USP47 deficiency in mice modulates tumor infiltrating immune cells and enhances antitumor immune responses in prostate cancer.

This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.

The 14-3-3 protein nt GF14e interacts with CIPK2 and increases low potassium stress in tobacco.

Potassium (K+) plays a role in enzyme activation, membrane transport, and osmotic regulation processes. An increase in potassium content can significantly improve the elasticity and combustibility of tobacco and reduce the content of harmful substances. Here, we report that the expression analysis of Nt GF14e, a 14-3-3 gene, increased markedly after low-potassium treatment (LK). Then, chlorophyll content, POD activity and potassium content, were significantly increased in overexpression of Nt GF14e transgenic tobacco lines compared with those in the wild type plants. The net K+ efflux rates were severely lower in the transgenic plants than in the wild type under LK stress. Furthermore, transcriptome analysis identified 5708 upregulated genes and 2787 downregulated genes between Nt GF14e overexpressing transgenic tobacco plants. The expression levels of some potassium-related genes were increased, such as CBL-interacting protein kinase 2 (CIPK2), Nt CIPK23, Nt CIPK25, H+-ATPase isoform 2 a (AHA2a), Nt AHA4a, Stelar K+ outward rectifier 1(SKOR1), and high affinity K+ transporter 5 (HAK5). The result of yeast two-hybrid and luciferase complementation imaging experiments suggested Nt GF14e could interact with CIPK2. Overall, these findings indicate that NtGF14e plays a vital roles in improving tobacco LK tolerance and enhancing potassium nutrition signaling pathways in tobacco plants.

Mechanisms of Neuronal Reactivation in Memory Consolidation: A Perspective from Pathological Conditions.

Memory consolidation refers to a process by which labile newly formed memory traces are progressively strengthened into long term memories and become more resistant to interference. Recent work has revealed that spontaneous hippocampal activity during rest, commonly referred to as "offline" activity, plays a critical role in the process of memory consolidation. Hippocampal reactivation occurs during sharp-wave ripples (SWRs), which are events associated with highly synchronous neural firing in the hippocampus and modulation of neural activity in distributed brain regions. Memory consolidation occurs primarily through a coordinated communication between hippocampus and neocortex. Cortical slow oscillations drive the repeated reactivation of hippocampal memory representations together with SWRs and thalamo-cortical spindles, inducing long-lasting cellular and network modifications responsible for memory stabilization.In this review, we aim to comprehensively cover the field of "reactivation and memory consolidation" research by detailing the physiological mechanisms of neuronal reactivation and firing patterns during SWRs and providing a discussion of more recent key findings. Several mechanistic explanations of neuropsychiatric diseases propose that impaired neural replay may underlie some of the symptoms of the disorders. Abnormalities in neuronal reactivation are common phenomenon and cause pathology impairment in several diseases, such as Alzheimer's disease (AD), temporal lobe epilepsy (TLE), and schizophrenia. However, the specific physiological mechanisms and pathological changes of reactivation in each disease are different. Recent work has also enlightened some of the underlying pathological mechanisms of neuronal reactivation in these diseases. In this review, we further describe how SWRs, ripples, and slow oscillations are affected in Alzheimer's disease, epilepsy, and schizophrenia. We then compare the differences of neuronal reactivation and discuss how different reactivation abnormalities cause pathological changes in these diseases. Aberrant neural reactivation provides insights into disease pathogenesis and may even serve as biomarkers for early disease progression and treatment response.

Engeletin alleviates depressive-like behaviours by modulating microglial polarization via the LCN2/CXCL10 signalling pathway.

Microglial polarization and associated inflammatory activity are the key mediators of depression pathogenesis. The natural Smilax glabra rhizomilax derivative engeletin has been reported to exhibit robust anti-inflammatory activity, but no studies to date have examined the mechanisms through which it can treat depressive symptoms. We showed that treatment for 21 days with engeletin significantly alleviated depressive-like behaviours in chronic stress social defeat stress (CSDS) model mice. T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) imaging revealed no significant differences between groups, but the bilateral prefrontal cortex of CSDS mice exhibited significant increases in apparent diffusion coefficient and T2 values relative to normal control mice, with a corresponding reduction in fractional anisotropy, while engeletin reversed all of these changes. CSDS resulted in higher levels of IL-1ß, IL-6, and TNF-a production, enhanced microglial activation, and greater M1 polarization with a concomitant decrease in M2 polarization in the mPFC, whereas engeletin treatment effectively abrogated these CSDS-related pathological changes. Engeletin was further found to suppress the LCN2/C-X-C motif chemokine ligand 10 (CXCL10) signalling axis such that adeno-associated virus-induced LCN2 overexpression ablated the antidepressant effects of engeletin and reversed its beneficial effects on the M1/M2 polarization of microglia. In conclusion, engeletin can alleviate CSDS-induced depressive-like behaviours by regulating the LCN2/CXCL10 pathway and thereby altering the polarization of microglia. These data suggest that the antidepressant effects of engeletin are correlated with the polarization of microglia, highlighting a potential avenue for future design of antidepressant strategies that specifically target the microglia.

Increased tumor-infiltrating plasmacytoid dendritic cells express high levels of PD-L2 and affect CD8+ T lymphocyte infiltration in human laryngeal squamous cell carcinoma.

The infiltration and prognostic significance of tumor-infiltrating plasmacytoid dendritic cells (TI-pDC) have been elucidated in various human solid cancers. However, the infiltrating patterns and functional importance of TI-pDC in laryngeal squamous cell carcinoma (LSCC) remain unknown. In this study, flow cytometric analyses were conducted to characterize the infiltration of dendritic cells and T lymphocytes, along with their respective subgroups in tumor tissues (TT), para-carcinoma tissues (PT), and peripheral blood (PB) from LSCC patients. Immunohistochemical staining for CD4 and CD8, as well as immunofluorescence staining for CD123, were performed on serial tissue sections to investigate the co-localization of TI-pDC and tumor-infiltrating T lymphocytes (TIL) within the tumor microenvironment (TME). Our results demonstrated significantly lower percentages of all three DC subsets in PB compared to TT and PT. Notably, the pDC percentage was markedly higher in TT than in PT. Moreover, TI-pDC percentage was significantly elevated in N+ stage patients compared to those with N0 stage. The results of survival analysis consistently demonstrated that high levels of TI-pDC infiltration were indicative of a poor prognosis. Further investigation revealed a significant negative correlation between TI-pDC and CD8+ TILs; notably, pDCs expressed an inhibitory surface molecule PD-L2 rather than PD-L1 within PT. Collectively, our findings suggest that increased TI-pDC is associated with adverse outcomes in LSCC patients while exhibiting an inhibitory phenotype that may play a crucial role in suppressing CD8+ TILs within LSCC tumors. These results highlight the potential therapeutic strategy targeting PD-L2+ pDCs for immunotherapies against LSCC.

Pyramidal and parvalbumin neurons modulate the process of electroacupuncture stimulation for stroke rehabilitation.

Electroacupuncture (EA) stimulation has been shown to be beneficial in stroke rehabilitation; however, little is known about the neurological mechanism by which this peripheral stimulation approach treats for stroke. This study showed that both pyramidal and parvalbumin (PV) neuronal activity increased in the contralesional primary motor cortex forelimb motor area (M1FL) after ischemic stroke induced by focal unilateral occlusion in the M1FL. EA stimulation reduced pyramidal neuronal activity and increased PV neuronal activity. These results were obtained by a combination of fiber photometry recordings, in vivo and in vitro electrophysiological recordings, and immunofluorescence. Moreover, EA was found to regulate the expression/function of N-methyl-D-aspartate receptors (NMDARs) altered by stroke pathology. In summary, our findings suggest that EA could restore disturbed neuronal activity through the regulation of the activity of pyramidal and PV neurons. Furthermore, NMDARs we shown to play an important role in EA-mediated improvements in sensorimotor ability during stroke rehabilitation.

Exploiting synthetic biology platforms for enhanced biosynthesis of natural products in Yarrowia lipolytica.

With the rapid development of synthetic biology, researchers can design, modify, or even synthesize microorganisms de novo, and microorganisms endowed with unnatural functions can be considered "artificial life" and facilitate the development of functional products. Based on this concept, researchers can solve critical problems related to the insufficient supply of natural products, such as low yields, long production cycles, and cumbersome procedures. Due to its superior performance and unique physiological and biochemical characteristics, Yarrowia lipolytica is a favorable chassis cell used for green biomanufacturing by numerous researchers. This paper mainly reviews the development of synthetic biology techniques for Y. lipolytica and summarizes the recent research progress on the synthesis of natural products in Y. lipolytica. This review will promote the continued innovative development of Y. lipolytica by providing theoretical guidance for research on the biosynthesis of natural products.

Transient inhibition of neutrophil functions enhances the antitumor effect of intravenously delivered oncolytic vaccinia virus.

Oncolytic viruses (OVs) possess the unique ability to selectively replicate within tumor cells, leading to their destruction, while also reversing the immunosuppression within the tumor microenvironment and triggering an antitumor immune response. As a result, OVs have emerged as one of the most promising approaches in cancer therapy. However, the effective delivery of intravenously administered OVs faces significant challenges imposed by various immune cells within the peripheral blood, hindering their access to tumor sites. Notably, neutrophils, the predominant white blood cell population comprising approximately 50%-70% of circulating white cells in humans, show phagocytic properties. Our investigation revealed that the majority of oncolytic vaccinia viruses (VV) are engulfed and degraded by neutrophils in the bloodstream. The depletion of neutrophils using the anti-LY6G Ab (1-A8) resulted in an increased accumulation of circulating oncolytic VV in the peripheral blood and enhanced deposition at the tumor site, consequently amplifying the antitumor effect. Neutrophils heavily rely on PI3K signaling to sustain their phagocytic process. Additionally, our study determined that the inhibition of the PI3Kinase delta isoform by idelalisib (CAL-101) suppressed the uptake of oncolytic VV by neutrophils. This inhibition led to a greater presence of oncolytic VV in both the peripheral blood and at the tumor site, resulting in improved efficacy against the tumor. In conclusion, our study showed that inhibiting neutrophil functions can significantly enhance the antitumor efficacy of intravenous oncolytic VV.

Reperfusion strategies on the clinical outcomes of ST-elevation myocardial infarction patients over 80 years old in China.

BACKGROUNDS AND AIMS: This study aims to explore the efficacy of reperfusion strategies on the clinical outcomes of ST-elevation myocardial infarction (STEMI) patients over 80 years old in China. METHODS: A retrospective cohort study was performed on STEMI patients over 80 years old who underwent reperfusion strategies and no reperfusion between January 2014 and December 2021 based on the China Cardiovascular Association (CCA) Database-Chest Pain Center. RESULTS: This study included a total of 42,699 patients (mean age 84.1 ± 3.6 years, 52.2% male) among which 19,280 (45.2%) underwent no reperfusion, 20,924 (49.0%) underwent primary percutaneous coronary intervention (PCI), and 2,495 (5.8%) underwent thrombolytic therapy. After adjusting for potential confounders, multivariable logistic regression analysis revealed that patients who underwent primary PCI strategy showed a significantly lower risk of in-hospital mortality (OR = 0.62, 95% CI: 0.57-0.67, P < 0.001) and the composite outcome (OR = 0.83, 95% CI: 0.79-0.87, P < 0.001) compared to those received no reperfusion. In contrast, patients with thrombolytic therapy exhibited a non-significantly higher risk of in-hospital mortality (OR = 0.99, 95% CI: 0.86-1.14, P = 0.890), and a significantly elevated risk of the composite outcome (OR = 1.15, 95% CI: 1.05-1.27, P = 0.004). During a median follow-up of 6.7 months post-hospital admission, there was a percentage 31.4% of patients died and patients in the primary PCI group consistently demonstrated a reduced incidence of all-cause mortality (HR = 0.58, 95% CI: 0.56-0.61, P < 0.001). CONCLUSION: STEMI patients over 80 years old who underwent the primary PCI strategy are more likely to have favorable clinical outcomes compared to those who received no reperfusion, whereas, thrombolytic therapy warrants careful assessment and monitoring.

Prognostic significance and immune escape implication of tumor-infiltrating neutrophil plasticity in human head and neck squamous cell carcinoma.

Tumor-infiltrating neutrophils play a crucial role in the progression of head and neck squamous cell carcinoma (HNSCC). Here, we aimed to statistically quantify the plasticity of HNSCC-infiltrating N2/N1 neutrophils and examine its impacts on survival and immune infiltration landscape. A retrospective study of 80 patients who underwent curative surgical resection for HNSCC between 2014 and 2017 was conducted in this study. HNSCC-infiltrating neutrophil phenotypes were classified using immunofluorescence staining, and the N2/N1 neutrophil plasticity was evaluated via the ratio of N2/N1 neutrophils. We then assessed the correlations between N2/N1 neutrophil plasticity, clinicopathological characteristics, and immune infiltration landscape using rigorous statistical methods. Infiltration variations of N1 and N2 neutrophils were observed between the tumor nest (TN) and tumor stroma (TS), with TN exhibiting higher N2 neutrophil infiltration and lower N1 neutrophil infiltration. High ratios of N2/N1 neutrophils were correlated with advanced TNM stage, large tumor size and invasion of adjacent tissue. High infiltration of N2 neutrophils was associated with decreased overall and relapse-free survival, which were opposite for N1 neutrophils. The independent prognostic role of N2/N1 neutrophil plasticity, particularly within the TN region, was confirmed by multivariate analyses. Moreover, the ratio of N2/N1 neutrophils within the TN region showed correlations with high CD8+ T cells infiltration and low FOXP3+ Tregs infiltration. We identify HNSCC-infiltrating N2/N1 neutrophil plasticity as a crucial prognostic indictor which potentially reflects the tumor microenvironment (TME) and immune escape landscape within HNSCC tissues. Further investigations and validations may provide novel therapeutic strategies for personalized immunomodulation in HNSCC patients.

Research trends and frontier hotspots of TRPV1 based on bibliometric and visualization analyses.

Background: Transient receptor potential vanilloid type1 (TRPV1) is a non-selective cation channel with multiple activation mechanisms, which has received increasing attention since it was first cloned in 1997. Methods: We used bibliometric and visualization analyses to evaluate the theme trends and knowledge structure of TRPV1 research-papers on TRPV1 from 2002 to 2022 obtained from the Web of Science Core Collection. VOSviewer and CiteSpace were used to analyze authors, institutions, countries, co-cited references, and keywords. Results: A total of 7413 papers were included. The main research area of TRPV1 was neuroscience; the most published country was the United States, and the University of California, San Francisco, had the highest centrality. Two major collaborative sub-networks were formed between the authors. The distribution of keywords shows that TRPV1 was initially studied extensively, and the recent studies focused on TRPV1 structure and diseases. "Oxidative stress," "TRPV1 structure," "cancer," and "model" have been the research hotspots in recent years. Conclusions: This research provides valuable information for the study of TRPV1. Disease research was focused on pain, cancer, and neurodegenerative diseases. Both agonists and antagonists of TRPV1 are gradually being used in clinical practice, and acupuncture was effective in treating TRPV1-mediated inflammatory pain. TRPV1 is involved in classical endogenous cannabis system signaling, and new signaling pathways continue to be revealed.

Establishment and characterization of a novel hypopharyngeal squamous cell carcinoma cell line CZH1 with genetic abnormalities.

Hypopharyngeal squamous cell carcinoma (HPSCC) has the worst prognosis among head and neck squamous cell carcinomas. The lack of available tumor cell lines poses a significant obstacle to the development of efficient treatments for HPSCC. In this study, we successfully established a novel cell line, named CZH1, from the postcricoid region of a Chinese male patient with a T3N0M0 HPSCC. Short tandem repeat analysis confirmed the uniqueness of CZH1. The cell line was characterized by its phenotypes, biomarkers, and genetics. Importantly, CZH1 cells retained the typical features of epithelial malignancy, similar to the primary tumor tissue. Furthermore, CZH1 demonstrated a greater capacity for invasion and increased susceptibility to irradiation in comparison to FaDu, which is the most commonly used HPSCC cell line. Whole-exome sequencing analysis revealed that CZH1 cells had typical genomic features of HNSCC, including mutations of TP53 and amplifications of multiple transcripts. Therefore, our newly developed CZH1 cell line could serve as an efficient tool for the in vitro investigation of the etiology, pathogenesis, and preclinical treatment of HPSCC.

Trichosanthin alleviates streptozotocin-induced type 1 diabetes mellitus in mice by regulating the balance between bone marrow-derived IL6+ and IL10+ MDSCs.

Myeloid-derived suppressor cells (MDSCs) occupy a pivotal role in the intricate pathogenesis of the autoimmune disorder, Type 1 diabetes mellitus (T1DM). Since our previous work demonstrated that trichosanthin (TCS), an active compound of Chinese herb medicine Tian Hua Fen, regulated immune response, we aimed to clarify the efficacy and molecular mechanism of TCS in the treatment of T1DM. To this end, T1DM mouse model was established by streptozotocin (STZ) induction. The mice were randomly divided into normal control group (Ctl), T1DM group (STZ), TCS treated diabetic group (STZ + TCS) and insulin-treated diabetic group (STZ + insulin). Our comprehensive evaluation encompassed variables such as blood glucose, glycosylated hemoglobin, body weight, pertinent biochemical markers, pancreatic histopathology, and the distribution of immune cell populations. Furthermore, we meticulously isolated MDSCs from the bone marrow of T1DM mice, probing into the expressions of genes pertaining to the advanced glycation end product receptor (RAGE)/NF-κB signaling pathway through RT-qPCR. Evidently, TCS exhibited a substantial capacity to effectively counteract the T1DM-induced elevation in random blood glucose, glycosylated hemoglobin, and IL-6 levels in plasma. Pathological scrutiny underscored the ability of TCS to mitigate the damage incurred by islets. Intriguingly, TCS interventions engendered a reduction in the proportion of MDSCs within the bone marrow, particularly within the IL-6+ MDSC subset. In contrast, IL-10+ MDSCs exhibited an elevation following TCS treatment. Moreover, we observed a significant down-regulation of relative mRNA of pro-inflammatory genes, including arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), RAGE and NF-κB, within MDSCs due to the influence of TCS. It decreases total MDSCs and regulates the balance between IL-6+ and IL-10+ MDSCs thus alleviating the symptoms of T1DM. TCS also down-regulates the RAGE/NF-κB signaling pathway, making it a promising alternative therapeutic treatment for T1DM. Collectively, our study offered novel insights into the underlying mechanism by which TCS serves as a promising therapeutic intervention for T1DM.

Isolation of tumor stem-like cells from primary laryngeal squamous cell carcinoma cells (FD-LS-6).

The development of efficient treatments for laryngeal squamous cell carcinoma (LSCC) is hindered by the lack of applicable tumor cell lines and animal models of the disease, especially those related to cancer stem-like cells (CSCs). CSCs play critical roles in tumor propagation and pathogenesis whereas no CSCs lines have been developed to date. In this study, we establish an LSCC cell line (FD-LS-6) from primary LSCC tumor tissue (not experienced single-cell cloning) and adapted a culturing condition for the expansion of potential stem cells (EPSCs) to isolate CSCs from FD-LS-6. We successfully derived novel CSCs and named them as LSCC sphere-forming cells (LSCSCs) which were subsequently characterized for their CSC properties. We showed that LSCSCs shared many properties of CSCs, including CSC marker, robust self-renewal capacity, tumorigenesis ability, potential to generate other cell types such as adipocytes and osteoblasts, and resistance to chemotherapy. Compared to parental cells, LSCSCs were significantly more potent in forming tumors in vivo in mice and more resistant to chemotherapy. LSCSCs have higher expressions of epithelial-mesenchymal transition proteins and chemotherapy resistance factors, and exhibit an activated COX2/PEG2 signaling pathway. Altogether, our work establishes the first CSCs of LSCC (FD-LS-6) and provides a tool to study tumorigenesis and metastasis of LSCC and help the development of anticancer therapies.

Genetic susceptibility loci of lung cancer are associated with malignant risk of pulmonary nodules and improve malignancy diagnosis based on CEA levels.

Objective: The heightened prevalence of pulmonary nodules (PN) has escalated its significance as a public health concern. While the precise identification of high-risk PN carriers for malignancy remains an ongoing challenge, genetic variants hold potentials as determinants of disease susceptibility that can aid in diagnosis. Yet, current understanding of the genetic loci associated with malignant PN (MPN) risk is limited. Methods: A frequency-matched case-control study was performed, comprising 247 MPN cases and 412 benign NP (BNP) controls. We genotyped 11 established susceptibility loci for lung cancer in a Chinese cohort. Loci associated with MPN risk were utilized to compute a polygenic risk score (PRS). This PRS was subsequently incorporated into the diagnostic evaluation of MPNs, with emphasis on serum tumor biomarkers. Results: Loci rs10429489G>A, rs17038564A>G, and rs12265047A>G were identified as being associated with an increased risk of MPNs. The PRS, formulated from the cumulative risk effects of these loci, correlated with the malignant risk of PNs in a dose-dependent fashion. A high PRS was found to amplify the MPN risk by 156% in comparison to a low PRS [odds ratio (OR)=2.56, 95% confidence interval (95% CI), 1.40-4.67]. Notably, the PRS was observed to enhance the diagnostic accuracy of serum carcinoembryonic antigen (CEA) in distinguishing MPNs from BPNs, with diagnostic values rising from 0.716 to 0.861 across low- to high-PRS categories. Further bioinformatics investigations pinpointed rs10429489G>A as an expression quantitative trait locus. Conclusions: Loci rs10429489G>A, rs17038564A>G, and rs12265047A>G contribute to MPN risk and augment the diagnostic precision for MPNs based on serum CEA concentrations.

Mechanism of analgesic effect of fire needle on peripheral sensitization in rats with neuropathic pain induced by chemotherapy. / ç«é’ˆå¯¹åŒ–ç–—æ‰€è‡´ç¥žç»ç— ç†æ€§ç–¼ç—›å¤§é¼ å¤–å‘¨æ•åŒ–çš„é•‡ç—›ä½œç”¨æœºåˆ¶.

OBJECTIVES: This study aims to explore the analgesic mechanism of fire needle on peripheral sensitization in rats with neuropathic pain(NP) induced by oxaliplatin, so as to investigate its mechanism in improving peri-pheral sensitization. METHODS: Male SD rats aged 8 weeks were randomly divided into 4 groups：normal group(n=6), model group(n=6), fire needle group(n=6), and medication group(n=6). NP rat model was established by intraperitoneal injection of oxaliplatin(4 mg/kg) on days 1, 2, 8, 9, 15, 16, 22, and 23. For rats in the fire needle group, fire needle treatment was performed at the "Jiaji"(EX-B2) acupoints of the L4-L6 segments on days 24, 26, and 28, ie. 1 day, 3 and 5 days after modeling. The medication group received intraperitoneal injection of pregabalin(100 mg/kg). Mechanical pain thresholds of the rats were measured before modeling, after modeling and intervention. Serum contents of tumor necrosis factor-α(TNF-α), interleukin-6(IL-6) and chemokine ligand 12(CXCL12) were detected by ELISA. Skin histopathology changes in the acupoint area were observed using HE staining. The number of mast cells in the skin of the acupoints was observed using toluidine blue staining. Immunohistochemical staining was performed to detect the postive expressions of transient receptor potential vanilloid 1(TRPV1), protease-activated receptor 2(PAR2) and tryptase(TPS) in the skin of the acupoint area. Western blot was used to detect the protein expressions of TRPV1 and PAR2 in the dorsal root ganglia(DRG). RESULTS: Compared with the normal group, the model group had decreased paw withdrawal threshold(PWT) after modeling(P<0.05), increased serum contents of IL-6, TNF-α, and CXCL12(P<0.05), increased number of mast cells in the acupoint area(P<0.05), and increased positive protein expressions of TPS, TRPV1, and PAR2 in the skin of the acupoint area(P<0.05). Compared with the model group, the fire needle group and medication group had increased PWT after intervention(P<0.05), decreased serum contents of IL-6, TNF-α, and CXCL12, and postive protein expressions of TPS, TRPV1, and PAR2 in the skin of the acupoint area(P<0.05)；while the medication group had decreased protein expressions of TRPV1 and PAR2 in DRG(P<0.05). HE staining showed thickened epidermis, disordered cellular arrangement, significant intercellular edema, and inflammatory cell infiltration in the model group. In the medication and fire needle groups, the epidermis was thinner, cellular arrangement was clearer, and the extent of tissue edema and inflammatory cell infiltration was reduced compared to the model group. CONCLUSIONS: Fire needle can improve mechanical pain threshold and reduce the contents of peripheral inflammatory factors in rats with oxaliplatin-induced NP. This effect may be related to the inhibition of mast cell activation and the inhibition of TPS, TRPV1 and PAR2 protein expressions, in the local areas of acupoints.

Association of nicotine dependence and gut microbiota: a bidirectional two-sample Mendelian randomization study.

Background: Nicotine dependence is a key factor influencing the diversity of gut microbiota, and targeting gut microbiota may become a new approach for the prevention and treatment of nicotine dependence. However, the causal relationship between the two is still unclear. This study aims to investigate the causal relationship between nicotine dependence and gut microbiota. Methods: A two-sample bidirectional Mendelian randomization (MR) study was conducted using the largest existing gut microbiota and nicotine dependence genome-wide association studies (GWAS). Causal relationships between genetically predicted nicotine dependence and gut microbiota abundance were examined using inverse variance weighted, MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO approaches. Cochrane's Q test, MR-Egger intercept test, and leave-one-out analysis were performed as sensitivity analyses to assess the robustness of the results. Multivariable Mendelian randomization analysis was also conducted to eliminate the interference of smoking-related phenotypes. Reverse Mendelian randomization analysis was then performed to determine the causal relationship between genetically predicted gut microbiota abundance and nicotine dependence. Results: Genetically predicted nicotine dependence had a causal effect on Christensenellaceae (ß: -0.52, 95% CI: -0.934-0.106, P = 0.014). The Eubacterium xylanophilum group (OR: 1.106, 95% CI: 1.004-1.218), Lachnoclostridium (OR: 1.118, 95% CI: 1.001-1.249) and Holdemania (OR: 1.08, 95% CI: 1.001-1.167) were risk factors for nicotine dependence. Peptostreptococcaceae (OR: 0.905, 95% CI: 0.837-0.977), Desulfovibrio (OR: 0.014, 95% CI: 0.819-0.977), Dorea (OR: 0.841, 95% CI. 0.731-0.968), Faecalibacterium (OR: 0.831, 95% CI: 0.735-0.939) and Sutterella (OR: 0.838, 95% CI: 0.739-0.951) were protective factor for nicotine dependence. The sensitivity analysis showed consistent results. Conclusion: The Mendelian randomization study confirmed the causal link between genetically predicted risk of nicotine dependence and genetically predicted abundance of gut microbiota. Gut microbiota may serve as a biomarker and offer insights for addressing nicotine dependence.

Trichosanthin-derived peptide Tk-PQ attenuates immune rejection in mouse tracheal allotransplant model by suppressing PI3K-Akt and inducing type II immune polarization.

Obliterative bronchiolitis (OB) is one of the main complications affecting long-term survival of post-lung transplantation patients. In this study, we evaluated the efficacy of Tk-PQ (a peptide derived from trichosanthin) in alleviating OB in a mouse ectopic tracheal transplant model. We found that post-transplantation treatment of Tk-PQ significant ameliorated OB symptoms including luminal occlusion, epithelial cells loss and fibrosis in the allograft. In addition, Tk-PQ promoted immune suppressive environment by inducing Th2 polarization and increasing Treg population which in turn led to elevated levels of anti-inflammatory cytokines IL-4, IL-10, IL-33 and decreased levels of pro-inflammatory IL-1ß. Mechanistically, we used transcriptome analysis of splenic T cells from allografted mice to show that Tk-PQ treatment down-regulated the PI3K-Akt signaling pathway. Indeed, the immune suppression phenotypes of Tk-PQ was recapitulated by a PI3K inhibitor LY294002. Taken together, Tk-PQ regulates post-transplantation immuno-rejection by modulating the balance of T cell response via the PI3K-Akt pathway, making it a promising peptide based immune rejection suppressant for patients receiving allotransplant.

Research status and hotspots in the surgical treatment of tremor in Parkinson's disease from 2002 to 2022: a bibliometric and visualization analysis.

Objective: This study aims to investigate the research status and hotspots of surgical treatment for tremor in Parkinson's disease (PD) from 2002 to 2022, utilizing bibliometric and visual analysis. Additionally, it aims to offer insights into future research trends in this field. Methods: This study collected publications on the surgical treatment of tremor in PD from 2002 to 2022 using the Web of Science (WOS) database. CiteSpace, VOSviewer, and Scimago Graphica were employed to quantify the number of publications and analyze the bibliographic information networks, including the contributions of countries/cities, authors, keywords, and co-cited references. Results: A total of 2,815 publications were included in the study, revealing that 541 scientific institutions experienced an increase in publications from 2002 to 2022. Michael Okun emerged as the most productive author, and the United States emerged as the leading hub for research. The study identified 772 keywords. Noteworthy citation bursts and long-term activity were observed in pallidotomy, bilateral stimulation, and focused ultrasound thalamotomy. The top 10 highly co-cited references comprised eight deep brain stimulation (DBS) studies (including two follow-up studies and six randomized controlled trials), one randomized controlled trial on focused ultrasound, and one consensus on tremor. Conclusion: This study uses an in-depth and systematic bibliometric and visualization analysis to visualize the evolution of research and identify emerging hotspots. The identified hotspots are as follows: Firstly, DBS has received significant attention and widespread recognition as a surgical treatment for tremor in PD. Secondly, there are various key aspects to consider in DBS, such as operative indications, operative targets, and surgical protocols. Lastly, magnetic resonance-guided focused ultrasound (MRgFUS) has emerged as a promising treatment option in the surgical management of tremor in Parkinson's disease. This research also provides insights into the phenomenon of these hotspots, offering valuable prompts and reminders for further research.

[Clinical efficacy of fire needling combined with cupping therapy on herpes zoster of acute stage and the effect on Th17/Treg cellular immune balance].

OBJECTIVE: To compare the clinical efficacy between the combined therapy of fire needling and cupping, and western medication on herpes zoster of acute stage, as well as the effects on Th17 and Treg cells and inflammatory factors, i.e. IL-10 and IL-17 in the peripheral blood. METHODS: Eighty patients with herpes zoster of acute stage were randomly divided into a combined therapy (fire needling plus cupping) group and a western medication group, 40 cases in each one. In the combined therapy group, the pricking and scattering techniques with fire needle were used at ashi points and Jiaji (EX-B 2) corresponding to the affected spinal segments; afterwards, cupping therapy was delivered. The combined treatment was given once daily. In the western medication group, valaciclovir hydrochloride tablet and vitamin B1 tablet were administered orally. The duration of treatment in each group was 10 days. Before each treatment from day 1 to day 10 and on day 11 , the score of symptoms and physical signs was observed in the two groups separately. Before each treatment from day 1 to day 10 and on day 11, 30, 60, the score of visual analogue scale (VAS) and skin lesion indexes were observed in the two groups. On day 60, the incidence of postherpetic neuralgia was recorded in the two groups. The levels of Th17 and Treg cells, Th17/Treg ratio in the peripheral blood, as well as serum levels of IL-10 and IL-17 were detected before and after treatment in the two groups. The clinical efficacy was compared between the two groups. RESULTS: From day 6 to day 10 during treatment and on day 11, the scores of symptoms and physical signs in the combined therapy group were lower than those of the western medication group (P<0.05, P<0.01). On day 3, day 6 to day 10 during treatment and day 11, day 30, VAS scores in the combined therapy group were lower than those of the western medication group (P<0.05, P<0.01). On day 60, the incidence of postherpetic neuralgia in the combined therapy group was lower compared with that in the western medication group (P<0.05). The blister arresting time and scabbing time in the combined therapy group were shorter than those of the western medication group (P<0.05). After treatment, the level of Th17, and Th17/Treg ratio in the peripheral blood, as well as the serum levels of IL-10 and IL-17 were all lower in comparison with those in the western medication group (P<0.05). The curative and remarkably effective rate was 82.5% (33/40) in the combined therapy group, higher than 62.5% (25/40) in the western medication group (P<0.05). CONCLUSION: The early application of fire needling combined with cupping therapy can effectively treat herpes zoster of acute stage, relieve pain, and reduce the incidence of postherpetic neuralgia, which may be related to reducing the levels of Th17 and Treg cells, and Th17/Treg ratio in the peripheral blood, as well as the serum levels of IL-10 and IL-17 so that the cellular immune balance is modulated.