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Patients with chronic pain frequently suffer from anxiety symptoms. It has been well established that gut microbiota is associated with the pathogenesis of pain and anxiety. However, it is unknown whether the gut microbiota, particularly the specific bacteria, play a role in the comorbidity of chronic pain and anxiety.Chronic inflammatory pain was induced in mice by a single injection of complete Freund's adjuvant (CFA). Mice were then separated into anxiety-susceptible and anxiety-resilient phenotypes by hierarchical clustering analysis of behaviors. Fecal samples were collected to perform 16S rRNA gene sequencing. Chronic diazepam intervention served as a therapeutic strategy and its effect on the composition of gut microbiota was also determined.α-Diversity and β-diversity both showed significant differences among the groups. A total of 12 gut bacteria were both altered after CFA injection and reversed by chronic diazepam treatment. More importantly, the pain hypersensitivity and anxiety-like behaviors were relieved by chronic diazepam treatment. Interestingly, we also found that Desulfovibrio was increased in anxiety-resilient group compared to control and anxiety-susceptible groups.Abnormal composition of gut microbiota plays an essential role in chronic pain as well as in anxiety. Besides, the increased level of Desulfovibrio in anxiety-resilient mice indicated its therapeutic effects on the comorbidity of pain and anxiety. Collectively, targeting gut microbiota, especially increasing the Desulfovibrio level, might be effective in the alleviation of chronic pain-anxiety comorbidity.

Ubiquitin D (UBD) is highly upregulated in many cancers, and plays a pivotal role in the pathophysiological processes of cancers. However, its roles and underlying mechanisms in oral squamous cell carcinoma (OSCC) are still unclear. In the present study, we investigated the role of UBD in patients with OSCC. Quantitative real-time polymerase chain reaction and Western blot were used to measure the expression of UBD in OSCC tissues. Immunohistochemistry assay was used to detect the differential expressions of UBD in 244 OSCC patients and 32 cases of normal oral mucosae. In addition, CCK-8, colony formation, wound healing and Transwell assays were performed to evaluate the effect of UBD on the cell proliferation, migration, and invasion in OSCC. Furthermore, a xenograft tumor model was established to verify the role of UBD on tumor formation in vivo. We found that UBD was upregulated in human OSCC tissues and cell lines and was associated with clinical and pathological features of patients. Moreover, the overexpression of UBD promoted the proliferation, migration and invasion of OSCC cells; however, the knockdown of UBD exerted the opposite effects. In this study, our results also suggested that UBD promoted OSCC progression through NF-κB signaling. Our findings indicated that UBD played a critical role in OSCC and may serve as a prognostic biomarker and potential therapeutic target for OSCC treatment.

Lymph node metastasis (LNM) is considered as an adverse prognostic indicator for cancer patients. Preoperative knowledge of LNM is valuable for pretreatment decision making. Here, we sought to develop and validate an LNM signature for preoperative prediction of LNM in patients with head and neck squamous cell carcinoma (HNSCC).By studying single cell RNA-sequencing data (scRNA-seq), differentially expressed mRNA were selected and analyzed through univariate logistic regression and least absolute shrinkage and selection operator (LASSO) to identify an LNM signature. Multivariate logistic regression was utilized to establish an LNM nomogram incorporating LNM signature and T-classification.The LNM signature was significantly associated with lymph node status and prognosis. The LNM signature and LNM nomogram displayed a robust predictive effect.Our study reveals that LNM signature is a powerful biomarker for preoperative prediction of LNM in patients with HNSCC, which may be effective to realize individualized outcome prediction.

With the aging of the world population, and improvements in medical and health technologies, there are increasing numbers of elderly patients undergoing anaesthesia and surgery. Perioperative neurocognitive dysfunction has gradually attracted increasing attention from academics. Very recently, 6 well-known journals jointly recommended that the term perioperative neurocognitive dysfunction (defined according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition) should be adopted to improve the quality and consistency of academic communications. Perioperative neurocognitive dysfunction currently includes preoperatively diagnosed cognitive decline, postoperative delirium, delayed neurocognitive recovery, and postoperative cognitive dysfunction. Increasing evidence shows that the gut microbiota plays a pivotal role in neuropsychiatric diseases, and in central nervous system functions via the microbiota-gut-brain axis. We recently reported that abnormalities in the composition of the gut microbiota might underlie the mechanisms of postoperative cognitive dysfunction and postoperative delirium, suggesting a critical role for the gut microbiota in perioperative neurocognitive dysfunction. This article therefore reviewed recent findings on the linkage between the gut microbiota and the underlying mechanisms of perioperative neurocognitive dysfunction.

Semaphorin 3A (Sema3A) has been recognized as a crucial regulator of morphogenesis and homeostasis over a wide range of organ systems. However, its function in cutaneous wound healing is poorly understood. In our study, we demonstrated that Sema3A adenovirus plasmids transfection limited keratinocyte proliferation and decreased migrative capacity as assessed by in vitro wound healing assay. Sema3A transduction inhibited TGF-β1-mediated keratinocyte migration and EMT process. Besides, we applied mice with K14-Cre-mediated deletion of Sema3A and found that Sema3A depletion postponed wound closure with decreased re-epithelialization and matrix growth. Contrary to the results obtained with full-length Sema3A plasmids transfection, increased keratinocyte migration with recombinant Sema3A proteins resulted in quicker closure of the wounding area after a scratch. Further, exogenously applied recombinant Sema3A worked with EGF to maintain the activation of EGFR by interacting with NRP1 and thereby regulated the internalization of the EGFR-NRP1 complex. Taken together, these results indicated a paradoxical role of autonomous and non-autonomous Sema3A expression during wound healing. Combined administration of recombinant EGF and Sema3A proteins could accelerate the process of wound repair, thus providing promising treatment prospects in the future.

BackgroundImmune landscape of cancer has been increasingly recognized as a key feature affecting disease progression, prognosis and therapeutic response. Here, we sought to comprehensively characterize the patterns of tumor-infiltrating immune cells (TIIs) in primary oral squamous cell carcinoma (OSCC) and develop immune features-derived models for prognostication and therapeutic prediction.MethodsA total number of 392 patients with OSCC receiving ablative surgery at three independent centers were retrospectively enrolled and defined as training, testing and validation cohorts. Detailed features of 12 types of TIIs at center of tumor and invasive margin were assessed by immunohistochemistry coupled with digital quantification. TIIs abundance in OSCC was also estimated by bioinformatics approaches using multiple publicly available data sets. Prognostic models based on selected immune features were trained via machine learning approach, validated in independent cohorts and evaluated by time-dependent area under the curves and concordance index (C-index). Immune types of OSCC were further identified by consensus clustering and their associations with genetic, molecular features and patient survival were clarified.ResultsPatterns of TIIs infiltration varied among patients and dynamically evolved along with tumor progression. Prognostic models based on selected TIIs were identified as efficient and sensitive biomarkers to stratify patients into subgroups with favorable or inferior survival as well as responders or non-responders to postoperative radiotherapy or immunotherapy. These models outperformed multiple conventional biomarkers and immune-related scores in prognostic prediction. Furthermore, we identified two main immune subtypes of OSCC (immune-hot and immune-cold) which harbored characteristic TIIs infiltrations and genomic and molecular features, and associated with patient survival.ConclusionsOur results delineated immune landscape and subtypes in OSCC, consolidated their clinical values as robust biomarkers to predict patient survival and therapeutic benefits and reinforced key roles of TIIs and tumor-immune interactions underlying oral tumorigenesis, ultimately facilitating development of tailed immunotherapeutic strategies.

Clinical evidence shows that chronic pain and depression often accompany each other, but the underlying pathogenesis of comorbid chronic pain and depression remains mostly undetermined. Biotechnology is gradually revealing the phenotype and function of microglia, with great progress regarding microglia's role in neurodegeneration, depression, chronic pain, and other conditions. This article summarizes the role of microglia in chronic pain, depression, and comorbidities, which is conducive to finding new targets to treat chronic pain and depression.

The non-competitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist, (R, S)-ketamine (ketamine), is known to exert rapid and long-lasting antidepressant-like effects. However, the widely use of ketamine is restricted owing to severe psychotomimetic side-effects and abuse liability. Very recently, we demonstrated that a major metabolite of ketamine, norketamine, in particular the (S)-enantiomer, had a potent antidepressant-like effect. We here examined the effects of a low-dose of norketamine enantiomers on depression symptoms and detected the changes in the composition of gut microbiota. In the behavioral tests, (S)-norketamine, but not (R)-norketamine, showed antidepressant-like effects in the lipopolysaccharide (LPS)-induced mice. At the genus level, (S)-norketamine, but not (R)-norketamine, significantly attenuated the increase in the levels of Escherichia-Shigella and Adlercreutzia, as well as the reduction in the levels of Harryflintia. At the species level, both (S)-norketamine and (R)-norketamine significantly attenuated the increase in the levels of bacterium ic1379 and Bacteroides sp. Marseille-P3166. Notably, (S)-norketamine was more potent than (R)-norketamine at reducing the levels of bacterium ic1379 and Bacteroides sp. Marseille-P3166. Furthermore, (S)-norketamine, but not (R)-norketamine, significantly attenuated the increased levels of Bacteroides caecigallinarum. In conclusion, this study suggests that the antidepressant-like effects of (S)-norketamine might be associated with the changes in the composition of gut microbiota. Therapeutic strategies improving the gut microbiota might facilitate the benefits for depression treatment.

Sarcopenia is the age-related loss of skeletal muscle mass, accompanied by reduced muscle strength or physical function. As the global population continues to age, the prevalence of sarcopenia is gradually increasing. It is conceivable that an increasing number of patients with sarcopenia will be scheduled for surgery and anesthesia in the near future. The complex pathogenesis and clinical features of sarcopenia have brought huge challenges to perioperative management, especially in clinical anesthesia. However, there are currently neither guidelines nor expert consensus on the perioperative management of patients with sarcopenia. In this review, we summarize and elaborate on the pathogenesis, diagnosis, and perioperative precautions of sarcopenia, thereby providing information on the perioperative and anesthestic management of patients with sarcopenia.

Fluvoxamine, a common antidepressant agent, is designed to exert its pharmacological effect by inhibiting synaptic serotonin reuptake. However, increasing evidence has demonstrated that σ1 receptors are likely to be involved in the mechanism of action of fluvoxamine. The present study aimed to observe the effects of fluvoxamine on the expression levels of mammalian target of rapamycin (mTOR), Ca2+/calmodulin-dependent protein kinase 2γ (Camk2γ) and glycogen synthase kinase-3β (GSK-3β) in fluvoxamine-treated N2a cells and attempted to elucidate whether σ1 receptors mediate the pharmacological effects of fluvoxamine. The N2a cells were randomly divided into three groups (each n=6): DMEM group (D group), 0.5 μmol/l fluvoxamine group (F group) and 0.2 μmol/l BD1047 (a σ1 receptor antagonist) + 0.5 μmol/l fluvoxamine group (BF group). Western blotting was used to determine the expression levels of mTOR, Camk2γ and GSK-3β in the cultured N2a cells after two days of incubation. The F group exhibited significant increases in the expression levels of mTOR and Camk2γ and a significant reduction in the expression levels of GSK-3β compared with those in the D group (P