Expression Characteristics, Immune Signature, and Prognostic Value of the SOCS Family Identified by Multiomics Integrative Analysis in Liver Cancer.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignancy with a high mortality rate worldwide. Suppressor of cytokine signaling (SOCS) family members play important roles in the proliferation, metabolism, and immunity of HCC cells by regulating cytokines and growth factors. However, it remains uncertain whether the level of SOCS family members can affect the prognosis of HCC patients. AIMS: This study aimed to comprehensively assess the role and mechanisms of SOCS family members in the development of HCC and to guide clinical selection. METHODS: We investigated the expression levels of SOCS family genes in HCC patients and their associations with various clinicopathological characteristics. We also utilized a public database to analyze the changes in the expression, potential functions, transcription factors, and immune invasion of SOCS family members. Additionally, we examined the prognostic value of the SOC family for HCC and its correlation with the SOC family and ferroptosis-related genes. RESULTS: This study revealed that the expression of SOCS2-7, and CISH was downregulated in HCC. The SOCS4, SOCS5, and SOCS7 genes were associated with the clinicopathological features of HCC patients. SOCS family genes are mainly related to the PIK3R3, GHR, and TNS4 pathways. Additionally, this study revealed that STAT3, PPAR-gamma 2, and IRF-2 are important transcription factors that regulate SOCS family members. The expression levels of SOCS family members are closely related to immune infiltration in liver cancer. The study also indicated that SOCS2 and SOCS4 are risk-related genes for predicting the prognosis of patients with liver cancer. Finally, this study suggested that the SOCS2 gene may be involved in the development and progression of HCC. CONCLUSION: Our study enhances the current understanding of SOCS gene function in liver cancer and can help clinicians select appropriate drugs and predict the prognosis of HCC patients.

Chemotherapy combined with lenvatinib and PD-1 may be a potential better alternative option for advanced unresectable intrahepatic cholangiocarcinoma: a retrospective real-world study.

Background: Currently, the prognosis of advanced intrahepatic cholangiocarcinoma (ICC) is poor, and the current treatment methods are not effective. Objective: The aim of this study was to evaluate the anticancer efficacy of chemotherapy combined with PD-1 inhibitors and tyrosine kinase inhibitors (TKIs) in patients with ICC. Methods: We retrospectively screened patients with advanced intrahepatic cholangiocarcinoma (ICC) who received chemotherapy combined with lenvatinib and PD-1. We evaluated overall survival (OS), progression-free survival (PFS), the objective response rate (ORR), the disease control rate (DCR), the tumor shrinkage rate, and safety. Results: We enrolled 95 patients with ICC and divided them into three groups with a median follow-up duration of 15.1 months. The chemotherapy group (chemo-regimen group), chemotherapy combined with immune checkpoint inhibitors (dual-regimen group), and chemotherapy combined with lenvatinib (triple-regimen group) had median OS times of 13.1 months, 20.8 months, and 39.6 months, respectively. Notably, the triple-regimen group had a significantly longer OS than did the chemo-regimen and dual-regimen groups. The chemo-regimen group, dual-regimen group, and triple-regimen group reported median PFS durations of 4.8 months, 11.9 months, and 23.4 months, respectively. Both combination groups exhibited significantly longer PFS than the chemotherapy-only group (P<0.05). The ORRs of the chemo-regimen, dual-regimen, and triple-regimen groups were 18.2%, 55.5%, and 54.7%, respectively. The DCRs were 72.7%, 90%, and 96.2%, respectively, indicating significantly better outcomes in the combination therapy groups. Conclusion: The combination of chemotherapy with PD-1 inhibitors and lenvatinib demonstrates considerable efficacy and tolerability as a treatment strategy for patients with advanced ICC.

Rising Star in Immunotherapy: Development and Therapeutic Potential of Small-Molecule Inhibitors Targeting Casitas B Cell Lymphoma-b (Cbl-b).

Casitas B cell lymphoma-b (Cbl-b) is a vital negative regulator of TCR and BCR signaling pathways, playing a significant role in setting an appropriate threshold for the activation of T cells and controlling the tolerance of peripheral T cells via a variety of mechanisms. Overexpression of Cbl-b leads to immune hyporesponsiveness of T cells. Conversely, the deficiency of Cbl-b in T cells results in markedly increased production of IL-2, even in the lack of CD28 costimulation in vitro. And Cbl-b-/- mice spontaneously reject multifarious cancers. Therefore, Cbl-b may be associated with immune-mediated diseases, and blocking Cbl-b could be considered as a new antitumor immunotherapy strategy. In this review, the possible regulatory mechanisms and biological potential of Cbl-b for antitumor immunotherapy are summarized. Besides, the potential roles of Cbl-b in immune-mediated diseases are comprehensively discussed, with emphasis on Cbl-b immune-oncology agents in the preclinical stage and clinical trials.

Antidepressant effect of the novel histone deacetylase-5 inhibitor T2943 in a chronic restraint stress mouse model.

Depression is a prevalent and debilitating psychiatric illness. However, the antidepressant drugs currently prescribed are only effective in a limited group of patients. Histone modifications mediated by histone acetylation are considered to play an important role in the pathogenesis and treatment of depression. Recent studies have revealed that histone deacetylase inhibitors may be involved in the pathogenesis of depression and the underlying mechanism of the antidepressant therapeutic action. Here, we first conducted virtual screening of histone deacetylase-5 (HDAC5) inhibitors against HDAC5, a target closely related to depression, and identified compound T2943, further verifying its inhibitory effect on enzyme activities in vitro. After stereotaxic injection of T2943 into the hippocampus of mice, the antidepressant effect of T2943 was evaluated using behavioral experiments. We also used different proteomic and molecular biology analyses to determine and confirm that T2943 promoted histone 3 lysine 14 acetylation (H3K14ac) by inhibiting HDAC5 activity. Following the overexpression of adenoviral HDAC5 in the hippocampus of mice and subsequent behavioral analyses, we confirmed that T2943 exerts antidepressant effects by inhibiting HDAC5 activity. Our findings highlight the efficacy of targeting HDAC5 to treat depression and demonstrate the potential of using T2943 as an antidepressant.

Neuroprotective strategies for neonatal hypoxic-ischemic brain damage: Current status and challenges.

Neonatal hypoxic-ischemic brain damage (HIBD) is a prominent contributor to both immediate mortality and long-term impairment in newborns. The elusive nature of the underlying mechanisms responsible for neonatal HIBD presents a significant obstacle in the effective clinical application of numerous pharmaceutical interventions. This comprehensive review aims to concentrate on the potential neuroprotective agents that have demonstrated efficacy in addressing various pathogenic factors associated with neonatal HIBD, encompassing oxidative stress, calcium overload, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory response, and apoptosis. In this review, we conducted an analysis of the precise molecular pathways by which these drugs elicit neuroprotective effects in animal models of neonatal hypoxic-ischemic brain injury (HIBD). Our objective was to provide a comprehensive overview of potential neuroprotective agents for the treatment of neonatal HIBD in animal experiments, with the ultimate goal of enhancing the feasibility of clinical translation and establishing a solid theoretical foundation for the clinical management of neonatal HIBD.

Recent advances of targeting nicotinamide phosphoribosyltransferase (NAMPT) for cancer drug discovery.

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme for the biosynthesis of NAD+ in the salvage pathway. NAMPT is overexpressed in various cancers, associating with a poor prognosis and tumor progression. Beyond cancer metabolism, recent evidence unravels additional roles of NAMPT in cancer biology, including DNA repair machinery, crosstalk with oncogenic signaling pathways, cancer cell stemness, and immune responses. NAMPT is a promising therapeutic target for cancer. However, first-generation NAMPT inhibitors exhibited limited efficacy and dose-limiting toxicities in clinical trials. Multiple strategies are being exploited to improve their efficacy and minimize toxic-side effects. This review discusses the biomarkers predictive of response to NAMPT inhibitors, and summarizes the most significant advances in the evolution of structurally distinct NAMPT inhibitors, the manipulation of targeted delivery technologies via antibody-drug conjugates (ADCs), PhotoActivated ChemoTherapy (PACT) and the intratumoral delivery system, as well as the development and pharmacological outcomes of NAMPT degraders. Finally, a discussion of future perspectives and challenges in this area is also included.

Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro).

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a great threat to public health while various vaccines are available worldwide. Main protease (Mpro) has been validated as an effective anti-COVID-19 drug target. Using medicinal chemistry and rational drug design strategies, we identified a quinazolin-4-one series of nonpeptidic, noncovalent SARS-CoV-2 Mpro inhibitors based on baicalein, 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one. In particular, compound C7 exhibits superior inhibitory activity against SARS-CoV-2 Mpro relative to baicalein (IC50 = 0.085 ± 0.006 and 0.966 ± 0.065 µM, respectively), as well as improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. In addition, C7 inhibits viral replication in SARS-CoV-2-infected Vero E6 cells more effectively than baicalein (EC50 = 1.10 ± 0.12 and 5.15 ± 1.64 µM, respectively) with low cytotoxicity (CC50 ＞ 50 µM). An X-ray co-crystal structure reveals a non-covalent mechanism of action, and a noncanonical binding mode not observed by baicalein. These results suggest that C7 represents a promising lead for development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 drugs.

hsa-mir-(4328, 4422, 548z and -628-5p) in diabetic retinopathy: diagnosis, prediction and linking a new therapeutic target.

AIMS: Growing evidence suggests that microRNAs (miRNAs) are crucial in controlling how diabetic retinopathy (DR) develops. We intend to mine miRNAs with diagnostic and predictive value for DR and to investigate new drug therapeutic targets. METHODS: After performing a differential analysis on the miRNA and mRNA datasets for DR and neovascularization (NEO), miRNA-mRNA networks were created. Combine the results of enrichment analysis, Protein-Protein Interaction Networks (PPI), and Cytoscape to identify key miRNAs. DrugBank was used to find drugs that interacted with transcription factors (TF) predicted by TransmiR. Finally, whole blood and clinical data were collected from 58 patients with type 2 diabetes mellitus (T2DM), and RT-qPCR, logistic analysis, and ROC were used to verify the value of key miRNAs. RESULTS: Differential analysis indicated the presence of genes and miRNAs that co-regulate DR and NEO. Enrichment analysis showed that key genes are inextricably linked to neovascularization. Combining the results of PPI and Cytoscape identified four key miRNAs, namely hsa-mir-(4328, 4422, 548z and -628-5p). RT-qPCR, logistic, and ROC results showed that decreased expression levels of hsa-mir-(4328, 4422, 548z and -628-5p) signal the risk of evolution to DR in T2DM patients. Finally, we constructed a TF-miRNA network to find the 15 TFs and the 35 drugs that interact with these TFs. CONCLUSION: hsa-mir-(4328, 4422, 548z and -628-5p) in whole blood are protective factors for DR as novel biomarkers for diagnosis and prediction. In addition, our research provides new drug directions for the treatment of DR, such as Diosmin, Atorvastatin, and so on.

A case report of adult juvenile polyposis syndrome with SMAD4 pathogenic variant.

Background: Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder that is a type of hamartomatous polyp syndrome, and its incidence rate is approximately 1/100000. The main clinical feature is the presence of multiple juvenile polyps in the gastrointestinal tract, most often in the colorectal tract. We present a case of juvenile polyposis syndrome with massive gastric polyposis. Case presentation: A 50-year-old male was admitted to the hospital due to abdominal distension and poor appetite. Gastroscopy revealed a large number of gastric polyps. Pathological findings revealed gastric juvenile polyps. Genetic testing revealed that he and his brother both carried SMAD4: c.266_269del germline pathogenic variant. The final diagnosis was juvenile polyposis syndrome of the stomach. He once suffered from colon cancer and bladder cancer. One of his brothers died of colon cancer, and the other brother suffered from colon polyps. Conclusions: Gastric involvement in juvenile polyposis syndrome is relatively rare. When massive gastric polyposis is found, gene detection should be carried out as soon as possible, so that rapid diagnosis and treatment can be obtained.

Targeting the chemokine ligand 2-chemokine receptor 2 axis provides the possibility of immunotherapy in chronic pain.

Chronic pain affects patients' physical and psychological health and quality of life, entailing a tremendous public health challenge. Currently, drugs for chronic pain are usually associated with a large number of side effects and poor efficacy. Chemokines in the neuroimmune interface combine with their receptors to regulate inflammation or mediate neuroinflammation in the peripheral and central nervous system. Targeting chemokines and their receptor-mediated neuroinflammation is an effective means to treat chronic pain. In recent years, growing evidence has shown that the expression of chemokine ligand 2 (CCL2) and its main chemokine receptor 2 (CCR2) is involved in its occurrence, development and maintenance of chronic pain. This paper summarises the relationship between the chemokine system, CCL2/CCR2 axis, and chronic pain, and the CCL2/CCR2 axis changes under different chronic pain conditions. Targeting chemokine CCL2 and its chemokine receptor CCR2 through siRNA, blocking antibodies, or small molecule antagonists may provide new therapeutic possibilities for managing chronic pain.

Neuroprotective effects of oxymatrine on hypoxic-ischemic brain damage in neonatal rats by activating the Wnt/ß-catenin pathway.

Neuronal apoptosis is a major pathological process associated with neurological dysfunction in neonates after hypoxic-ischemic brain damage (HIBD). Our previous study demonstrated that oxymatrine (OMT) exerts potential neuroprotective effects on neonatal rats subjected to hypoxic-ischemic insult. However, the underlying molecular mechanism remains unclear. In this study, we investigated the effects of OMT-mediated neuroprotection on neonatal HIBD by attempting to determine its effect on the Wnt/ß-catenin signaling pathway and explored the underlying mechanism. Both 7-day-old rat pups and primary hippocampus neurons were used to establish the HIBD and oxygen-glucose deprivation (OGD) injury models, respectively. Our results demonstrated that OMT treatment significantly increased cerebral blood flow and reduced S100B concentration, infarct volume, and neuronal apoptosis in neonatal rats. In vitro, OMT markedly increased cell viability and MMP level and decreased DNA damage. Moreover, OMT improved the mRNA and protein levels of Wnt1 and ß-catenin, inhibited the expression of DKK1 and GSK-3ß, enhanced the nuclear transfer of ß-catenin, and promoted the binding activity of ß-catenin with Tcf-4; however, it downregulated the expression of cleaved caspase-3 and cleaved caspase-9. Notably, the introduction of XAV-939 (a Wnt/ß-catenin signaling inhibitor) reversed the positive effects of OMT both in vivo and in vitro. Collectively, our findings demonstrated that OMT exerted a neuroprotective effect on neonatal HIBD by inhibiting neuronal apoptosis, which was partly via the activation of the Wnt/ß-catenin signaling pathway.

Protective effects of leonurine hydrochloride on pyroptosis in premature ovarian insufficiency via regulating NLRP3/GSDMD pathway.

BACKGROUND: Premature ovarian insufficiency is common in clinically infertile patients. The NOD-like receptor family pyrin domain-containing 3 (NLRP3)/Gasdermin D (GSDMD) signaling pathway plays a key role in premature ovarian insufficiency. Leonurine (Leo) is one of the important active ingredients extracted from Leonurus japonicus Houttuyn, which can inhibit NLRP3 activation. However, whether leonurine hydrochloride plays a protective role in premature ovarian insufficiency through actions on NLRP3/GSDMD signaling is not yet known. METHODS: After cyclophosphamide-induced premature ovarian insufficiency was established in female mice, Leo was injected intraperitoneally over four weeks to evaluate the ovarian function and anti-pyroptosis effects using the metrics of fertility, serum hormone level, ovary weight, follicle number, expression of NLRP3/GSDMD pathway-related proteins, and serum IL-18 and IL-1ß levels. RESULTS: Intraperitoneal administration of leonurine hydrochloride was found to significantly protect fertility and maintain both serum hormone levels and follicle number in mice with premature ovarian insufficiency. Mice treated with leonurine hydrochloride consistently resisted cyclophosphamide-induced ovarian damage by inhibiting the activation of NLRP3 inflammasome, Caspase-1 and GSDMD in both ovarian tissue and granulosa cells, which led to lower levels of IL-18 and IL-1ß in the serum (p < 0.05, p < 0.01, p < 0.001). CONCLUSION: Intraperitoneal administration of leonurine hydrochloride prevents cyclophosphamide-induced premature ovarian insufficiency in mice by inhibiting NLRP3/GSDMD-mediated pyroptosis.

Cyclic hexadepsipeptides from the fermentation of Fusarium sp. DCJ-A and their cytotoxic activities.

Beauvercin H (1), a new cyclic hexadepsipeptide, and two known ones (2 and 3) were isolated from the EtOH extract of the solid culture of Fusarium sp. Their structures were elucidated by spectroscopic analysis, including extensive 1D and 2D NMR techniques, as well as comparison with literature values. Additionally, compounds 1-3 were tested for their cytotoxic activities. The results showed that all isolated compounds exhibited cytotoxic activities against five human cancer cell lines with IC50 values ranging from 1.379 to 13.12 µM.

Cidan Capsule in Combination with Adjuvant Transarterial Chemoembolization Reduces Recurrence Rate after Curative Resection of Hepatocellular Carcinoma: A Multicenter, Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy and safety of Cidan Capsule combined with adjuvant transarterial chemoembolization (TACE) in patients with a high risk of early recurrence after curative resection of hepatocellular carcinoma (HCC). METHODS: A multicenter, randomized controlled trial was conducted in patients with high-risk recurrence factors after curative resection of HCC from 9 medical centers between July 2014 and July 2018. Totally 249 patients were randomly assigned to TACE with or without Cidan Capsule administration groups by stratified block in a 1:1 ratio. Postoperative adjuvant TACE was given 4-5 weeks after hepatic resection in both groups. Additionally, 125 patients in the TACE plus Cidan group were administrated Cidan Capsule (0.27 g/capsule, 5 capsules every time, 4 times a day) for 6 months with a 24-month follow-up. Primary endpoints included disease-free survival (DFS) and tumor recurrence rate (TRR). Secondary endpoint was overall survival (OS). Any drug-related adverse events (AEs) were observed and recorded. RESULTS: As the data cutoff in July 9th, 2018, the median DFS was not reached in the TACE plus Cidan group and 234.0 days in the TACE group (hazard ratio, 0.420, 95% confidence interval, 0.290-0.608; P<0.01). The 1- and 2-year TRR in the TACE plus Cidan and TACE groups were 31.5%, 37.1%, and 60.8%, 63.4%, respectively (P<0.01). Median OS was not reached in both groups. The 1- and 2-year OS rates in TACE plus Cidan and TACE groups were 98.4%, 98.4%, and 89.5%, 87.9%, respectively (P<0.05). The most common grade 3-4 AEs included fatigue, abdominal pain, lumbar pain, and nausea. One serious AE was reported in 1 patient in the TACE plus Cidan group, the death was due to retroperitoneal mass hemorrhage and hemorrhagic shock, and was not related to study drug. CONCLUSIONS: Cidan Capsule in combination with TACE can reduce the incidence of early recurrence in HCC patients at high-risk of recurrence after radical hepatectomy and may be an appropriate option in postoperative anti-recurrence treatment. (Registration No. NCT02253511).

Epigenetic modulation: Research progress on histone acetylation levels in major depressive disorders.

Depression is a serious mental illness and a prevalent condition with multiple aetiologies. The impact of the current therapeutic strategies is limited and the pathogenesis of the illness is not well understood. According to previous studies, depression onset is influenced by a variety of environmental and genetic factors, including chronic stress, aberrant changes in gene expression, and hereditary predisposition. Transcriptional regulation in eukaryotes is closely related to chromosome packing and is controlled by histone post-translational modifications. The development of new antidepressants may proceed along a new path with medications that target epigenetics. Histone deacetylase inhibitors (HDACis) are a class of compounds that interfere with the function of histone deacetylases (HDACs). This review explores the relationship between HDACs and depression and focuses on the current knowledge on their regulatory mechanism in depression and the potential therapeutic use of HDACis with antidepressant efficacy in preclinical research. Future research on inhibitors is also proposed and discussed.

Expert Consensus on Pathological Diagnosis of Intrahepatic Cholangiocarcinoma (2022 version).

Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.

Development of protective agents against ovarian injury caused by chemotherapeutic drugs.

BACKGROUND: Chemotherapy is one of the causes of ovarian injury and infertility. Although assisted reproductive technology helps young female patients with cancer become pregnant, preventing chemotherapy-induced ovarian injury will often possess even more significant benefits. OBJECTIVE: We aimed at demonstrating the hazardous effects and mechanisms of ovarian injury by chemotherapeutic agents, as well as demonstrating agents that protect the ovary from chemotherapy-induced injury. RESULTS: Chemotherapeutic agents cause death or accelerate activation of follicles and damage to the blood vessels in the ovary, resulting in inflammation. These often require drug development to protect the ovaries from injury. CONCLUSIONS: Our findings provide a basis for the development of drugs to protect the ovaries from injury. Although there are many preclinical studies on potential protective drugs, there is still an urgent need for a large number of clinical experiments to verify their potential use.

Geniposide attenuates spermatogenic dysfunction via inhibiting endoplasmic reticulum stress in male mice.

BACKGROUND: Spermatogenesis dysfunction is common in clinically infertile patients. Geniposide (GP) is one of the important active ingredients extracted from Eucommia ulmoides. However, the protective effect and mechanism of GP in the treatment of spermatogenic dysfunction is not known yet. METHODS: After cyclophosphamide-induced spermatogenic dysfunction was established in male mice, we gavaged GP for 4 weeks to evaluate spermatogenic function and anti-apoptotic effects by fertility, testicular weight, sperm quality, endoplasmic reticulum stress (ER stress), comet assay and serum testosterone level. RESULTS: GP can improve the damage of fertility and reproductive organs induced by cyclophosphamide and increase the number and activity of sperm. In comet assay, it was found that GP administration could alleviate sperm DNA damage induced by cyclophosphamide. In addition, GP treatment can significantly reduce ThT fluorescence intensity and improve endoplasmic reticulum stress induced by cyclophosphamide. Besides, TUNEL staining and WB showed that GP could inhibit the excessive apoptosis of cells and protect testis. (p < 0.05, p < 0.01, p < 0.001). CONCLUSION: The protective effect of Geniposide on cyclophosphamide-induced spermatogenic dysfunction in mice is related to the inhibition of endoplasmic reticulum stress.

Lenvatinib Plus Programmed Cell Death Protein-1 Inhibitor Beyond First-Line Systemic Therapy in Refractory Advanced Biliary Tract Cancer: A Real-World Retrospective Study in China.

Background: Currently, no second-line systemic treatment regimen has been recommended in advanced biliary tract cancer (BTC). Cumulative clinical evidence showed that systemic treatment with tyrosine kinase inhibitors (TKIs) in combination with immunotherapy may shed light on the dim clinical outcome in advanced BTC. Objective: The aim of this study is to evaluate the anticancer efficacy of lenvatinib plus programmed cell death protein-1 (PD-1) antibody in patients with BTC who progressed after first-line cisplatin/gemcitabine (CisGem) chemotherapy. Methods: Patients with advanced BTCs who progressed after CisGem were recruited. A combination regimen of lenvatinib (8/12 mg daily) plus PD-1 antibody (200/240 mg injection every 3 weeks) was prescribed. Clinicopathological information and therapeutic outcome, including tumor subtypes, biomarkers, treatment duration, adverse events (AE), progression-free survival (PFS), and overall survival (OS), were recorded and estimated. Results: A total of 351 patients with BTCs were reviewed and 74 were recruited eventually: 35 had intrahepatic cholangiocarcinoma (47.3%), 4 had extrahepatic cholangiocarcinoma (5.4%), and 35 had gallbladder cancer (47.3%). The median administered cycles of PD-1 antibody were 6.43 (95% CI: 5.83-7.04) cycles, and the median duration of lenvatinib medication was 21.0 weeks (95% CI: 18.04-23.93). Twenty-eight patients (37.83%) experienced detectable objective response per RECIST1.1 within a median follow-up duration of 15.0 months. The objective response rate (ORR) was 20.27% (95% CI: 10.89%-29.65%), and the disease control rate (DCR) was 71.62% (95% CI: 61.11%-82.14%). The median PFS and OS were 4.0 months (95% CI: 3.5-5.0) and 9.50 months (95% CI: 9.0-11.0), respectively. Seventy-three patients (98.64%) reported AEs and 39 (52.70%) experienced ≥grade 3 AEs. In subgroup analyses, tumoral PD-L1 expression ≥50% and tumor mutation burden (TMB) ≥2.5 Muts/Mb were associated with prolonged PFS. Conclusion: Lenvatinib plus PD-1 antibody treatment shows an active trend towards improving survival in patients with advanced BTCs after failure with CisGem chemotherapy. The treatment-related AEs are worthy of attention and are manageable.

Analgesic effect of nobiletin against neuropathic pain induced by the chronic constriction injury of the sciatic nerve in mice.

Neuropathic pain is chronic pain resulting from central or peripheral nerve damage that remains difficult to treat. Current evidence suggests that nobiletin, isolated from Citrus reticulata Blanco, possesses analgesic and neuroprotective effects. However, its effect on neuropathic pain has not been reported. This study evaluated the analgesic effect of nobiletin on neuropathic pain induced by chronic constriction injury (CCI) in mice. In vivo, mice were intragastrically administered with nobiletin (30, 60, 120 mg/kg) for eight consecutive days, respectively. Our study indicated that nobiletin ameliorated mechanical allodynia, cold allodynia and thermal hyperalgesia on CCI mice at doses that do not induce significant sedation. Moreover, nobiletin could ameliorate axonal and myelin injury of the sciatic nerve and further restore abnormal sciatic nerve electrical activity on CCI mice. In vitro studies indicated that nobiletin could suppress the proteins and mRNA expression of the IRF5/P2X4R/BDNF signalling pathway in fibronectin-induced BV2 cells. Overall, our results indicated that nobiletin might exert an analgesic effect on CCI-induced neuropathic pain in mice by inhibiting the IRF5/P2X4R/BDNF signalling pathway in spinal microglia. This study provided a novel potential therapeutic drug for neuropathic pain and new insights into the pharmacological action of nobiletin.