Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1.

Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and ß-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM CB-05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.

Intramedullary lesion resection as an effective treatment of spinal cord microscopic polyangiitis: a case report.

BACKGROUND: Microscopic polyangiitis (MPA), an autoimmune disease, is a subtype of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. The lungs and kidneys are the most common targets, whereas spinal cord involvement is rare. METHODS: We reported the clinical manifestations, diagnosis, and management of a patient with spinal cord MPA. RESULTS: The patient showed spinal compression symptoms and was diagnosed with MPA following magnetic resonance imaging (MRI) and histological examination. Spinal compression symptoms were completely relieved after intramedullary lesion resection and postoperative treatment with methylprednisolone. CONCLUSION: The diagnosis of MPA without typical manifestations can be challenging. MRI and histological examination are of great importance in spinal cord MPA diagnosis. Intramedullary lesion resection is an effective treatment for spinal cord MPA. Methylprednisolone is also recommended for postoperative treatment.

PHBHHx Facilitated the Residence, Survival and Stemness Maintain of Transplanted Neural Stem Cells in Traumatic Brain Injury Rats.

Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) is a polyhydroxyalkanoate (PHA) with broad application prospects in various biomedical fields. Our previous study demonstrated the great biocompatibility of PHBHHx with neural stem cells (NSCs) in vitro. In this study, we went a step further and implanted the NSC-carrying PHBHHx film to in vivo into the lesion region in a rat traumatic brain injury (TBI) model. The in vivo biocompatibility of PHBHHx, as well as the survival, migration and differentiation of the transplanted NSCs were investigated. The results showed that PHBHHx did not induce additional reactive gliosis and supported the in vivo survival and growth of the transplanted stem cells. The transplanted NSCs were able to migrate into the brain tissue and differentiated into both neurons and astrocytes. Moreover, PHBHHx seemed to be able to maintain the stemness of the attached NSCs both in vitro and in vivo. The major monomer of PHBHHx, 3-hydroxybutyrate (3-HB), might contribute to this bioactivity because the addition of low concentrations of 3-HB facilitated the self-renewal of NSCs by shortening the G1 phase, promoted their proliferation, and enhanced the expression of a key regulatory transcription factor which helped to keep the stemness of NSCs. These results highlight the application of PHBHHx as a promising bioactive material for NSC transplantation in the brain and open up a wide space for further studies on functional recovery following the transplantation of NSCs attached to PHBHHx.

Biomarker levels in gingival crevicular fluid of generalized aggressive periodontitis patients after non-surgical periodontal treatment.

OBJECTIVES: The aim of this study was to assess the effects of non-surgical periodontal treatment on gingival crevicular fluid (GCF) cytokines in patients with generalized aggressive periodontitis (GAgP), in relation to clinical parameters. MATERIALS AND METHODS: Data were obtained from 16 GAgP patients and 15 periodontally healthy controls. Periodontal parameters and GCF biomarker levels were evaluated at baseline and repeated 3 and 6 months after treatment for GAgP subjects. Moderate and deep pocket sites were analyzed separately. The amount of interleukin (IL)-1ß, IL-9, tumor necrosis factor (TNF)-α, platelet-derived growth factor (PDGF-bb), and vascular endothelial growth factor (VEGF) were measured using a highly specific and sensitive multiplex bead immunoassay. RESULTS: At baseline, cytokine levels in the moderate and deep pocket sites of GAgP patients were higher than those of the healthy control sites. In GAgP group, periodontal treatment led to improvement in all examined clinical parameters and resulted in a statistically significant reduction in the total amounts of IL-1ß, VEGF, and TNF-α, in comparison to baseline, already 3 months after therapy in both moderate and deep pocket sites and of PDGF-bb in deep sites (p < 0.01). At the concentration level, only IL-1ß and VEGF were affected. CONCLUSION: Non-surgical treatment of GAgP provided significant clinical benefits leading to a marked decrease in the GCF levels of some pro-inflammatory and pro-angiogenic cytokines, but not of IL-9 and PDGF-bb. CLINICAL RELEVANCE: Although the periodontal therapy successfully decreased clinical signs of inflammation, the GCF levels of some inflammatory cytokines were still elevated.

[Dynamic observation of clinical course in patients with subacute 1, 2-dichloroethane poisoning].

OBJECTIVE: To observe the clinical characteristics and regular patterns of subacute 1, 2-dichloroethane poisoning patients for providing evidences to it's diagnosis, treatment and prognosis. METHODS: 51 cases of subacute 1, 2-dichloroethane poisoning analyzed. They were divided into 3 groups according to their main clinical manifestation: group A mainly with intracranial hypertension (n = 25), group B with limbs tremor (n = 18), group C with mental and behavior disorder (n = 8). All cases' clinical symptoms, cranial computer tomography, cerebrospinal pressure (Group A) were observed, the durations of the onset, deterioration, improvement, recovery and whole course of the disease were compared between groups and in each group. RESULTS: In all of 51 cases, only the differences between the deterioration duration of cranial CT and symptom was significantly (t = 2.555, P<0.05), which indicate the deterioration of symptom was earlier than radiological change. The symptom deterioration of group C was the fastest than group A and group B (P<0.00). As to the change of symptom duration, group B's improvement, recovery and whole course was the longest comparing with group A and group C (P<0.05). As to the change of cranial CT duration, group B's recovery duration was the shortest and group A's recovery duration was the longest (P<0.01); group B's whole course was also the shortest and group A's whole course was the longest (P<0.05). The clinical course of symptoms, cranial computer tomography, cerebrospinal pressure (Group A) was compared in each group, in group A, the duration of improvement and whole course of the cranial CT and cerebrospinal pressure change was longer than that of the symptom change (P<0.01), this indicated that group A has longer asymptomatic intracranial hypertension and their cranial radiography recover slowly. In group B, their symptoms (3.94 ± 4.31 days) deteriorated is earlier than cranial CT changes (P<0.05), the recovery (92.39 ± 55.04 days) and whole course of symptom was longer than cranial CT change (all P<0.01). In group C, symptom deterioration was earlier than CT deterioration (P< 0.05). CONCLUSION: The clinical characteristic of subacute 1, 2- dichloroethane poisoning is central nervous system damage, it differs according to the different stage of course, the regions and severity of pathology lesions.

Middle ear neuroendocrine tumor with multiple brain metastases: a case report and literature review.

Middle ear neuroendocrine tumor (MeNET) is a low-grade tumor with rare recurrence or metastasis. Here, we describe the case of a 29-year-old man who suffered from MeNET that recurred 3 times over 10 years and eventually metastasized to the brain. The patient was treated with surgical resection, radiotherapy, and chemotherapy. However, the tumor was not entirely removed as the brain metastatic tumor adhered tightly to the brainstem. Due to tumor rupture and bleeding after multiple brain tumor removal, profound coma developed. Finally, the patient died 10 months after the last surgery. To our knowledge, this is the first report of a MeNET case with multiple brain metastases. Characteristics of the present case indicate that CK, SYN, increased Ki67 index, and ATRX may be potential biomarkers of invasive MeNET. The survival of patients with brain metastatic MeNET may be extended by surgical resection, radiotherapy, and chemotherapy. Close follow-up of distinctive metastases and biomarkers related to recurrence is also suggested.

Establishment and evaluation of a nomogram prediction model for the risk of vascular calcification in stage 5 chronic kidney disease patients.

Vascular calcification (VC) is a common complication of chronic kidney disease (CKD) that has a detrimental effect on patients' survival and prognosis. The aim of this study was to develop and validate a practical and reliable prediction model for VC in CKD5 patients. The medical records of 544 CKD5 patients were reviewed retrospectively. Multivariate logistic regression analysis was used to identify the independent risk factors for vascular calcification in patients with CKD5 and then created a nomogram prediction model. The area under the receiver operating characteristic curve (AUC), Hosmer-Lemeshow test, and decision curve analysis (DCA) were used to assess model performance. The patients were split into groups with normal and high serum uric acid levels, and the factors influencing these levels were investigated. Age, BUN, SUA, P and TG were independent risk factors for vascular calcification in CKD5 patients in the modeling group (P < 0.05). In the internal validation, the results of model showed that the AUC was 0.917. No significant divergence between the predicted probability of the nomogram and the actual incidence rate (x2 = 5.406, P = 0.753) was revealed by the calibration plot and HL test, thus confirming that the calibration was satisfactory. The external validation also showed good discrimination (AUC = 0.973). The calibration chart and HL test also demonstrated good consistency. Besides, the correlation analysis of serum uric acid levels in all CKD5 patients revealed that elevated uric acid levels may be related to gender, BUN, P, and TG.

Structural basis of neuropeptide Y signaling through Y1 and Y2 receptors.

Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs display varying selectivity and exert diverse physiological effects through their interactions with this receptor family. [Pro34]-NPY and [Leu31, Pro34]-NPY, mainly acting on Y1R, reportedly increases blood pressure and postsynaptically potentiates the effect of other vasoactive substances above all, while N-terminal cleaved NPY variants in human body primary mediates angiogenesis and neurotransmitter release inhibition through Y2R. However, the recognition mechanisms of Y1R and Y2R with specific agonists remain elusive, thereby hindering subtype receptor-selective drug development. In this study, we report three cryo-electron microscopy (cryo-EM) structures of Gi2-coupled Y1R and Y2R in complexes with NPY, as well as Y1R bound to a selective agonist [Leu31, Pro34]-NPY. Combined with cell-based assays, our study not only reveals the conserved peptide-binding mode of NPY receptors but also identifies an additional sub-pocket that confers ligand selectivity. Moreover, our analysis of Y1R evolutionary dynamics suggests that this sub-pocket has undergone functional adaptive evolution across different species. Collectively, our findings shed light on the molecular underpinnings of neuropeptide recognition and receptor activation, and they present a promising avenue for the design of selective drugs targeting the NPY receptor family.

[Association of vitamin D receptor gene haplotypes and genotype combinations with susceptibility to occupational elevated blood lead].

OBJECTIVE: To investigate the association of the haplotypes and genotype combinations of vitamin D receptor (VDR) BsmI (rs1544410), Tru9I (rs757343), ApaI (rs7975232), and TaqI (rs731236) with the susceptibility to elevated blood lead in Chinese Han population. METHODS: According to Diagnostic Criteria of Occupational Chronic Lead Poisoning (GBZ 37-2002) and Occupational Exposure Limits for Hazardous Agents in the Workplace Part 1: Chemical Hazardous Agents (GBZ 2.1-2007), the workers were divided into high-exposure group (lead dust ≥ 0.05 mg/m(3), lead fume ≥ 0.03 mg/m(3)) and low-exposure group based on the concentrations of lead fume and lead dust in the workplace. The high-exposure group was further divided into normal-blood lead subgroup and high-blood lead subgroup. Fasting peripheral venous blood (5 ml) was collected using a heparin tube; genomic DNA was extracted from the peripheral blood cells with a Qiagen kit; single nucleotide polymorphisms were detected by allelic discrimination assay using TaqMan probes (carrying fluorescent dyes); haplotypes were analyzed and compared by Haploview. RESULTS: VDR BsmI, Tru9I, ApaI, and TaqI were in Hardy-Weinberg equilibrium between the normal-blood lead subgroup and high-blood lead subgroup (P > 0.05). Compared with haplotype CCCA which had the highest distribution frequency, haplotypes CCAA and CTCA were the high-risk factors for elevated blood lead (OR = 1.814, 95%CI = 1.055 ∼ 3.119; OR = 1.919, 95%CI = 1.040 ∼ 3.540). Compared with genotype combination CC + CC + CC + AA which had the highest distribution frequency, genotype combination CC + CC + AC + AA was the high-risk factor for elevated blood lead (OR = 2.800, 95%CI = 1.282 ∼ 6.116). CONCLUSION: As for VDR BsmI, Tru9I, ApaI, and TaqI, haplotypes CCAA and CTCA and genotype combination CC + CC + AC + AA are associated with the susceptibility to elevated blood lead.

Flexible ultrathin Nitrogen-Doped carbon mediates the surface charge redistribution of a hierarchical tin disulfide nanoflake electrode for efficient capacitive deionization.

Constructing pseudocapacitive electrodes with high specific capacities is indispensable for increasing the large-scale application of capacitive deionization (CDI). However, the insufficient CDI rate and cycling performance of pseudocapacitive-based electrodes have led to a decline in their use due to the corresponding volumetric expansion and contraction that occurs during long-term CDI processes. Herein, hierarchical porous SnS2 nanoflakes are encapsulated inside an N-doped carbon (NC) matrix to achieve efficient CDI. Benefiting from the synergistic properties of the pseudocapacitive SnS2 nanoflakes and few-layered N-doped carbon, the heterogeneous interface simultaneously provides more available vigorous sites and demonstrates rapid charge-transfer kinetics, resulting in a superior desalination capability (49.86 mg g-1 at 1.2 V), rapid desalination rate (1.66 mg g-1 min-1) and better cyclic stability. Computational research reveals a work function-induced surface charge redistribution of the SnS2@NC heterojunction, which can lead to an auspicious surface electronic structure that reduces the adsorption energy to improve the diffusion kinetics toward sodium adsorption. This work contributes to providing a thoughtful understanding of the interface engineering between transition metal dichalcogenides and NC to construct high-performance CDI electrode materials for further industrialization.

DC-CIK combined with chemotherapy on the efficacy, immune function, and life quality in colorectal cancer patients after radical resection.

OBJECTIVE: To investigate the efficacy of combined treatment of dendritic cell-cytokine-induced killer cells (DC-CIK) and chemotherapy on colorectal cancer (CRC) patients who have undergone radical resection, and its effect on immune function and quality of life. METHODS: Data of 103 CRC patients after radical resection admitted to Xianyang First People's Hospital and Yanan University Affiliated Hospital from March 2018 to March 2020 were retrospectively analyzed. A total of 50 patients treated with XELOX chemotherapy were included in the control group (CG). The remaining 53 patients treated with XELOX chemotherapy combined with DC-CIK were included in the observation group (OG). The therapeutic efficacy, immune function indicators, serum tumor markers before and after the treatment, adverse reactions, 2-year survival rate, and quality of life 6 months after the treatment were observed and compared between the two groups. RESULTS: The OG was identified to have a better therapeutic effect than the CG (P<0.05). After the treatment, the OG was assessed with significantly higher levels of IgG, IgA, and IgM than the CG. The CEA, CA724, and CA199 levels in the OG were significantly lower than those in the CG after the treatment (P<0.05). No significant difference was identified regarding the incidence of adverse reactions between the two groups (P>0.05). The quality of life six months after the treatment and the 2-year survival rate in the OG were significantly higher than those in the CG (P<0.05). The logistic regression analysis showed that pathological stage, differentiation, and treatment regimen were independent risk factors for poor prognosis (P<0.05). CONCLUSION: DC-CIK combined with chemotherapy can improve the clinical efficacy, immune function, and long-term survival rate of CRC patients who have undergone radical resection. This combined regimen shows safety and is worthy of promotion in clinical practice.

Intracranial dissemination in a primary small cell carcinoma of the brain: a case report and literature review.

Primary intracranial small cell carcinoma (SCC) is extremely rare with only 8 previously reported cases. We describe a case of primary intracranial SCC with intracranial metastasis. A 46-year-old man presented with decreased vision and a red and swollen left eye. Brain magnetic resonance imaging (MRI) revealed a heterogeneously enhanced tumor on the left frontal lobe. Preoperative systemic computed tomography (CT), MRI, and positron emission tomography (PET)-CT revealed no extracranial tumors. The tumor on the left frontal lobe was excised. Immunohistochemical staining on the excision showed positivity for CD56, synaptophysin (Syn), cytokeratin (CK), and Ki-67 (30%), and negativity for thyroid transcriptional factor-1 (TTF-1), glial fibrillary acidic protein (GFAP), B-cell lymphoma 6 (Bcl-6), multiple myeloma oncogene 1 (MUM-1), C-Myc, Vimentin, P40, P53, CK7, CD3, CD5, CD20, CD79a, CD10, and CD23. The pathological examination strongly suggested that the tumor was a primary intracranial SCC. One year after the surgery, the patient was readmitted with slurred speech and slow movements. Three well-defined tumors were found in the left upper frontal lobe by brain MRI. Tumor resection was then performed. Further immunohistochemical examination of the excised tissue displayed the same pattern as previously, indicating the recurrence of intracranial SCC in the left frontal lobe. The patient received adjuvant chemotherapy and radiotherapy after the tumor resection. At the 2-year follow-up, he remained asymptomatic.

A Highly Efficient Electromagnetic Wave Absorption System with Graphene Embedded in Hybrid Perovskite.

To cope with the explosive increase in electromagnetic radiation intensity caused by the widespread use of electronic information equipment, high-performance electromagnetic wave (EMW)-absorbing materials that can adapt to various frequency bands of EMW are also facing great demand. In this paper, CH3NH3PbI3/graphene (MG) high-performance EMW-absorbing materials were innovatively synthesized by taking organic-inorganic hybrid perovskite (OIHP) with high equilibrium holes, electron mobility, and accessible synthesis as the main body, graphene as the intergranular component, and adjusting the component ratio. When the component ratio was 16:1, the thickness of the absorber was 1.87 mm, and MG's effective EMW absorption width reached 6.04 GHz (11.96-18.00 GHz), achieving complete coverage of the Ku frequency band. As the main body of the composite, CH3NH3PbI3 played the role of the polarization density center, and the defects and vacancies in the crystal significantly increased the polarization loss intensity; graphene, as a typical two-dimensional material distributed in the crystal gap, built an efficient electron transfer channel, which significantly improved the electrical conductivity loss strength. This work effectively broadened the EMW absorption frequency band of OIHP and promoted the research process of new EMW-absorbing materials based on OIPH.

Aspirin reduces the mortality risk of sepsis-associated acute kidney injury: an observational study using the MIMIC IV database.

Introduction: Sepsis-associated acute kidney injury (SA-AKI) is a complication of sepsis and is characterized by high mortality. Aspirin affects cyclooxygenases which play a significant role in inflammation, hemostasis, and immunological regulation. Sepsis is an uncontrolled inflammatory and procoagulant response to a pathogen, but aspirin can inhibit platelet function to attenuate the inflammatory response, thus improving outcomes. Several studies have generated contradictory evidence regarding the effect of aspirin on patients with sepsis-associated acute kidney injury (SA-AKI). We conducted an analysis of the MIMIC IV database to investigate the correlation between aspirin utilization and the outcomes of patients with SA-AKI, as well as to determine the most effective dosage for aspirin therapy. Materials and methods: SA-AKI patients' clinical data were extracted from MIMIC-IV2.1. Propensity score matching was applied to balance the baseline characteristics between the aspirin group and the non-user group. Subsequently, the relationship between aspirin and patient death was analyzed by Kaplan-Meier method and Cox proportional hazard regression models. Results: 12,091 patients with SA-AKI were extracted from the MIMIC IV database. In the propensity score-matched sample of 7,694 individuals, lower 90-day mortality risks were observed in the aspirin group compared to the non-users group (adjusted HR: 0.722; 95%CI: 0.666, 0.783) by multivariable cox proportional hazards analysis. In addition, the Kaplan-Meier survival curves indicated a superior 90-day survival rate for aspirin users compared to non-users (the log-rank test p-value was 0.001). And the median survival time of patients receiving aspirin treatment was significantly longer than those not receiving (46.47 days vs. 24.26 days). In the aspirin group, the average ICU stay length was shorter than non-users group. (5.19 days vs. 5.58 days, p = 0.006). There was no significant association between aspirin and an increased risk of gastrointestinal hemorrhage (p = 0.144). Conclusion: Aspirin might reduce the average ICU stay duration and the 30-day or 90-day mortality risks of SA-AKI patients. No statistically significant difference in the risk of gastrointestinal hemorrhage was found between the aspirin group and the control group.

ZnO-decorated SiC@C hybrids with strong electromagnetic absorption.

A novel strategy is provided to improve the absorption of SiC nanomaterials through surface carbonization of SiC nanowires and hydrolysis. SiC@C-ZnO composites were synthesized with different dosages of ZnNO3·6H2O. Composition, microstructure, and electromagnetic properties of the composites were characterized and analyzed. Results from TEM and XRD show that crystalline ZnO particles adhere to the surface of amorphous carbon, and the ZnO content increases as a function of a dosage of ZnNO3·6H2O. The as-prepared SiC@C-ZnO hybrids exhibit effective electromagnetic absorption, which is related to a synergy effect of different dielectric loss processes. The minimum reflection loss reached -65.4 dB at 11 GHz at a sample thickness of 3.1 mm, while the effective absorption bandwidth (EAB) reached 7 GHz at a sample thickness of 2.56 mm. Furthermore, the EAB of the samples can also cover the whole X band and Ku band at small sample thicknesses (2.09-3.47 mm). The excellent properties of the materials suggest great prospect as electromagnetic absorbers.

The impact of statin use before intensive care unit admission on patients with acute kidney injury after cardiac surgery.

Background: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious complication after cardiac surgery. The influence of statin use before surgery on the renal outcome of patients undergoing cardiac surgery is controversial. The purpose of this study was to evaluate the effect of statins on postoperative renal outcomes in patients undergoing cardiac surgery. Methods: We included CSA-AKI patients in the Medical Information Mart for Intensive Care (MIMIC)-IV database and were divided into statin group and non-statin group according to whether they used statins before entering intensive care units (ICU). The main outcomes were hospitalization and 30-day mortality, and the secondary outcomes were 60-day mortality and 90-day mortality. We used propensity score matching (PSM) to adjust for confounding factors. The 95% confidence interval (CI) and risk ratio (RO) were calculated by the COX proportional regression model. At the same time, stratified analysis was used to explore whether the relationship between the statins use before intensive care units and mortality was different in each subgroup and whether the relationship between different doses of Atorvastatin and mortality was different. Result: We identified 675 pre-ICU statin users and 2095 non-statin users. In the COX proportional regression model, pre-ICU statin use was associated with decreased in-hospital (HR = 0.407, 95%confidence interval 0.278-0.595, p < 0.001) and 30-day mortality (HR = 0.407, 95%CI 0.279-0.595, p < 0.001). The survival rate of patients who took statins before entering ICU was significantly higher than that of those who did not use statins at 30 days, 60 days and 90 days. There is a significant interaction between patients with aged>65 years (HR = 0.373, 95%CI 0.240-0.581, p < 0.001), Acute kidney injury grade I (HR = 0.244, 95%CI 0.118-0.428, p < 0.001), and without post-myocardial infarction syndrome (HR = 0.344, 95%CI 0.218-0.542, p < 0.001). The mortality in hospital and 60 days of CSA-AKI patients treated with ≥80 mg Atorvastatin before operation was significantly reduced (p < 0.05). Conclusion: The pre-ICU statin use was significantly associated with decreased risk in hospital and 30-day mortality. The preoperative use of ≥80 mg Atorvastatin may improve the prognosis of CSA-AKI.

Corrigendum to "The novel putative methyltransferase METTL7A as one prognostic biomarker potentially associated with immune infiltration in human renal cancer".

[This corrects the article DOI: 10.1016/j.heliyon.2023.e15371.].

The novel putative methyltransferase METTL7A as one prognostic biomarker potentially associated with immune infiltration in human renal cancer.

Among urological cancers, renal cancer has the highest fatality rate. In a previous pan-cancer study of the METTL family, we observed a stronger association between the METTL family members and the risk of renal cancer compared to other cancers. Among these members, METTL7A, a potential methyltransferase, was identified as a protective factor, although its role and mechanism in renal cancer remain unclear. In this study, we utilized public databases to examine the expression of METTL7A in renal cancer tissues and normal tissues and found that METTL7A expression was much lower in renal cancer tissues. We also noticed a link between low METTL7A expression and poor prognosis for patients. According to the results of our functional enrichment analysis, METTL7A may have a role in immunological functions in renal cancer. METTL7A expression was strongly linked with the degrees of immune cell infiltration and expression of numerous immunological components. METTL7A had significantly different effects on the survival times of renal cancer patients with high or low immune infiltration. Our findings suggest that METTL7A may be used as both a prognostic biomarker and an immunological target for kidney cancer. In conclusion, our study sheds light on the importance of METTL7A in renal cancer and emphasizes the potential of targeting METTL7A as a novel therapeutic strategy for kidney cancer.

Structure, function and drug discovery of GPCR signaling.

G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes and responses, such as sensory perception (e.g., vision, taste, and smell), immune response, hormone regulation, and neurotransmission. Their diverse and essential roles in the body make them a significant focus for pharmaceutical research and drug development. Currently, approximately 35% of marketed drugs directly target GPCRs, underscoring their prominence as therapeutic targets. Recent advances in structural biology have substantially deepened our understanding of GPCR activation mechanisms and interactions with G-protein and arrestin signaling pathways. This review offers an in-depth exploration of both traditional and recent methods in GPCR structure analysis. It presents structure-based insights into ligand recognition and receptor activation mechanisms and delves deeper into the mechanisms of canonical and noncanonical signaling pathways downstream of GPCRs. Furthermore, it highlights recent advancements in GPCR-related drug discovery and development. Particular emphasis is placed on GPCR selective drugs, allosteric and biased signaling, polyphamarcology, and antibody drugs. Our goal is to provide researchers with a thorough and updated understanding of GPCR structure determination, signaling pathway investigation, and drug development. This foundation aims to propel forward-thinking therapeutic approaches that target GPCRs, drawing upon the latest insights into GPCR ligand selectivity, activation, and biased signaling mechanisms.

Neurotrophin-3 gene transduction of mouse neural stem cells promotes proliferation and neuronal differentiation in organotypic hippocampal slice cultures.

BACKGROUND: The transplantation of neural stem cells (NSCs) has been accepted as a promising therapeutic strategy for central nervous system disorders. However, the beneficial effect of NSC transplantation upon functional recovery is limited due to the unfavorable microenvironment (niche) at the site of trauma or degenerative disease in the brain. Combination of transplantation of NSCs with neurotrophins may overcome the hurdles of impaired cell survival and neuronal differentiation. MATERIAL/METHODS: In the current study, the neurotrophin-3 (NT-3) gene was transduced into cultured mouse embryonic cortical NSCs via an AAV vector (NSC-NT-3). The effect of NT-3 over-expression on cell proliferation and differentiation in NSCs was observed by immunohistochemistry, cell culture and organotypic hippocampal slice cultures.
RESULTS: The characteristics of self-renewal and multiple differentiation of NSCs were well-preserved. Cells in the NSC-NT-3 group proliferated faster and differentiated into more ß-tubulin III-positive neurons compared to the control group in vitro. Furthermore, cells in the NSC-NT-3 group survived in a significantly higher percentage and undertook neuronal differentiation preferably in organotypic hippocampal slice cultures. CONCLUSIONS: Our results suggest that the transduction of NT-3 into NSCs could effectively promote NSCs survival, proliferation, and neuronal differentiation in vitro without change of the stemness of NSCs. This work also offers evidence to better understand the safety and efficiency of combined treatment with NT-3 and NSCs for the central nervous system disorders.