Hypidone hydrochloride(YL-0919)ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.

P2Y1 receptor in Alzheimer’s disease

Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.

Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes:A systematic review with multiple network meta-regressions

BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.

Identification of transient receptor potential channel genes and functional characterization of TRPA1 in Spodoptera frugiperda

Spodoptera frugiperda is a highly destructive pest that has become a global problem due to its robust reproductive and migratory capabilities.Transient receptor potential(TRP)channels,which constitute a vast ion channel family,play pivotal roles in sensing the external environment and maintaining internal homeostasis in insects.TRP channels have been widely investigated for their critical roles in regulating various insect behaviors in recent years.In this study,we identified 15 TRP gene loci encoding 26 transcripts in the genome of S.frugiperda and analyzed their expression profiles at different developmental stages.The results revealed that S.frugiperda possesses four TRPC genes,six TRPA genes,one TRPM gene,two TRPV genes,one TRPN gene,and one TRPML gene,while a canonical TRPP is absent.Moreover,the SfruTRPA1 was functionally characterized using the Xenopus oocyte expression system.The results showed that SfruTRPA1 is activated by temperature increases from 20 to 45℃,and there is no significant desensitization after repeated stimuli within the same temperature range.Additionally,SfruTRPA1 is activated by certain natural chemicals,including allyl isothiocyanate(AITC)and cinnamaldehyde(CA).These findings provide valuable insights to the TRP genes in S.frugiperda.

Transcatheter arterial chemoembolization combined with PD-1 inhibitors and Lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus

BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhibitor,transcatheter arterial chemoembolization(TACE)and Lenvatinib in HCC subjects comorbid with PVTT.METHODS From January 2019 to December 2020,HCC patients with PVTT types Ⅰ-Ⅳ were retrospectively enrolled at Beijing Ditan Hospital.They were distributed to either the PTL or TACE/Lenvatinib(TL)group.The median progression-free survival(mPFS)was set as the primary endpoint,while parameters like median overall survival,objective response rate,disease control rate(DCR),and toxicity level served as secondary endpoints.RESULTS Forty-one eligible patients were finally recruited for this study and divided into the PTL(n=18)and TL(n=23)groups.For a median follow-up of 21.8 months,the DCRs were 88.9%and 60.9%in the PTL and TL groups(P=0.046),res-pectively.Moreover,mPFS indicated significant improvement(HR=0.25;P<0.001)in PTL-treated patients(5.4 months)compared to TL-treated(2.7 months)patients.There were no treatment-related deaths or differences in adverse events in either group.CONCLUSION A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types Ⅰ-Ⅳ.

Advanced Lung Adenocarcinoma with EGFR 19-del Mutation Transformed into SCC after EGFR-tyrosine Kinase inhibitors Treatment:A Case report

BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)significantly improve the survival of patients with Epidermal growth factor receptor(EGFR)sensitive mutations in non-small cell lung cancer(NSCLC).CASE SUMMARY A 67-year-old female patient in advanced lung adenocarcinoma suffered from drug resistance after EGFR-TKIs treatment.Secondary pathological tissue biopsy confirmed squamous cell carcinoma(SCC)transformation.Patients inevitably encountered drug resistance issues after receiving EGFR-TKIs treatment for a certain period of time,while EGFR-TKIs can significantly improve the survival of patients with EGFR-sensitive mutations in NSCLC.Notably,EGFR-TKIs resistance includes primary and acquired.Pathological transformation is one of the mechanisms of acquired resistance in EGFR-TKIs,with SCC transformation being relatively rare.Our results provide more detailed results of the patient’s diagnosis and treatment process on SCC transformation after EGFR-TKIs treatment for lung adenocarcinoma.CONCLUSION Squamous cell carcinoma transformation is one of the acquired resistance mechanisms of EGFR-TKIs in advanced lung adenocarcinoma with EGFR mutations.

Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes:A new horizon

Type 1 diabetes(T1D)is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels.However,this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells.Recent research has explored the potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)as a novel intervention to modify the disease course and delay the onset of T1D.GLP-1RAs are medications initially developed for treating type 2 diabetes.They exert their effects by enhancing glucose-dependent insulin secretion,suppressing glucagon secretion,and slowing gastric emptying.Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D.This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D,possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells.This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification,which should open new avenues for preventing and treating T1D,improving the quality of life and long-term outcomes for individuals at risk of T1D.

Effect of angiotensin Ⅱ type 1 receptor blocker and angiotensin converting enzyme inhibitor on the intraocular growth factors and their receptors in streptozotocin-induced diabetic rats

AIM： To investigate the effect of angiotensin II type 1 receptor blocker （ARB） and angiotensin converting enzyme inhibitor （ACEI） on intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. METHODS： Forty Sprague-Dawley rats were divided into 4 groups： control, diabetes mellitus （DM）, candesartan- treated DM, and enalapril-treated DM （each group, n---10）. After the induction of DM by streptozotocin, candesartan [ARB, 5 mg/（kg · d）] and enalapril [ACEI, 10 mg/（kg · d）] were administered to rats orally for 4Wko Vascular endothelial growth factor （VEGF） and angiotensin II （Ang II） concentrations in the vitreous were measured using enzyme-linked immunosorbent assays, and VEGF receptor 2 and angiotensin II type 1 receptor （ATIR） levels were assessed at week 4 by Western blotting. RESULTS： Vitreous Ang II levels were significantly higher in the DM group and candesartan-treated DM group than in the control （P=0.04 and 0.005, respectively）. Vitreous ATIR increased significantly in DM compared to the other three groups （P〈0.007）. Candesartan-treated DM rats showed higher vitreal ATIR concentration than the enalapril-treated DM group and control （P〈0.001 and P=0.005, respectively）. No difference in vitreous Ang II and ATIR concentration was found between the enalapril- treated DM group and control. VEGF and its receptor were below the minimum detection limit in all 4 groups. CONCLUSION： Increased Ang II and ATIR in the hyperglycemic state indicate activated the intraocular renin-angiotensin system, which is inhibited more effectively by systemic ACEI than systemic ARB.

Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population:Role of serine protease inhibitor Kazal 1type and alcohol

AIM： To test the hypothesis that calcium sensing receptor （CASR） polymorphisms are associated with chronic pancreatitis （CP）, and to determine whether serine protease inhibitor Kazal 1type （SPINK1） N34S or alcohol are necessary co-factors in its etiology. METHODS： Initially, 115 subjects with pancreatitis and 66 controls were evaluated, of whom 57 patients and 21 controls were predetermined to carry the high-risk SPINK1 N34S polymorphism. We sequenced CASR gene exons 2, 3, 4, 5 and 7, areas containing the majority of reported polymorphisms and novel mutations. Based on the initial results, we added 223 patients and 239 controls to analyze three common nonsynonymous single nucleotide polymorphisms （SNPs） in exon 7 （A986S, R990G, and Q1011E）. RESULTS： The CASR exon 7 R990G polyrnorphism was significantly associated with CP （OR, 2.01; 95% CI, 1.12-3.59; P = 0.015）. The association between CASR R990G and CP was stronger in subjects who reported moderate or heavy alcohol consumption （OR, 3.12; 95% CI, 1.14-9.13; P = 0.018）. There was no association between the various CASR genotypes and SPINK1 N34S in pancreatitis. None of the novel CASR polymorphisms reported from Germany and India was detected. CONCLUSION： Our United States-based study confirmed an association of CASR and CP and for the first time demonstrated that CASR R990G is a significant risk factor for CP. We also conclude that the risk of CP with CASR R990G is increased in subjects with moderate to heavy alcohol consumption.

THE INCREASE IN PLASMINOGEN ACTIVATOR INHIBITOR TYPE-1 EXPRESSION BY STIMULATION OF ACTIVATORS FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS IN HUMAN ENDOTHELIAL CELLS

Objective.To investigate the effect of peroxis ome proliferator-activated recept ors(PPARs )activators on plasminogen activator inhibitor ty pe-1(PAI-1)expression in human umbilical vein e ndothelial cells and the possi-ble mechanism.Methods.Human umbilical vein endothelial ce lls(HUVECs )were obtained from normal fetus,and cul-tured conventionally.Then the HUVECs were exposed to test agents(linolenic acid,linoleic acid,oleic acid,stearic acid and prostaglandin J 2 respectively)in varying concentrations with fresh media.RT -PCR and ELISA were applied to determine the expression of PPARs and PAI-1in HUVECs.Results.PPARα,PPARδand PPARγmRNA were detected by using RT-PCR in HUVECs.Treatment of HUVECs with PPARαand PPARγactivators---linolenic acid,linoleic acid,oleic acid and prostaglandin J 2 respectively,but not with stearic a cid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner.However,the mRNA expressions of 3subclasses of PPAR with their activators in HUVECs were not changed compared w ith controls.Conclusion.HUVECs express PPARs.PPARs activators may increase PAI-1expression in ECs,but the underlying mechanism remains uncle ar.Although PPARs expression was not enhanced after stimulated by their activators in ECs,the role of functionally active PPARs in regulating PA I-1expression in ECs needs to be further investigated by using transient gen e transfection assay.

Effects of Insulin-like Growth Factor 1 Receptor and Its Inhibitor AG1024 on the Progress of Lung Cancer

Summary： The type 1 insulin-like growth factor receptor （IGF-1R） and its downstream signaling com- ponents have been increasingly recognized to drive the development of malignancies, including non-small cell lung cancer （NSCLC）. This study aimed to investigate the effects of IGF-1R and its in- hibitor, AG1024, on the progression of lung cancer. Tissue microarray and immunohistochemistry were employed to detect the expressions of IGF-1 and IGF-1R in NSCLC tissues （n=198）. Western blotting was used to determine the expressions oflGF-1 and phosphorylated IGF-1R （p-IGF-1R） in A549 human lung carcinoma cells, and MTT assay to measure cell proliferation. Additionally, the expressions of IGF-1, p-IGF-1R and IGF-1R in a mouse model of lung cancer were detected by Western blotting and real-time fluorescence quantitative polymerase chain reaction （FQ-PCR）, respectively. The results showed that IGF-1 and IGF-1R were overexpressed in NSCLC tissues. The expression levels of IGF-1 and p-IGF-1R were significantly increased in A549 cells treated with IGF-1 as compared to those treated with IGF-1 ＋AG 1024 or untreated cells. In the presence of IGF-1, the proliferation of A549 cells was significantly increased. The progression of lung cancer in mice treated with IGF-1 was significantly increased as compared to the group treated with IGF-l＋AG1024 or the control group, with the same trend mirrored in IGF-1/p-IGF-1R/IGF-1R at the protein and/or mRNA levels. It was concluded that IGF- 1 and IGF inhibitor AG 1024 promotes lung cancer progression.

Potential protective role of ACE-inhibitors and AT1 receptor blockers against levodopa-induced dyskinesias:a retrospective case-control study

Growing evidence has highlighted that angiotensin-converting enzyme(ACE)-inhibitors(ACEi)/AT1 receptor blockers(ARBs)may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway,thus affecting the development of levodopa-induced dyskinesia in Parkinson’s disease(PD).In the present study,we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia,using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital“Maggiore della Carità”.We conducted a retrospective case-control study identifying PD patients with dyskinesias(PwD;n=47)as cases.For each PwD we selected a non-dyskinetic control(NoD),nearly perfectly matched according to sex,Unified Parkinson’s Disease Rating Scale(UPDRS)part III score,and duration of antiparkinsonian treatment.Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use.Ninety-four PD patients were included,aged 72.18±9 years,with an average disease duration of 10.20±4.8 years and 9.04±4.9 years of antiparkinsonian treatment.The mean UPDRS part III score was 18.87±7.6 and the median HY stage was 2.In the NoD group,25(53.2%)were users and 22(46.8%)non-users of ACEi/ARBs.Conversely,in the PwD group,11(23.4%)were users and 36 non-users(76.6%)of this drug class(Pearson chi-square=8.824,P=0.003).Concerning general medication,there were no other statistically significant differences between groups.After controlling for tremor dominant phenotype,levodopa equivalent daily dose,HY 3-4,and disease duration,ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia(OR=0.226,95%CI:0.080-0.636,P=0.005).Therefore,our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and,thanks to good tolerability and easy management,represent a feasible choice when dealing with the treatment of hypertension in PD patients.The study was approved by the Ethics Committee of Novara University Hospital“Maggiore della Carità”(CE 65/16)on July 27,2016.

Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Both GLP-1 receptor agonists(GLP-1RA)and SGLT-2 inhibitors(SGLT-2I)are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure(SBP)modestly.Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c,body weight,and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects.Since several agents from each class of these drugs have shown an improvement in cardiovascular(CV)and renal outcomes in their respective cardiovascular outcome trials(CVOT),combination therapy is theoretically expected to have additional CV and renal benefits.In this comprehensive opinion review,we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone,although body weight lowering was nearly additive and the SBP lowering was more than additive.Our additional meta-analysis of CV outcomes with GLP1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone,against placebo.Interestingly,a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials.Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.

Review on the Effect of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease（NAFLD） is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus（T2DM）, dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1（GLP-1） analogues and dipeptidyl peptidase-4（DPP-4） inhibitors were widely used to treat T2 DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor（GLP-1R） is present and functional in human and rat hepatocytes. In this review, we present data from animal researches and human clinical studies that showed GLP-1 analogues and DPP-4 inhibitors can decrease hepatic triglyceride（TG） content and improve hepatic steatosis, although some effects could be a result of improvements in metabolic parameters. Multiple hepatocyte signal transduction pathways and m RNA from key enzymes in fatty acid metabolism appear to be activated by GLP-1 and its analogues. Thus, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies to treat patients with NAFLD.

Glucagon-like peptide 1 receptor activation:anti-inflammatory effects in the brain

The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity.Glucagon-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues,including diffe rent brain regions.Glucagon-like peptide 1 activates several signaling pathways related to neuroprotection,like the support of cell growth/survival,enhancement promotion of synapse formation,autophagy,and inhibition of the secretion of proinflammatory cytokines,microglial activation,and apoptosis during neural morphogenesis.The glial cells,including astrocytes and microglia,maintain metabolic homeostasis and defe nse against pathogens in the central nervous system.After brain insult,microglia are the first cells to respond,followed by reactive astrocytosis.These activated cells produce proinflammato ry mediators like cytokines or chemokines to react to the insult.Furthermore,under these circumstances,mic roglia can become chro nically inflammatory by losing their homeostatic molecular signature and,consequently,their functions during many diseases.Several processes promote the development of neurological disorders and influence their pathological evolution:like the formation of protein aggregates,the accumulation of abnormally modified cellular constituents,the formation and release by injured neurons or synapses of molecules that can dampen neural function,and,of critical impo rtance,the dysregulation of inflammato ry control mechanisms.The glucagonlike peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies,restoring brain cell homeostasis under inflammatory conditions,modulating mic roglia activity,and decreasing the inflammato ry response.This review summarizes recent advances linked to the anti-inflammato ry prope rties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis,Alzheimer’s disease,Parkinson’s disease,vascular dementia,or chronic migraine.

The synergistic regulatory effect of PTP1B and PTK inhibitors on the development of Oedaleus decorus asiaticus Bei-Bienko

Tyrosine phosphorylation is crucial for controlling normal cell growth,survival,intercellular communication,gene transcription,immune responses,and other processes.protein tyrosine phosphatase(PTP)and protein tyrosine kinases(PTK)can achieve this goal by regulating multiple signaling pathways.Oedaleus decorus asiaticus is an important pest that infests the Mongolian Plateau grassland.We aimed to evaluate the survival rate,growth rate,overall performance,and ovarian developmental morphology of the 4th instar nymphs of O.decorus asiaticus while inhibiting the activity of protein tyrosine phosphatase-1B(PTP1B)and PTK.In addition,the expression and protein phosphorylation levels of key genes in the MAPK signaling pathway and antioxidant enzyme activity were assessed.The results showed no significant differences in survival rate,growth rate,or overall performance between PTP1B inhibitor treatment and control.However,after PTK inhibitor treatment,these indexes were significantly lower than those in the control.The ovarian size of female larvae after 15 days of treatment with PTK inhibitors showed significantly slower development,while female larvae treated with PTP1B exhibited faster ovarian growth than the control group.In comparison to controls and nymphs treated with PTK inhibitors,the expression and phosphorylation levels of key genes in the MAPK signaling pathway under PTP1B inhibitor treatments were significantly higher in 4th instar nymphs.However,reactiveoxygen(ROS)species levels and the activities of NADPH oxidase and other antioxidant enzymes were considerably reduced,although they were significantly greater in the PTK inhibitor treatment.The results suggest that PTP1B and PTK feedback inhibition in the mitogen-activated-protein kinases(MAPK)signal transfer can regulate the physiological metabolism of the insect as well as its developmental rate.These findings can facilitate future uses of PTP1B and PTK inhibitors in controlling insect development to help control pest populations.

Glucagon-like peptide 1 receptor agonist:A potential game changer for cholangiocarcinoma

Glucagon-like peptide-1 receptor(GLP-1R)agonist,a subgroup of incretin-based anti-diabetic therapies,is an emerging medication with benefits in reducing blood glucose and weight and increasing cardiovascular protection.Contrarily,concerns have been raised about GLP-1R agonists increasing the risk of particular cancers.Recently,several epidemiological studies reported contradictory findings of incretin-based therapy on the risk modification for cholangiocarcinoma(CCA).The first cohort study demonstrated that incretin-based therapy was associated with an increased risk of CCA.Later studies,however,showed a null effect of incretinbased therapy on CCA risk for dipeptidyl peptidase-4 inhibitor nor GLP-1R agonist.Mechanistically,glucagon-like peptide 1 receptor is multifunctional,including promoting cell growth.High GLP-1R expressions were associated with progressive phenotypes of CCA cells in vitro.Unexpectedly,the GLP-1R agonist showed anti-tumor effects on CCA cells in vitro and in vivo with unclear mechanisms.Our recent report also showed that GLP-1R agonists suppressed the expression of GLP-1R in CCA cells in vitro and in vivo,leading to the inhibition of CCA tumor growth.This editorial reviews recent evidence,discusses the potential effects of GLP-1R agonists in CCA patients,and proposes underlying mechanisms that would benefit from further basic and clinical investigation.

GLP-1 receptor agonists and myocardial metabolism in atrial fibrillation

Atrial fibrillation(AF)is the most common cardiac arrhythmia.Many medical conditions,including hypertension,diabetes,obesity,sleep apnea,and heart failure(HF),increase the risk for AF.Cardiomyocytes have unique metabolic characteristics to maintain adenosine triphosphate production.Significant changes occur in myocardial metabolism in AF.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)have been used to control blood glucose fluctuations and weight in the treatment of type 2 diabetes mellitus(T2DM)and obesity.GLP-1RAs have also been shown to reduce oxidative stress,inflammation,autonomic nervous system modulation,and mitochondrial function.This article reviews the changes in metabolic characteristics in cardiomyocytes in AF.Although the clinical trial outcomes are unsatisfactory,the findings demonstrate that GLP-1 RAs can improve myocardial metabolism in the presence of various risk factors,lowering the incidence of AF.

Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma

BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.

Efficacy comparison of fruquintinib,regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer

BACKGROUND Regorafenib(R)and fruquintinib(F)are the standard third-line regimens for colorectal cancer(CRC)according to the National Comprehensive Cancer Network guidelines,but both have limited efficacy.Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair(MSS/pMMR)CRC.Due to the lack of studies comparing the efficacy between F,R,F plus programmed death-1(PD-1)inhibitor,and R plus PD-1 inhibitors(RP),it is still unclear whether the combination therapy is more effective than monotherapy.AIM To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC(mCRC)patients in clinical practice.METHODS A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital,and 313 MSS/pMMR mCRC patients were finally included.RESULTS A total of 313 eligible patients were divided into F(n=70),R(n=67),F plus PD-1 inhibitor(FP)(n=95)and RP(n=81)groups.The key clinical characteristics were well balanced among the groups.The median progression-free survival(PFS)of the F,R,FP,and RP groups was 3.5 months,3.6 months,4.9 months,and 3.0 months,respectively.The median overall survival(OS)was 14.6 months,15.7 months,16.7 months,and 14.1 months.The FP regimen had an improved disease control rate(DCR)(P=0.044)and 6-month PFS(P=0.014)and exhibited a better trend in PFS(P=0.057)compared with F,and it was also significantly better in PFS than RP(P=0.030).RP did not confer a significant survival benefit;instead,the R group had a trend toward greater benefit with OS(P=0.080)compared with RP.No significant differences were observed between the R and F groups in PFS or OS(P>0.05).CONCLUSION FP is superior to F in achieving 6-month PFS and DCR,while RP is not better than R.FP has an improved PFS and 6-month PFS compared with RP,but F and R had similar clinical efficacy.Therefore,FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.