Nrf2 prevents diabetic cardiomyopathy via antioxidant effect and normalization of glucose and lipid metabolism in the heart.

Metabolic disorders and oxidative stress are the main causes of diabetic cardiomyopathy. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a powerful antioxidant effect and prevents the progression of diabetic cardiomyopathy. However, the mechanism of its cardiac protection and direct action on cardiomyocytes are not well understood. Here, we investigated in a cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) the direct effect of Nrf2 on cardiomyocytes in DCM and its mechanism. In this study, cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) were used to directly observe whether cardiomyocyte-specific overexpression of Nrf2 can prevent diabetic cardiomyopathy and correct glucose and lipid metabolism disorders in the heart. Compared to wild-type mice, Nrf2-TG mice showed resistance to diabetic cardiomyopathy in a streptozotocin-induced type 1 diabetes mouse model. This was primarily manifested as improved echocardiography results as well as reduced myocardial fibrosis, cardiac inflammation, and oxidative stress. These results showed that Nrf2 can directly act on cardiomyocytes to exert a cardioprotective role. Mechanistically, the cardioprotective effects of Nrf2 depend on its antioxidation activity, partially through improving glucose and lipid metabolism by directly targeting lipid metabolic pathway of AMPK/Sirt1/PGC-1α activation via upstream genes of sestrin2 and LKB1, and indirectly enabling AKT/GSK-3ß/HK-Ⅱ activity via AMPK mediated p70S6K inhibition.

Causal association between tea consumption and head and neck cancer: a Mendelian randomization study.

Although evidence supports an observational association between tea consumption and susceptibility to head and neck cancer, the causal nature of this association remains unclear. We performed a two-sample Mendelian randomization (MR) analysis to determine the causal effects of tea consumption on head and neck cancer. We employed a fixed-effects inverse variance-weighted model for the MR analysis. Genome-wide association study (GWAS) summary data for tea consumption were obtained from the UK Biobank Consortium, and GWAS data for head and neck cancer were derived from two data sources and were used as the outcomes. Our MR analysis revealed limited evidence for a causal relationship between various types of tea intake and head and neck cancer. After adjustment for smoking and alcohol consumption, there was no causal relationship between tea consumption and head and neck cancer. Further experimental studies are required to confirm its potential role in these malignancies.

Function of Akkermansia muciniphila in type 2 diabetes and related diseases.

The prevalence of type 2 diabetes (T2D) is increasing worldwide, with many patients developing long-term complications that affect their cardiovascular, urinary, alimentary, and other systems. A growing body of literature has reported the crucial role of gut microbiota in metabolic diseases, one of which, Akkermansia muciniphila, is considered the "next-generation probiotic" for alleviating metabolic disorders and the inflammatory response. Although extensive research has been conducted on A. muciniphila, none has summarized its regulation in T2D. Hence, this review provides an overview of the effects and multifaceted mechanisms of A. muciniphila on T2D and related diseases, including improving metabolism, alleviating inflammation, enhancing intestinal barrier function, and maintaining microbiota homeostasis. Furthermore, this review summarizes dietary strategies for increasing intestinal A. muciniphila abundance and effective gastrointestinal delivery.

The role of the gut microbiota in gastric cancer: the immunoregulation and immunotherapy.

Gastric cancer (GC) is one of the most common cancers, leading to the deaths of millions of people worldwide. Therefore, early detection and effective therapeutic strategies are of great value for decreasing the occurrence of advanced GC. The human microbiota is involved not only in the maintenance of physiological conditions, but also in human diseases such as obesity, diabetes, allergic and atopic diseases, and cancer. Currently, the composition of the bacteria in the host, their functions, and their influence on disease progression and treatment are being discussed. Previous studies on the gut microbiome have mostly focused on Helicobacter pylori (Hp) owing to its significant role in the development of GC. Nevertheless, the enrichment and diversity of other bacteria that can modulate the tumor microenvironment are involved in the progression of GC and the efficacy of immunotherapy. This review provides systematic insight into the components of the gut microbiota and their application in GC, including the specific bacteria of GC, their immunoregulatory effect, and their diagnostic value. Furthermore, we discuss the relationship between the metabolism of microbes and their potential applications, which may serve as a new approach for the diagnosis and treatment of GC.

Mendelian randomization analysis to investigate the gut microbiome in oral and oropharyngeal cancer.

Background: Evidence supports an observational association between the gut microbiome and susceptibility to extraintestinal cancers, but the causal relationship of this association remains unclear. Methods: To identify the specific causal gut microbiota of oral and oropharyngeal cancer, we performed two-sample Mendelian randomization (MR) analysis of gut microbiota on oral and oropharyngeal cancer using a fixed-effects inverse-variance-weighted model. Gut microbiota across five different taxonomical levels from the MiBioGen genome-wide association study (GWAS) were used as exposures. Oral cancer, oropharyngeal cancer and a combination of the two cancers defined from three separate data sources were used as the outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher abundance of microbiome. Results & Conclusions: There was little evidence for a causal effect of gut microbiota on oral and oropharyngeal cancer when using a genome-wide p-value threshold for selecting instruments. Secondary analyses using a more lenient p-value threshold indicated that there were 90 causal relationships between 58 different microbial features but that sensitivity analyses suggested that these were possibly affected by violations of MR assumptions and were not consistent across MR methodologies or data sources and therefore are also to unlikely reflect causation. These findings provide new insights into gut microbiota-mediated oral and oropharyngeal cancers and warrant further investigation.

Essential role of Nrf2 in sulforaphane-induced protection against angiotensin II-induced aortic injury.

AIMS: Cardiovascular disease (CVD) is the leading cause of death worldwide. Inflammation and oxidative stress are the primary factors underlying angiotensin II (Ang II)-induced aortic damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important antioxidative stress factor. Sulforaphane (SFN), which is naturally found in cruciferous vegetables, is an Nrf2 agonist that is safe for oral administration. Here, we aimed to explore the potential of SFN in protecting against Ang II-induced aortic damage by upregulating Nrf2 expression via the extracellular signal-regulated kinase (ERK)/glycogen synthase kinase-3 beta (GSK-3ß)/Fyn pathway. MAIN METHODS AND KEY FINDINGS: Wild-type (WT) C57BL/6J and Nrf2-knockout (Nrf2-KO) mice were injected with Ang II to induce aortic inflammation, oxidative stress, and cardiac remodeling (increased fibrosis and wall thickness). SFN treatment prevented aortic damage via Nrf2 activation in the WT mice. However, the protective effect of SFN on Ang II-induced aortic damage and upregulation of genes downstream of Nrf2 were not observed in Nrf2-KO mice. SFN induced the upregulation of aortic Nrf2 and inhibited the accumulation of ERK, GSK-3ß, and Fyn in the nuclei. SIGNIFICANCE: These results revealed that Nrf2 plays a central role in protecting against Ang II-induced aortic injury. Furthermore, SFN prevented Ang II-induced aortic damage by activating Nrf2 through the ERK/GSK-3ß/Fyn pathway.

Immunotherapy Advances in Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma and Its Relationship With Human Papillomavirus.

Head and neck cancer (HNC) is the sixth most common malignancy worldwide; head and neck squamous cell carcinoma (HNSCC) account for the most cases of HNC. Past smoking and alcohol consumption are common risk factors of HNSCC; however, an increasing number of cases associated with human papillomavirus (HPV) infection have been reported in recent years. The treatment of HNSCC is integrated and multimodal including traditional surgery, radiotherapy, chemotherapy, and targeted therapy. Since pembrolizumab was approved in 2016, an increasing number of studies have focused on immunotherapy. However, not all of HNSCC patients have a better outcome on immunotherapy. Immunotherapy has been reported to be more effective in HPV-positive patients, but its molecular mechanism is still unclear. Some researchers have proposed that the high proportion of infiltrating immune cells in HPV-positive tumors and the difference in immune checkpoint expression level may be the reasons for their better response. As a result, a series of individualized immunotherapy trials have also been conducted in HPV-positive patients. This paper summarizes the current status of HNSCC immunotherapy, individualized immunotherapy in HPV-positive patients, and immune differences in HPV-positive tumors to provide new insights into HNSCC immunotherapy and try to identify patients who may benefit from immunotherapy.

Evaluation of Risk Factors for Laryngeal Squamous Cell Carcinoma: A Single-Center Retrospective Study.

BACKGROUND: The survival rate of patients with laryngeal squamous cell carcinoma (LSCC) is correlated with several factors. However, the independent prognostic factors of patients with LSCC remain unclear. Thus, we sought to identify prognostic factors affecting LSCC outcomes in the Chinese population. METHODS: The survival and potential prognostic factors of 211 patients with LSCC between April 2011 and July 2019 were retrospectively analyzed. Overall survival (OS) and progression free survival (PFS) were estimated by the Kaplan Meier method, and a log-rank test was used to compare the possible prognostic factors between different groups. The Cox proportional hazard model was used to perform multivariable analysis of significant covariants. RESULTS: A total of 211 LSCC patients were included, of which 164 (77.7%) were male and 47 (22.3%) were female. Mean age was 62.19 ± 8.328 years. A univariate analysis showed that seven factors including pathological differentiation, clinical stage, tobacco consumption, alcohol consumption, T stage, N stage, and concurrent chemoradiotherapy were correlated with survival (P<0.05). Cox proportional hazards regression analyses revealed that clinic stage (hazard ratio=3.100, p=0.048), pathological differentiation (hazard ratio = 2.538, p=0.015), alcohol consumption (hazard ratio = 8.456, p =0.004) were associated with OS in LSCC. Pathological differentiation (hazard ratio =5.677, p=0.000), alcohol consumption (hazard ratio =6.766, p=0.000) were associated with PFS in LSCC. CONCLUSIONS: Pathological differentiation, alcohol consumption, are independent prognostic factors and predictors of recurrence in LSCC. These factors could help inform guidelines for clinical treatment and prognosis.

Role of the gut microbiota in type 2 diabetes and related diseases.

Type 2 diabetes is the fastest-growing metabolic disease in the world. Many clinical studies have found that type 2 diabetes patients have metabolic disorders and chronic inflammatory states accompanied by disturbances in the gut microbiota. The gut microbiota plays an important role in body metabolism and immune regulation, and disturbances in the gut microbiota in conjunction with destruction of the intestinal barrier in type 2 diabetes patients causes damage to multiple organs. Therefore, the gut microbiota may be a new therapeutic target for treating type 2 diabetes and related diseases. In this review, we introduce the characteristics of the gut microbiota in type 2 diabetes and related diseases, as well as highlight the potential molecular mechanisms of their effects on intestinal barrier disruption, metabolic disorders, and chronic inflammation. Finally, we summarize an intestinal microecological therapeutic strategy, with a focus on shaping the intestinal bacteria, to improve the malignant progress of type 2 diabetes and related diseases. AUTHOR SUMMARY: Type 2 diabetes (T2D) is the fastest-growing metabolic disease in the world. Many clinical studies have found that T2D patients have metabolic disorders and chronic inflammatory states, accompanied by disturbances of the gut microbiota and increased intestinal permeability. The number of human gut microbiota is more than 10 times of human cells, and they play an important role in the body's metabolism and immune regulation. The abnormal intestinal metabolites and intestinal barrier disruption caused by the gut microbiota dysbiosis in the T2D facilitate intestinal bacteria and their harmful metabolites entering the circulatory system. The abnormal entering will cause the damage to multiple organs through disturbing insulin sensitivity, glucose metabolism, and immune homeostasis. Therefore, the gut microbiota may be a new therapeutic target for improving T2D and its related diseases. In this review, we introduce the compositional characteristics of the gut microbiota in T2D, and highlight some new molecular mechanisms of their effects on intestinal barrier disruption, metabolic disorders and chronic inflammation in T2D and its related diseases. Finally, we summarize an intestinal microecological therapeutic strategy, with a focus on shaping the intestinal bacteria, to improve the malignant progress of T2D and related diseases.

The role of short-chain fatty acids in intestinal barrier function, inflammation, oxidative stress, and colonic carcinogenesis.

Short-chain fatty acids (SCFAs), mainly including acetate, propionate, and butyrate, are metabolites produced during the bacterial fermentation of dietary fiber in the intestinal tract. They are believed to be essential factors affecting host health. Most in vitro and ex vivo studies have shown that SCFAs affect the regulation of inflammation, carcinogenesis, intestinal barrier function, and oxidative stress, but convincing evidence in humans is still lacking. Two major SCFA signaling mechanisms have been identified: promotion of histone acetylation and activation of G-protein-coupled receptors. In this review, we introduce the production and metabolic characteristics of SCFAs, summarize the potential effects of SCFAs on the four aspects mentioned above and the possible mechanisms. SCFAs have been reported to exert a wide spectrum of positive effects and have a high potential for therapeutic use in human-related diseases.

Molecular mechanisms underlying increased radiosensitivity in human papillomavirus-associated oropharyngeal squamous cell carcinoma.

Oropharyngeal squamous cell carcinoma (OPSCC) is an important type of head and neck squamous cell carcinoma (HNSCC). The traditional risk factors for OPSCC include carcinogen intake, smoking, alcohol consumption, and lifestyle. In recent years, cases of human papillomavirus (HPV)-related OPSCC have gradually increased. At present, HPV-related OPSCC in developed Western countries comprise up to 90% of all OPSCC cases, while in other developing countries, the proportion of HPV-related OPSCC cases is also gradually increasing. Compared with HPV-negative OPSCC, HPV-positive OPSCC patients have better overall survival rates and local control rates and this improved prognosis may be related to the increased radiosensitivity of HPV-positive tumors. Due to this more favorable prognosis, many downgraded treatment schemes are gradually emerging, including simple radiotherapy instead of concurrent radiotherapy or reduced radiotherapy dose. However, there is insufficient theoretical basis for such schemes. Some studies have shown that delayed repair of DNA damage after radiation, G2/M arrest, increased hypoxia, and decreased proliferation capacity are the main reasons for the increased radiosensitivity of HPV-positive tumor cells. In this review, we discuss the four principles of tumor cell damage caused by radiation, including repair, reoxygenation, redistribution, and regeneration in order to reveal the mechanism whereby HPV increases the radiosensitivity of tumor cells. An attempt was made to provide sufficient information to facilitate more individualized treatment for HPV-positive OPSCC patients, under the premise of good tumor control.

Vascular Endothelial Growth Factor-D (VEGF-D) is Elevated in Bronchoalveolar Lavage Fluid of Patients with Lung Squamous Carcinoma.

BACKGROUND: Previous studies have found that vascular endothelial growth factor (VEGF) is associated with lung cancer, yet little is known about vascular endothelial growth factor-D (VEGF-D) in bronchoalveolar lavage fluid (BALF) of lung cancer patients. In this study, we aim to investigate the expression and evaluation of VEGF-D in BALF for lung cancer diagnosis. METHODS: BALF samples were acquired from 81 patients: 40 with benign diseases and 41 with lung cancer. The expression of VEGF-D in BALF was measured using sandwich enzyme-linked immune sorbent assays (ELISA), and the evaluation of VEGF-D in BALF for lung cancer diagnosis was also investigated. RESULTS: In the BALF samples, the levels of VEGF-D in the lung cancer group were higher than in the benign disease group; however, there was no statistical significance between the two groups (p > 0.05). In the pathological classification of lung cancer, the levels of VEGF-D in the BALF differed significantly between the lung squamous carcinoma group and the benign disease group (p < 0.05). The diagnostic accuracies of VEGF-D in BALF for discrimination between patients with squamous cell carcinoma and benign disease were reasonable based on receiver operating characteristic (ROC curve) analysis, with a corresponding sensitivity of 64.7% and specificity of 60%, respectively. CONCLUSIONS: This study demonstrated that the detection of VEGF-D levels in BALF is a valuable diagnostic tool for lung squamous carcinoma.