Herbal Medicine Treatment for Its Addiction

With the proliferation of synthetic drugs,research on the mechanism of action of addictive drugs and treatment methods is of great significance.Among them,methamphetamine(METH)is the most representative amphetamine synthetic drug,and the treatment of METH addiction has become an urgent medical and social problem.In recent years,the therapeutic effects of Chinese herbal medicines on METH addiction have gained widespread attention because of their non-addictiveness,multiple targets,low side effects,low cost,and other characteristics.Previous studies have identified a variety of Chinese herbal medicines with effects on METH addiction.Based on the research on METH in recent years,this article summarizes the mechanism of action of METH as the starting point and briefly reviews the Chinese herbal medicine-based treatment of METH.

Influence of weight management on the prognosis of steatohepatitis in chronic hepatitis B patients during antiviral treatment

Background:Although concomitant nonalcoholic steatohepatitis(NASH)is common in chronic hepatitis B(CHB),the impact of viral factors on NASH and the outcome of CHB patients concomitant with NASH remain unclear.We aimed to investigate the outcomes of NASH in CHB patients receiving antiviral treatment.Methods:In the post-hoc analysis of a multicenter trial,na?ve CHB patients receiving 72-week entecavir treatment were enrolled.We evaluated the biochemical,viral and histopathological responses of these patients.The histopathological features of NASH were also evaluated,using paired liver biopsies at baseline and week 72.Results:A total of 1000 CHB patients were finally enrolled for analysis,with 18.2%of whom fulfilling the criteria of NASH.A total of 727 patients completed entecavir antiviral treatment and received the second biopsy.Serum HBe Ag loss,HBe Ag seroconversion and HBV-DNA undetectable rates were similar between patients with or without NASH(P>0.05).Among patients with NASH,the hepatic steatosis,ballooning,lobular inflammation scores and fibrosis stages all improved during follow-up(all P<0.001),46%(63/136)achieved NASH resolution.Patients with baseline body mass index(BMI)≥23 kg/m2(Asian criteria)[odds ratio(OR):0.414;95%confidence interval(95%CI):0.190-0.899;P=0.012]and weight gain(OR:0.187;95%CI:0.050-0.693;P=0.026)were less likely to have NASH resolution.Among patients without NASH at baseline,22(3.7%)developed NASH.Baseline BMI≥23 kg/m2(OR:12.506;95%CI:2.813-55.606;P=0.001)and weight gain(OR:5.126;95%CI:1.674-15.694;P=0.005)were predictors of incident NASH.Conclusions:Lower BMI and weight reduction but not virologic factors determine NASH resolution in CHB.The value of weight management in CHB patients during antiviral treatment deserves further evaluation.

Surgery and antibiotics for the treatment of lupus nephritis with cerebral abscesses:A case report

BACKGROUND Systemic lupus erythematosus(SLE)patients are extremely susceptible to opportunistic infections due to glucocorticoid and immunosuppressive treatments,which often occur in the respiratory system,the urinary system and the skin.However,multiple cerebral infections are rarely reported and their treatment is not standardized,especially when induced by a rare pathogen.CASE SUMMARY A 46-year-old woman was treated with glucocorticoid and immunosuppressant for SLE involving the hematologic system and kidneys(class IV-G lupus nephritis)for more than one year.She was admitted to hospital due to headache and fever,and was diagnosed with multiple cerebral abscesses.Brain enhanced magnetic resonance imaging showed multiple nodular abnormal signals in both frontal lobes,left parietal and temporal lobes,left masseteric space(left temporalis and masseter region).The initial surgical plan was only to remove the large abscesses in the left parietal lobe and right frontal lobe.After surgery,based on the drug susceptibility test results(a rare pathogen Nocardia asteroides was found)and taking into consideration the patient’s renal dysfunction,a multi-antibiotic regimen was selected for the treatment.The immunosuppressant mycophenolate mofetil was discontinued on admission and the dose of prednisone was reduced from 20 mg/d to 10 mg/d.Re-examination at 3 mo post-surgery showed that the intracranial lesions were reduced,the edema around the lesions was absorbed and dissipated,and her neurological symptoms had disappeared.The patient had no headaches or other neurological symptoms and lupus nephritis was stable during the 2-year follow-up period.CONCLUSION In this report,we provide reasonable indications for immunosuppression,anti-infective therapy and individualized surgery for an SLE patient complicated with multiple cerebral abscesses caused by a rare pathogen,which may help improve the diagnosis and treatment of similar cases.

Influence of Intestinal Lymphatic Ligation on Pulmonary Injury in Rats with Severe Acute Pancreatitis

Objective:The present study explored the mechanisms involved in intestinal lymphatic ligation in rats with severe acute pancreatitis(SAP).Methods:Male Sprague Dawley rats were randomly divided into 4 groups:saline group,saline+ligation group,SAP group,and SAP+ligation group.Rats in the SAP group were administered sodium taurocholate solution.Isolated mesenteric lymph duct ligation was administered to the saline+ligation and SAP+ligation groups.Endotoxin(ET),nitric oxide(NO),tumor necrosis factor-α(TNF-α),interleukin-1(IL-1),myeloperoxidase(MPO),and superoxide dismutase(SOD)were detected.Nuclear factor-KB(NF-κB)and intercellular cell adhesion molecule-1(ICAM-1)proteins were observed.The mRNA of inducible nitric oxide synthase(iNOS)and Toll-like receptor 4(TLR4)was detected by PCR.Results:Pathomorphological analysis showed that necrosis was present in the lung of rats in the SAP group,but only mild lesions in the SAP+ligation group.ET,NO,TNF-α,and IL-1 in the serum and lung tissue were significantly decreased and MPO was increased in the SAP+ligation group as compared with the SAP group.However,MPO was increased.The expression of NF-κB and ICAM-1,either iNOS or TLR4,was upregulated in the SAP group,but downregulated in the SAP+ligation group.Intestinal lymph duct ligation prevented ET translocation,the release of inflammation factors,and inflammation injury.Conclusion:The intestinal lymph duct ligation could alleviate SAP-induced pulmonary injury by suppressing NF-κB activation in rats.

Effect of splitting combination of different components of Zhilong Huoxue Tongyu Capsule on vascular remodeling in hypertension

目的：观察蛭龙活血通瘀胶囊拆方组分对大鼠血管NF-κB-P65、ICAM-1表达的影响,探讨蛭龙活血通瘀胶囊及其拆方组分对高血压血管重构的影响及作用机制.方法：手术组缩窄左肾动脉建立肾性高血压大鼠模型.分别给予相应药物1次/日灌胃,以同体积生理盐水灌胃正常组、假手术组与模型组.灌胃4周后,取大鼠胸主动脉,依次固定、包埋、切片、HE染色,免疫组化的方法检测血管NF-κB-p65.结果：1.药物对高血压大鼠胸主动脉NF-κB蛋白表达的影响（免疫组化法）：电镜下,棕黄色颗粒为NF-κB蛋白阳性表达,主要分布于血管中膜平滑肌.正常组及假手术组可见少量的棕黄色颗粒;模型组可见散在分布的大量表达棕黄色颗粒;经治疗后,卡托普利组、全方组表达较模型组明显减少,补气组、温通经络组、活血化瘀组表达较模型组有所减少.其中卡托普利组较全方组有所减少;补气组较活血化瘀组表达明显减少,与温通经络组表达相当.结论：蛭龙活血通瘀胶囊其对肾性高血压大鼠血管重构机制,可能与其降低血压、抗氧化应激、抗炎作用有关.各组方配伍后产生了显著的协同增效作用,其配伍后体现了中医药多靶点的治疗优势.

Chinese herbal medicines for treating ulcerative colitis via regulating gut microbiota-intestinal immunity axis

Ulcerative colitis(UC)is one of types of inflammatory bowel disease with high recurrence.Recent studies have highlighted that microbial dysbiosis as well as abnormal gut immunity are crucial factors that initiate a series of inflammatory responses in the UC.Modulating the gut microbiota-intestinal immunity loop has been suggested as one of key strategies for relieving UC.Many Chinese herbal medicines including some of single herb,herbal formulas and the derived constituents have been reported with protective effect against UC through modulating gut microbiome and intestinal immunity.Some clinical trials have shown promising results.This review thus focused on the current knowledge on using Chinese herbal medicines for treating UC from the mechanism aspects of regulating intestinal homeostasis involving microbiota and gut immunity.The existing clinical trials are also summarized.

ZIF-8 coated gold nanospheres: A multi-responsive drug delivery system promoting the killing effect of photothermal therapy against osteosarcoma cells

Photothermal therapy(PTT)has been widely used in the treatment of tumors,but its efficacy is greatly limited by the inability of precise drug delivery and the increase of heat shock proteins(HSPs)caused by high temperature.This article describes a therapeutic strategy to enhance PTT with starvation therapy in conjunction with ferroptosis mechanism.A nanoparticle platform ZIF-8@GA was constructed by wrapping together glucose oxidase(GOX)and gold nanospheres(AuNPs)loaded with dihydroartemisinin(DHA)with zeolitic imidazolate framework-8(ZIF-8).This platform can take advantage of the micro-environment of osteosarcoma(OS)cells,featuring low pH and high reactive oxygen species(ROS),for precision drug delivery.GOX can effectively catalyze glucose to produce gluconic acid and H_(2)O_(2),and DHA can also induce ROS production in OS cells.ROS produced by GOX and DHA can further generate lipid peroxidation(LPO)and lead to ferroptosis of OS cells.At the same time,ROS and LPO produced can inhibit the expression of HSPs,thereby increasing the therapeutic effect of PTT.In vitro experiments show that the nanoparticles are pH and ROS responsive.1μg/mL GOX combined with 0.2μg/mL DHA promotes ferroptosis of OS cells,and increases the killing effect of near-infrared(NIR)on OS cells.Further in vivo experiments showed that the nano drug-delivery platform combined with PTT can effectively inhibit the growth of OS cells.Meanwhile,this study provides a new idea for the treatment of OS with biomaterials combined with various treatment methods.

Combination of graphene oxide and platelet-rich plasma improves tendon-bone healing in a rabbit model of supraspinatus tendon reconstruction

The treatment of rotator cuff tear is one of the major challenges for orthopedic surgeons.The key to treatment is the reconstruction of the tendon-bone interface(TBI).Autologous platelet-rich plasma(PRP)is used as a therapeutic agent to accelerate the healing of tendons,as it contains a variety of growth factors and is easy to prepare.Graphene oxide(GO)is known to improve the physical properties of biomaterials and promote tissue repair.In this study,PRP gels containing various concentrations of GO were prepared to promote TBI healing and supraspinatus tendon reconstruction in a rabbit model.The incorporation of GO improved the ultrastructure and mechanical properties of the PRP gels.The gels containing 0.5 mg/ml GO(0.5 GO/PRP)continuously released transforming growth factor-b1(TGF-b1)and platelet-derived growth factor(PDGF)-AB,and the released TGF-b1 and PDGF-AB were still at high concentrations,1063.451 pg/ml and814.217 pg/ml,respectively,on the 14th day.In vitro assays showed that the 0.5 GO/PRP gels had good biocompatibility and promoted bone marrow mesenchymal stem cells proliferation and osteogenic and chondrogenic differentiation.After 12 weeks of implantation,the magnetic resonance imaging,microcomputed tomography and histological results indicated that the newly regenerated tendons in the 0.5 GO/PRP group had a similar structure to natural tendons.Moreover,the biomechanical results showed that the newly formed tendons in the 0.5 GO/PRP group had better biomechanical properties compared to those in the other groups,and had more stable TBI tissue.Therefore,the combination of PRP and GO has the potential to be a powerful advancement in the treatment of rotator cuff injuries.

Shenweifang-containing serum inhibits transforming growth factor-β1–induced myofibroblast differentiation in normal rat kidney interstitial fibroblast cells

OBJECTIVE:To investigate the efficacy of Shenweifang(SWF)-containing serum on transforming growth factor(TGF)-β1–induced fibroblast-myofibroblast transition in normal rat kidney interstitial fibroblast cells(NRK-49 F).METHODS:Sprague-Dawley rats were gavaged with one of five solutions:(a)saline;(b)saline plus low-dose SWF;(c)saline plus medium-dose SWF;(d)saline plus highdose SWF;and(e)saline plus valsartan.NRK-49 F cells were treated with TGF-β1 and cultured using serum from the gavaged rats.RESULTS:TGF-β1 treatment increased the expression ofα-smooth muscle actin,proliferating cell nuclear antigen,collagenⅠ,Smad3,mitogen-activated protein kinase(MAPK)10,and c-Jun N-terminal kinase(JNK)3 and induced abnormalities in cell morphology,cell cycle progression,and cell proliferation.CONCLUSIONS:SWF-or valsartan-containing serum corrected(or partially corrected)TGF-β1–induced abnormal changes in this in vitro system.SWF-containing serum reversed abnormalities in morphology,cell cycle progression,and proliferation in TGF-β1–treated NRK-49F cells,probably by blocking the TGF-β1/Smads and TGF-β1/MAPK/JNK pathways.