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Despite the intense CD8+ T-cell infiltration in the tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate in clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit immunotherapy efficacy in nasopharyngeal carcinoma, here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that nasopharyngeal carcinoma cells enhance development and suppressive activity of regulatory T cells via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression and thus reinvigorate CD8+ T-cell immunity. Anti-CD70+ anti-PD-1 therapy is evaluated in xenograft-derived organoids and humanized mice, exhibiting an improved tumor-killing efficacy. Mechanistically, CD70 knockout inhibits a collective lipid signaling network in CD4+ naïve and regulatory T cells involving mitochondrial integrity, cholesterol homeostasis, and fatty acid metabolism. Furthermore, ATAC-Seq delineates that CD70 is transcriptionally upregulated by NFKB2 via an Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ nasopharyngeal carcinoma cells as a metabolic switch that enforces the lipid-driven development, functional specialization and homeostasis of Tregs, leading to immune evasion. This study also demonstrates that CD70 blockade can act synergistically with anti-PD-1 treatment to reinvigorate T-cell immunity against nasopharyngeal carcinoma.

BackgroundIn recent years, the research interest in m6A has remained high, and the reason is that N6-methyladenosine (m6A) is the most common reversible methylation modification of eukaryotic mRNA and plays a significant role in tumorigenesis. However, abnormalities of the RNA m6A regulators (writers, erasers, and readers) have rarely been reported in nasopharyngeal carcinoma. The expression of m6A regulators in nasopharyngeal carcinoma is highly diverse, and this diversity has important implications for the prognosis and progression of nasopharyngeal carcinoma. MethodsWe firstly performed differential analysis of FTO expression in NPC and adjacent tissues, survival analysis of NPC patients associated with FTO expression, and immune signature of FTO immunity to NPC, in addition we did molecular biological function experiments and mouse tumorigenesis models were established to explore the role of FTO in the occurrence and development of nasopharyngeal carcinoma. Finally, we performed FTO gene set enrichment analysis (GSEA) to explore potential downstream pathways of FTO.ResultsIn the present study, we showed that FTO, one of the writers, was downregulated in NPC. Functional studies showed that FTO was underexpressed in nasopharyngeal carcinoma and promoted the invasion and migration of NPC cells. However, overexpression of FTO reversed this effect and inhibited the migration and invasion of nasopharyngeal carcinoma cells. Furthermore, to investigate the effect of FTO on immune infiltration of NPC. We performed Gene Set Enrichment Analysis (GSEA) with immune cells and functional gene sets, we found that FTO also had a positive effect on the infiltration and activation of immune cells in the NPC microenvironment. We conducted Gene Set Enrichment Analysis to explore the potential downstream pathways of FTO. Our data demonstrate the significant correlation of FTO expression with the Kyoto Encyclopedia of Genes and Genomes (KEGG) genome closely related to cancer development, and the protective role of FTO during NPC progression. ConclusionsOur data demonstrate the significant correlation of FTO expression with the KEGG genome closely related to cancer development, and the protective role of FTO during NPC progression, and suggest that FTO may be a promising target for future NPC therapy.

Background: Head and neck squamous cell carcinoma (HNSC) is a prevalent and heterogeneous malignancy with poor prognosis and high mortality rates. There is significant evidence of alternative splicing (AS) contributing to tumor development, suggesting its potential in predicting prognosis and therapeutic efficacy. This study aims to establish an AS-based prognostic signature in HNSC patients.Methods: The expression profiles and clinical information of 486 HNSC patients were downloaded from the TCGA database, and the AS data were downloaded from the TCGA SpliceSeq database. The survival-associated AS events were identified by conducting a Cox regression analysis and utilized to develop a prognostic signature by fitting into a LASSO-regularized Cox regression model. Survival analysis, univariate and multivariate Cox regression analysis, and receiver operating characteristic (ROC) curve analysis were performed to evaluate the signature and an independent cohort was used for validation. The immune cell function and infiltration were analyzed by CIBERSORT and the ssGSEA algorithm.Results: Univariate Cox regression analysis identified 2726 survival-associated AS events from 1714 genes. The correlation network reported DDX39B, PRPF39, and ARGLU1 as key splicing factors (SF) regulating these AS events. Eight survival-associated AS events were selected and validated by LASSO regression to develop a prognostic signature. It was confirmed that this signature could predict HNSC outcomes independent of other variables via multivariate Cox regression analysis. The risk score AUC was more than 0.75 for 3 years, highlighting the signature’s prediction capability. Immune infiltration analysis reported different immune cell distributions between the two risk groups. The immune cell content was higher in the high-risk group than in the low-risk group. The correlation analysis revealed a significant correlation between risk score, immune cell subsets, and immune checkpoint expression.Conclusion: The prognostic signature developed from survival-associated AS events could predict the prognosis of HNSC patients and their clinical response to immunotherapy. However, this signature requires further research and validation in larger cohort studies.

Type 2 Diabetes causes learning and memory deficits that might be mediated by hippocampus neuron apoptosis. Studies found that taurine might improve cognitive deficits under diabetic condition because of its ability to prevent hippocampus neuron apoptosis. However, the effect and mechanism is not clear. In this study, we explore the effect and mechanism of taurine on inhibiting hippocampus neuron apoptosis. Sixty male Sprague-Dawley rats were randomly divided into control, T2D, taurine treatment (giving 0.5%, 1%, and 2% taurine in drinking water) groups. Streptozotocin was used to establish the diabetes model. HT-22 cell (hippocampus neurons line) was used for in vitro experiments. Morris Water Maze test was used to check the learning and memory ability, TUNEL assay was used to measure apoptosis and nerve growth factor (NGF); Akt/Bad pathway relevant protein was detected by western blot. Taurine improved learning and memory ability and significantly decreased apoptosis of the hippocampus neurons in T2D rats. Moreover, taurine supplement also inhibited high glucose-induced apoptosis in HT-22 cell in vitro. Mechanistically, taurine increased the expression of NGF, phosphorylation of Trka, Akt, and Bad, as well as reduced cytochrome c release from mitochondria to cytosol. However, beneficial effects of taurine were blocked in the presence of anti-NGF antibody or Akt inhibitor. Taurine could inhibit hippocampus neuron apoptosis via NGF-Akt/Bad pathway. These results provide some clues that taurine might be efficient and feasible candidate for improvement of learning and memory ability in T2D rats.

Affiliations of authors Muhammad Shahbaz and Shahid Alam were incorrect in the published book. This has now been corrected as below.

It was reported that apoptosis of Schwann cells could increase in the diabetic rats. The studies showed that taurine inhibited apoptosis in a variety of cells. However, there were few reports on studying the protection of taurine against apoptosis of Schwann cells induced by high glucose (HG) and the underlying mechanism. In our study, the cells were divided into five groups: Control: the normal medium; HG group: 50 mM high glucose; T1: 50 mM high glucose+Taurine (10 mM) group; T2: 50 mM high glucose+Taurine (20 mM) group; T3: 50 mM high glucose+Taurine (40 mM) group. We used MTT and Tunel assays to measure the cell viability and apoptosis, respectively. Then, we also used western blotting to detect the protein levels of apoptosis-related protein. The results demonstrate that taurine promoted cell viability and decreased apoptosis in RSC96 cells exposed to HG. Furthermore, taurine markedly improved imbalance of Bax and Bcl-2, inhibited the translocation of Cytochrome C (Cyt C) from mitochondria to cytosol and reduced caspase-3 activity in HG-induced RSC96 cells. Our results indicate that taurine protect against apoptosis of Schwann cells induced by HG via inhibiting mitochondria-dependent caspase-3 pathway.

Taurine protect against diabetic neuropathy. However, the protective mechanism of taurine has been poorly understood. It has been demonstrated that microRNAs (miRNAs) are involved in regulating gene expression. Therefore, it is interested in whether taurine affects miRNAs expression profile in peripheral nerve tissue of diabetic neuropathy. In the present study, rats were treated as three group: (1) control (Con) group, (2) diabetic mellitus (DM) group and (3) taurine treatment (Tau) group. Sciatic nerve tissue was harvested and miRNA expression was determined using sequencing. The results showed that 80 miRNAs showed significant difference in DM group compared to Con group, of which 20 miRNAs showed up-regulating, as well as, 60 miRNAs showed down-regulating. On the other hand, 215 differential miRNAs were found between DM and Tau groups. Moreover, the numbers of up-regulated and down-regulated miRNAs were 1 and 214, respectively. Twelve specific miRNAs were screened out and the target genes were obtained by target analysis software. GO and KEGG enrichment analyses showed that these potential target genes for the miRNAs might be involved in axon guidance, generation of neurons, nervous system development and neurogenesis. Our results provided a miRNA profile for further exploring protective mechanisms of taurine against diabetic peripheral neuropathy.

Diabetic neuropathy (DN) is the most common chronic complication of DM and its major pathological changes show axonal dysfunction, atrophy and loss. However, there are few reports that taurine promotes neurite growth of dorsal root ganglion (DRG) cells. In current study, DRG neurons were exposed to high glucose (HG) with or without taurine. The neurite outgrowth of DRG neurons was observed by fluorescent immunohistochemistry method. Expression of Gap-43, Akt, phosphorylated Akt, mTOR and phosphorylated mTOR was determined by Western blot assay. Our results showed that HG significantly decreased the neurite outgrowth and expression of Gap-43 in DRG neurons. Moreover, phosphorylated levels of Akt and mTOR were downregulated in DRG neurons exposed to HG. On the contrary, taurine supplementation significantly reversed the decreased neurite outgrowth and Gap-43 expression, and the downregulated phosphorylated levels of Akt and mTOR. However, the protective effects of taurine were blocked in the presence of PI3K antagonists LY294002 or Akt antagonists Perifosine. These results indicate that taurine promotes neurite outgrowth of DRG neurons exposed to HG via activating Akt/mTOR signal pathway.

Diabetes mellitus (DM) is a condition characterized by chronic hyperglycemia, which leads to diabetic neuropathy and apoptosis in the spinal cord. Taurine has been found to ameliorate the diabetic neuropathy and control apoptosis in various tissues. However, there are few reports that discuss the direct relationship between spinal cord and anti-apoptotic effect of taurine. In this study, DM was induced in male SD rats with STZ @ 25 mg/Kg of body weight in combination with high fat diet. After 2 weeks, they were divided into four groups as DM: diabetic rats, T1 (0.5%), T2 (1%) and T3 (2%) taurine solution, while control group was non-diabetic rats (no treatment). The results showed that DM increased apoptosis, decreased phosphorylated Akt and Bad. DM decreased expression of Bcl-2 and increased the Bax. Moreover, the release of cytochrome c into cytosol was increased in DM and activation of caspase-3 was also increased. However, taurine reversed all these abnormal changes in a dose dependent manner. Our results suggested the involvement of Akt/Bad signaling pathway and mitochondrial apoptosis pathway in protective effect of taurine against apoptosis in the spinal cord of diabetic rats. Therefore, taurine may be a potential medicine against diabetic neuropathy by controlling apoptosis.

Diabetic peripheral neuropathy is a common complications of Type 2 Diabetes and its main pathological feature is myelin sheath damage of peripheral nerve that was induced by Schwann cells (SCs) apoptosis. Increasing evidence suggested that taurine might play a role in improving DPN because of its ability to prevent SCs apoptosis. In this study, we explore the effect of taurine on preventing SCs apoptosis and its underlying mechanism. Sprague Dawley rats were treated with streptozotocin to establish the diabetes model. Rats were randomly divided into control, diabetes, taurine treatment (as giving 0.5%, 1% and 2% taurine in drinking water) groups. RSC96 cell (a rat SCs line) was used for intervention experiments in vitro. Results showed that taurine significantly corrected morphology of damaged myelin sheath and inhibited SCs apoptosis in sciatic nerve of diabetic rats. Moreover, taurine prevented apoptosis of RSC96 cells exposed to high glucose. Mechanistically, taurine up-regulated NGF expression and phosphorylation levels of Akt and GSK3β, while, blocking activation of NGF and phosphorylation of Akt and GSK3β increased apoptosis of high glucose-exposed RSC96 cells with taurine supplement. These results revealed taurine improved the myelin sheath damage of sciatic nerve in diabetic rats by controlling SCs apoptosis via NGF/Akt/GSK3β signaling pathways, which provides some clues that taurine might be effective and feasible candidate for the treatment of DPN.

Diabetes mellitus (DM) is a condition characterized by chronic hyperglycemia, which leads to diabetic neuropathy and apoptosis in the spinal cord. Taurine has been found to ameliorate the diabetic neuropathy and control apoptosis in various tissues. However, there are few reports that discuss the direct relationship between spinal cord and anti-apoptotic effect of taurine. In this study, DM was induced in male SD rats with STZ @ 25 mg/Kg of body weight in combination with high fat diet. After 2 weeks, they were divided into four groups as DM: diabetic rats, T1 (0.5%), T2 (1%) and T3 (2%) taurine solution, while control group was non-diabetic rats (no treatment). The results showed that DM increased apoptosis, decreased phosphorylated Akt and Bad. DM decreased expression of Bcl-2 and increased the Bax. Moreover, the release of cytochrome c into cytosol was increased in DM and activation of caspase-3 was also increased. However, taurine reversed all these abnormal changes in a dose dependent manner. Our results suggested the involvement of Akt/Bad signaling pathway and mitochondrial apoptosis pathway in protective effect of taurine against apoptosis in the spinal cord of diabetic rats. Therefore, taurine may be a potential medicine against diabetic neuropathy by controlling apoptosis.

Taurine protect against diabetic neuropathy. However, the protective mechanism of taurine has been poorly understood. It has been demonstrated that microRNAs (miRNAs) are involved in regulating gene expression. Therefore, it is interested in whether taurine affects miRNAs expression profile in peripheral nerve tissue of diabetic neuropathy. In the present study, rats were treated as three group: (1) control (Con) group, (2) diabetic mellitus (DM) group and (3) taurine treatment (Tau) group. Sciatic nerve tissue was harvested and miRNA expression was determined using sequencing. The results showed that 80 miRNAs showed significant difference in DM group compared to Con group, of which 20 miRNAs showed up-regulating, as well as, 60 miRNAs showed down-regulating. On the other hand, 215 differential miRNAs were found between DM and Tau groups. Moreover, the numbers of up-regulated and down-regulated miRNAs were 1 and 214, respectively. Twelve specific miRNAs were screened out and the target genes were obtained by target analysis software. GO and KEGG enrichment analyses showed that these potential target genes for the miRNAs might be involved in axon guidance, generation of neurons, nervous system development and neurogenesis. Our results provided a miRNA profile for further exploring protective mechanisms of taurine against diabetic peripheral neuropathy.

Diabetic neuropathy (DN) is the most common chronic complication of DM and its major pathological changes show axonal dysfunction, atrophy and loss. However, there are few reports that taurine promotes neurite growth of dorsal root ganglion (DRG) cells. In current study, DRG neurons were exposed to high glucose (HG) with or without taurine. The neurite outgrowth of DRG neurons was observed by fluorescent immunohistochemistry method. Expression of Gap-43, Akt, phosphorylated Akt, mTOR and phosphorylated mTOR was determined by Western blot assay. Our results showed that HG significantly decreased the neurite outgrowth and expression of Gap-43 in DRG neurons. Moreover, phosphorylated levels of Akt and mTOR were downregulated in DRG neurons exposed to HG. On the contrary, taurine supplementation significantly reversed the decreased neurite outgrowth and Gap-43 expression, and the downregulated phosphorylated levels of Akt and mTOR. However, the protective effects of taurine were blocked in the presence of PI3K antagonists LY294002 or Akt antagonists Perifosine. These results indicate that taurine promotes neurite outgrowth of DRG neurons exposed to HG via activating Akt/mTOR signal pathway.

It was reported that apoptosis of Schwann cells could increase in the diabetic rats. The studies showed that taurine inhibited apoptosis in a variety of cells. However, there were few reports on studying the protection of taurine against apoptosis of Schwann cells induced by high glucose (HG) and the underlying mechanism. In our study, the cells were divided into five groups: Control: the normal medium; HG group: 50 mM high glucose; T1: 50 mM high glucose+Taurine (10 mM) group; T2: 50 mM high glucose+Taurine (20 mM) group; T3: 50 mM high glucose+Taurine (40 mM) group. We used MTT and Tunel assays to measure the cell viability and apoptosis, respectively. Then, we also used western blotting to detect the protein levels of apoptosis-related protein. The results demonstrate that taurine promoted cell viability and decreased apoptosis in RSC96 cells exposed to HG. Furthermore, taurine markedly improved imbalance of Bax and Bcl-2, inhibited the translocation of Cytochrome C (Cyt C) from mitochondria to cytosol and reduced caspase-3 activity in HG-induced RSC96 cells. Our results indicate that taurine protect against apoptosis of Schwann cells induced by HG via inhibiting mitochondria-dependent caspase-3 pathway.

Affiliations of authors Muhammad Shahbaz and Shahid Alam were incorrect in the published book. This has now been corrected as below.

Diabetes causes memory loss. Hippocampus is responsible for memory and increased apoptosis was found in diabetes patients. Taurine improved memory in diabetes condition. However, mechanism is unclear. In current study, hippocampal cell line HT-22 cells were subjected to analysis as five groups i.e. Control, High glucose (HG) at concentration of 150 mM, HG + 10 mM (T1), 20 mM (T2) and 40 mM (T3) taurine solution. TUNEL assay showed that HG increased the number of apoptotic cell significantly while taurine reduced apoptosis. Taurine increased phosphorylation of Akt in HT-22 cell treated with HG, and increased phosphorylation of Bad (p-Bad) was seen suggesting involvement of Akt/Bad signaling pathway. Expression of Bcl-2 was reduced in HG group but taurine improved this. Bax expression showed opposite trend. This indicated that taurine may reduce apoptosis by controlling balance of Bcl-2 and Bax. When the activation of Akt was blocked by using of perifosine, the effect of taurine disappears either partially or altogether. Thus, it was clear that taurine reduces apoptosis via Akt/Bad pathway in HT-22 cells exposed to HG which further improves downstream balance of Bcl-2 and Bax. This mechanism may be involved in apoptosis of hippocampus cells in diabetic condition.

Diets in rats and humans have shown promising results. Taurine improved glucagon activity, promoted glycemic stability, modified glucose levels, successfully addressed hyperglycemia via advanced glycation end-product control, improved insulin secretion and had a beneficial effect on insulin resistance. Taurine treatment performed well against oxidative stress in brain, increased the secretion of required hormones and protected against neuropathy, retinopathy and nephropathy in diabetes compared with the control. Taurine has been observed to be effective in treatments against diabetic hepatotoxicity, vascular problems and heart injury in diabetes. Taurine was shown to be effective against oxidative stress. The mechanism of action of taurine cannot be explained by one pathway, as it has many effects. Several of the pathways are the advanced glycation end-product pathway, PI3-kinase/AKT pathway and mitochondrial apoptosis pathway. The worldwide threat of diabetes underscores the urgent need for novel therapeutic measures against this disorder. Taurine (2-aminoethane sulfonic acid) is a natural compound that has been studied in diabetes and diabetes-induced complications.