Therapeutic effect of implanted and non-invasive vagus nerve stimulation on heroin-induced anxiety.

Substance addiction causes anxiety, which in turn reinforces the maintaining of substance use, resulting in a vicious circle. And this circle is one of the reasons why addiction is so hard to cure. However, there is no treatment involved in addiction-induced anxiety at present. We tested whether VNS (vagus nerve stimulation) can improve heroin-induced anxiety, and made a comparison between nVNS (transcervical vagus nerve stimulation) and taVNS (transauricular vagus nerve stimulation) on therapeutic effect. Mice were subjected to nVNS or taVNS before heroin administration. By observing c-Fos expression in the NTS (nucleus of the solitary tract), we assessed vagal fiber activation. Using the OFT (open field test) and the EPM (elevated cross maze test), we evaluated the anxiety-like behaviors of the mice. Using immunofluorescence, we observed the proliferation and activation of microglia in the hippocampus. And ELISA was used to measure the levels of proinflammatory factors in the hippocampus. Both nVNS and taVNS significantly increased the expression of c-Fos in the nucleus of solitary tract, suggesting the feasibility of nVNS and taVNS. The anxiety level of heroin-treated mice was significantly increased, microglia in the hippocampus was significantly proliferated and activated, and the proinflammatory factors (IL-1ß, IL-6, TNF-α) in the hippocampus were significantly up-regulated. Crucially, both nVNS and taVNS reversed the above changes caused by heroin addiction. SIGNIFICANCE: It was confirmed that the therapeutic effect of VNS on heroin-induced anxiety may be an effective treatment method to break the "addiction-anxiety" cycle and provides some insights for subsequent treatment of addiction.

The role of germanium in diseases: exploring its important biological effects.

With the development of organic germanium and nanotechnology, germanium serves multiple biological functions, and its potential value in biochemistry and medicine has increasingly captured the attention of researchers. In recent years, germanium has gradually gained significance as a material in the field of biomedicine and shows promising application prospects. However, there has been a limited amount of research conducted on the biological effects and mechanisms of germanium, and a systematic evaluation is still lacking. Therefore, the aim of this review is to systematically examine the application of germanium in the field of biomedicine and contribute new insights for future research on the functions and mechanisms of germanium in disease treatment. By conducting a comprehensive search on MEDLINE, EMBASE, and Web of Science databases, we systematically reviewed the relevant literature on the relationship between germanium and biomedicine. In this review, we will describe the biological activities of germanium in inflammation, immunity, and antioxidation. Furthermore, we will discuss its role in the treatment of neuroscience and oncology-related conditions. This comprehensive exploration of germanium provides a valuable foundation for the future application of this element in disease intervention, diagnosis, and prevention.

Dysregulation of memory B cells and circulating T follicular helper cells is a predictor of poor immune recovery in HIV-infected patients on antiretroviral therapy.

T follicular helper (Tfh) cells and their interactions with B cells within the germinal center play extensive roles in human immunodeficiency virus (HIV) pathology. However, their association with immune reconstitution during antiretroviral therapy (ART) is still unclear. The aim of this study was to determine the impact of Tfh and memory B cell function on T helper cell recovery in patients with acute or chronic HIV infection. A total of 100 HIV-infected individuals were enrolled in our study, classified into acute and chronic HIV infection groups (60 and 40, respectively), and subsequently classified into immunological responder (IR) and immunological nonresponder (INR) subgroups according to immune recovery outcomes after 96 weeks of ART. Liquid chromatography-mass spectrometry was used to quantify the temporal regulation patterns of B and CD4+ T-cell profiles among patients, and flow cytometry was used to investigate certain subsets of B and T cells. Here we showed that the prevalence of Tfh cells in the T helper cell population correlated negatively with CD4+ T-cell recovery. The proportion of CXCR3-  Tfh cells in patients with acute or chronic infection was associated with CD4+ T-cell count recovery, and the proportion of CD21+ memory B cells at baseline was significantly higher in those with improved immune recovery outcomes. Universal proteomic dysregulation of B and CD4+ T cells at baseline was detected in patients with acute infected and poor CD4+ T-cell recovery. Proteomics analysis revealed distinct temporal regulation profiles of both T helper cells and B cells between IRs and INRs among patients with acute infection. Our results suggest that the functions of memory B cells in INRs are dysregulated at the early stage of ART, possibly through disruption of Tfh cell function. The frequency and function of Tfh cells and their subsets are potential predictors of poor immune recovery.

Mucosal-associated invariant T cells: A cryptic coordinator in HIV-infected immune reconstitution.

Human immunodeficiency virus type 1 (HIV-1) infection causes considerable morbidity and mortality worldwide. Although antiretroviral therapy (ART) has largely transformed HIV infection from a fatal disease to a chronic condition, approximately 10%-40% of HIV-infected individuals who receive effective ART and sustain long-term viral suppression still cannot achieve optimal immune reconstitution. These patients are called immunological nonresponders, a state associated with poor clinical prognosis. Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved unconventional T-cell subset defined by expression of semi-invariant αß T-cell receptor (TCR), which recognizes metabolites derived from the riboflavin biosynthetic pathway presented on major histocompatibility complex-related protein-1. MAIT cells, which are considered to act as a bridge between innate and adaptive immunity, produce a wide range of cytokines and cytotoxic molecules upon activation through TCR-dependent and TCR-independent mechanisms, which is of major importance in defense against a variety of pathogens. In addition, MAIT cells are involved in autoimmune and immune-mediated diseases. The number of MAIT cells is dramatically and irreversibly decreased in the early stage of HIV infection and is not fully restored even after long-term suppressive ART. In light of the important role of MAIT cells in mucosal immunity and because microbial translocation is inversely associated with CD4+ T-cell counts, we propose that MAIT cells participate in the maintenance of intestinal barrier integrity and microbial homeostasis, thus further affecting immune reconstitution in HIV-infected individuals.

Progress in the study of intestinal microbiota involved in morphine tolerance.

Morphine is a widely used opioid for treatment of pain. The attendant problems including morphine tolerance and morphine dependence pose a major public health challenge. In recent years, there has been increasing interest in the gastrointestinal microbiota in many physiological and pathophysiological processes. The connectivity network between the gut microbiota and the brain is involved in multiple biological systems, and bidirectional communication between them is critical in gastrointestinal tract homeostasis, the central nervous system, and the microbial system. Many research have previously shown that morphine has a variety of effects on the gastrointestinal tract, but none have determined the function of intestinal microbiota in morphine tolerance. This study reviewed the mechanisms of morphine tolerance from the perspective of dysregulation of microbiota-gut-brain axis homeostasis, by summarizing the possible mechanisms originating from the gut that may affect morphine tolerance and the improvement of morphine tolerance through the gut microbiota.

Cerebral blood flow in the paracentral lobule is associated with poor subjective sleep quality among patients with a history of methadone maintenance treatment.

Introduction: Sleep disorders are prevalent and significant among individuals receiving methadone maintenance treatment (MMT), adversely affecting their quality of life and treatment adherence. While cerebral blood flow (CBF) plays a crucial role in the development of various diseases, its relationship with sleep disorders remains uncertain. This observational study focuses on possible correlations between CBF and poor subjective sleep quality in MMT patients. Methods: A total of 75 participants with a history of MMT were recruited and assessed using pseudo-continuous arterial spin labeling magnetic resonance imaging to determine CBF. A LAASO regression model was employed to identify the region of interest (ROI) most associated with sleep disturbance. The association between the CBF of the ROI and the Pittsburgh Sleep Quality Index (PSQI) was examined using regression analyses. Age, gender, BMI, history of hypertension, diabetes, hyperlipidemia, and methadone withdrawal were included as covariates. Results: Among MMT patients with poor subjective sleep quality, significantly higher CBF was observed in the right paracentral lobule (56.1057 ± 11.1624 ml/100 g/min, p = 0.044), right cerebelum_3 (56.6723 ± 15.3139 ml/100 g/min, p = 0.026), right caudate nucleus (48.9168 ± 6.9910 ml/100 g/min, p = 0.009), and left caudate nucleus (47.6207 ± 6.1374 ml/100 g/min, p = 0.006). Furthermore, a positive correlation was found between CBF in the right paracentral lobule and the total PSQI score (ß = 0.1135, p = 0.0323), with the association remaining significant even after adjustment for covariates (ß = 0.1276, p = 0.0405). Conclusion: MMT patients with poor subjective sleep quality exhibited significantly altered CBF in multiple brain regions. The association between increased CBF in the right paracentral lobule and subjective sleep quality in MMT patients could be crucial in understanding sleep disorders in individuals undergoing MMT. Clinical trial registration: https://www.chictr.org.cn/, identifier: ChiCTR2100051931.

Ketogenic diet: a potential adjunctive treatment for substance use disorders.

Substance use disorders (SUD) can lead to serious health problems, and there is a great interest in developing new treatment methods to alleviate the impact of substance abuse. In recent years, the ketogenic diet (KD) has shown therapeutic benefits as a dietary therapy in a variety of neurological disorders. Recent studies suggest that KD can compensate for the glucose metabolism disorders caused by alcohol use disorder by increasing ketone metabolism, thereby reducing withdrawal symptoms and indicating the therapeutic potential of KD in SUD. Additionally, SUD often accompanies increased sugar intake, involving neural circuits and altered neuroplasticity similar to substance addiction, which may induce cross-sensitization and increased use of other abused substances. Reducing carbohydrate intake through KD may have a positive effect on this. Finally, SUD is often associated with mitochondrial damage, oxidative stress, inflammation, glia dysfunction, and gut microbial disorders, while KD may potentially reverse these abnormalities and serve a therapeutic role. Although there is much indirect evidence that KD has a positive effect on SUD, the small number of relevant studies and the fact that KD leads to side effects such as metabolic abnormalities, increased risk of malnutrition and gastrointestinal symptoms have led to the limitation of KD in the treatment of SUD. Here, we described the organismal disorders caused by SUD and the possible positive effects of KD, aiming to provide potential therapeutic directions for SUD.

Related Effects of Methamphetamine on the Intestinal Barrier via Cytokines, and Potential Mechanisms by Which Methamphetamine May Occur on the Brain-Gut Axis.

Methamphetamine (METH) is an illegal drug widely abused in many countries. Methamphetamine abuse is a major health and social problem all over the world. However, the effects of METH on the digestive system have rarely been reported. Previous studies and clinical cases have shown that METH use can lead to the impaired intestinal barrier function and severe digestive diseases. METH can cause multiple organ dysfunction, especially in the central nervous system (CNS). The gut microbiota are involved in the development of various CNS-related diseases via the gut-brain axis (GBA). Here, we describe the related effects of METH on the intestinal barrier via cytokines and the underlying mechanisms by which METH may occur in the brain-gut axis.

Messenger RNA expression profiles and bioinformatics analysis of mouse hippocampi during exercise alleviates methamphetamine dependence via mRNA profile change in hippocampi.

Background: Methamphetamine (METH) is a highly addictive, psychoactive drug which can harm individual health and lead to great social problems. Various approaches have been adopted to address the problems arising from METH addiction, but relapse rates remain high. Recently, it has been found that comprehensive treatment combined with scientific and appropriate exercise interventions can improve the mental state and physical fitness of drug addicts and promote their physical and mental rehabilitation. Long-term, regular exercise improves the symptoms of METH withdrawal and reduces METH relapse. This study aimed to investigate the effects and regulated gene expression related to running exercise in METH-addicted mice. Methods: Male C57BL/6J mice were used to construct a METH addiction model. We performed a running exercise intervention and used conditioned place preference (CPP) to measure the effects of the running intervention on the METH-addicted mice. We also performed RNA sequencing (RNA-seq) and transcriptome analysis on the mice hippocampi, and the functions and differentially expressed genes (DEGs) that were significantly regulated by exercise intervention in the METH-addicted mice were analyzed and noted. Results: The results showed that days of CPP were shortened to 3 days in METH-addicted mice that underwent moderate exercise intervention, compared to 6 days in METH-addicted mice that went without exercise intervention. In addition, hippocampal transcriptome analysis revealed 12 DEGs significantly regulated by exercise intervention. By performing Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, it was revealed that the function of immune responses was significantly enriched in the METH-addicted mice undertaking exercise. The expression of 12 DEGs was verified by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), which showed that relative messenger RNA (mRNA) expression of DEGs was consistent with the RNA-seq results. Conclusions: A running intervention can promote the recovery of METH addiction in mice, and the 12 candidate DEGs from the mouse hippocampus can be used for further research on the regulatory mechanisms of exercise in METH-addicted mice.

Transcriptomic Profiling Reveals Underlying Immunoregulation Mechanisms of Resistant Hypertension in Injection Drug Users.

Background: Hypertension is a common complication in injection drug users (IDU), especially a high proportion of resistant hypertension occurs among them. However, the involving mechanisms remain largely unknown. Methods: We here investigated the key signaling moieties in resistant hypertension in drug users. Analyses were performed with high-throughput transcriptomic sequencing data of peripheral blood from individuals with drug-sensitive hypertension (Ctrl-DS), IDU with resistant hypertension (IDU-DR), and IDU with sensitive hypertension (IDU-DS). Results: We showed that 17 and 1 genes in IDU-DS, 48 and 4 genes in IDU-DR were upregulated and downregulated compared Ctrl-DS, and 2 and 4 genes were upregulated and downregulated in IDU-DR compared with IDU-DS, respectively (p ≤ 0.01 and |log2(FC)| ≥ 1). Differentially expressed genes (DEGs) between Ctrl-DS and IDU-DS were mainly involved in Gene ontology terms of immunoglobulin complex and blood microparticle. DEGs between IDU-DS and IDU-DR were mainly involved in immune system process and immunoglobulin complex. DEGs between Ctrl-DS and IDU-DR were mainly involved in immunoglobulin complex, blood microparticle and cytoplasmic vesicle lumen. We identified 2 gene clusters (brown modules, MEbrown; turquoise module, MEturquoise) correlated with IDU-DR and a gene cluster (magenta module, MEmagenta) correlated with IDU-DS by weighted gene co-expression network analysis (WGCNA). Functional analysis demonstrated that pathways of focal adhesion and focalin-1-rich granule lumen were involved in the development of IDU-DR, and the cytosolic large ribosomal subunit may relate to IDU-DR. Further, immune cell infiltration analysis demonstrated that the abundance of dendritic cells (DCs), natural Treg cells (nTreg), and exhausted T cells (Tex) in IDU-DR and IDU-DS, naïve CD8+ T cells in IDU-DS was significantly different compared with that in Ctrl-DS. The abundance of cytotoxic T cells (Tc) was significantly different between IDU-DS and IDU-DR. Conclusion: Our findings indicated a potential function of immunoregulation mechanisms for resistant hypertension.

Effects and associated transcriptomic landscape changes of methamphetamine on immune cells.

BACKGROUND: Methamphetamine (METH) abuse causes serious health problems, including injury to the immune system, leading to increased incidence of infections and even making withdrawal more difficult. Of course, immune cells, an important part of the immune system, are also injured in methamphetamine abuse. However, due to different research models and the lack of bioinformatics, the mechanism of METH injury to immune cells has not been clarified. METHODS: We examined the response of three common immune cell lines, namely Jurkat, NK-92 and THP-1 cell lines, to methamphetamine by cell viability and apoptosis assay in vitro, and examined their response patterns at the mRNA level by RNA-sequencing. Differential expression analysis of two conditions (control and METH treatment) in three types of immune cells was performed using the DESeq2 R package (1.20.0). And some of the differentially expressed genes were verified by qPCR. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of differentially expressed genes by the clusterProfiler R package (3.14.3). And gene enrichment analysis was also performed using MetaScape ( www.metascape.org ). RESULTS: The viability of the three immune cells was differentially affected by methamphetamine, and the rate of NK-cell apoptosis was significantly increased. At the mRNA level, we found disorders of cholesterol metabolism in Jurkat cells, activation of ERK1 and ERK2 cascade in NK-92 cells, and disruption of calcium transport channels in THP-1 cells. In addition, all three cells showed changes in the phospholipid metabolic process. CONCLUSIONS: The results suggest that both innate and adaptive immune cells are affected by METH abuse, and there may be commonalities between different immune cells at the transcriptome level. These results provide new insights into the potential effects by which METH injures the immune cells.

Dynamics and correlations in multiplex immune profiling reveal persistent immune inflammation in male drug users after withdrawal.

Drug withdrawal elicits immune responses that contribute to the development of withdrawal symptoms and relapse. The understanding of the immunologic dynamics after drug withdrawal is limited, precluding the finding of promising immune intervention measures. Here, we performed cytokine and multiplex immune profiling in heroin, methamphetamine (METH) and ephedrine users after withdrawal and identified the correlation between cytokines and other immune parameters. We showed that broad and strong inflammatory responses occurred at the early stage after drug withdrawal, and the inflammatory responses showed a downtrend with the extension of withdrawal time. Notably, immune dysregulation remained through and may last longer than 12 months after withdrawal in heroin and METH users. Our findings suggest that cytokines, immune cells, complement and immunoglobulin form a complex immune network that regulates immune responses after withdrawal. These data provide a reference for future scientific research and drug research and development.

A promising research direction for colorectal cancer immunotherapy: The regulatory mechanism of CCL5 in colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, with high morbidity and mortality rates worldwide. Therefore, there is an urgent need to develop more effective treatments for CRC patients. In recent years, there has been some success in the immunotherapy of tumors, and immunotherapy has been used in many solid tumors including CRC. To date, the clinical efficacy of immunotherapy for CRC is limited, so more effective immunotherapy methods need to be explored. In patients with CRC, the CC chemokine CCL5 plays a role in the development of CRC and the recruitment and activation of immune cells, suggesting that it has potential for immunotherapy. This review mainly introduces the latest advances in the study of CCL5 acting as a marker of CRC and related mechanisms of immunotherapy, as well as the latest understanding of how CCL5 is involved in the invasion and development of CRC.

Exercise modulates central and peripheral inflammatory responses and ameliorates methamphetamine-induced anxiety-like symptoms in mice.

Anxiety-like symptoms are common symptoms of methamphetamine (METH) users, especially in the acute withdrawal period, which is an important factor for the high relapse rate during METH acute withdrawal. Exercise has been demonstrated to relieve anxiety-like symptoms during METH withdrawal, but the underlying mechanisms of this anti-anxiety effect are still unclear. Activated microglia and abnormal neuroinflammation play an important role in the pathogenesis of anxiety-like symptoms after METH withdrawal. Moreover, peripheral immune factors were also significantly associated with anxiety symptoms. However, the effects of treadmill exercise on microglial function and neuroinflammation in the striatum and hippocampus during acute METH withdrawal have not been reported. In the current study, we found severe peripheral immune dysfunction in METH users during acute withdrawal, which may in part contribute to anxiety symptoms during METH acute withdrawal. We also showed that 2 weeks of METH exposure induced anxiety-like symptoms in the acute withdrawal period. Additionally, METH exposure resulted in increased microglial activation and proinflammatory cytokines released in the mouse striatum and hippocampus during acute withdrawal. We next evaluated the effects of treadmill exercise in countering anxiety-like symptoms induced by METH acute withdrawal. The results showed that anxiety-like symptoms induced by acute METH withdrawal were attenuated by coadministration of treadmill exercise. In addition, treadmill exercise counteracted METH-induced microglial activation in the mouse striatum and various subregions of the hippocampus. Furthermore, treadmill exercise also reversed the increase in proinflammatory cytokines induced by acute METH withdrawal in the mouse striatum, hippocampus and serum. Our findings suggest that the anti-anxiety effect of treadmill exercise may be mediated by reducing microglial activation and regulating central and peripheral inflammatory responses.