Impact of non-alcoholic fatty liver disease and fibrosis on mortality and kidney outcomes in patients with type 2 diabetes and chronic kidney disease: A multi-cohort longitudinal study.

AIM: To evaluate the impact of non-alcoholic fatty liver disease (NAFLD) presence and fibrosis risk on adverse outcomes in patients with type 2 diabetes and chronic kidney disease. METHODS: Data were sourced from two longitudinal cohorts: 1172 patients from the National Health and Nutrition Examination Survey (NHANES) and 326 patients from the kidney biopsy cohort at the West China Hospital of Sichuan University. Cox regression estimated hazard ratios (HRs) for NAFLD and liver fibrosis concerning adverse clinical outcomes. Subsequently, a two-sample Mendelian randomization study using genome-wide association study statistics explored NAFLD's potential causal link to cardio-cerebrovascular events. RESULTS: In the NHANES cohort, NAFLD stood as an independent risk factor for various outcomes: overall mortality [HR 1.53 (95% confidence interval, CI 1.21-1.95)], mortality because of cardio-cerebrovascular diseases [HR 1.63 (95% CI 1.12-2.37)], heart disease [HR 1.58 (95% CI 1.00-2.49)], and cerebrovascular disease [HR 3.95 (95% CI 1.48-10.55)]. Notably, advanced liver fibrosis, identified by a fibrosis-4 (FIB-4) score >2.67, exhibited associations with overall mortality, cardio-cerebrovascular disease mortality and heart disease mortality. Within the kidney biopsy cohort, NAFLD correlated with future end-stage kidney disease [ESKD; HR 2.17 (95% CI 1.41-3.34)], while elevated FIB-4 or NAFLD Fibrosis Scores predicted future ESKD, following full adjustment. Liver fibrosis was positively correlated with renal interstitial fibrosis and tubular atrophy in biopsies. Further Mendelian randomization analysis supported a causal relationship between NAFLD and cardio-cerebrovascular events. CONCLUSIONS: In patients with type 2 diabetes and chronic kidney disease, the NAFLD presence and elevated FIB-4 scores link to heightened mortality risk and ESKD susceptibility. Moreover, NAFLD shows a causal relationship with cardio-cerebrovascular events.

N6-methyladenosine-modified ALDH9A1 modulates lipid accumulation and tumor progression in clear cell renal cell carcinoma through the NPM1/IQGAP2/AKT signaling pathway.

Aldehyde dehydrogenases superfamily (ALDHs), which are ubiquitously present in various organisms with diverse subcellular localizations, play a crucial role in regulating malignant tumor progression; Nevertheless, their involvement in clear cell renal cell carcinoma (ccRCC) has not been elucidated. In this study, we performed comprehensive bioinformatics analyses on the 19 ALDHs genes, and identified ALDH9A1 as a key contributor in ccRCC. Expression patterns and clinical relevance of ALDH9A1 were determined using bioinformatics analyses, real-time PCR, western blotting, and immunohistochemistry. To explore the underlying mechanism behind the tumor suppressor role of ALDH9A1, RNA sequencing, methylated RNA immunoprecipitation, luciferase reporter assay, mass spectroscopy, immunoprecipitation, mutational studies and immunofluorescence were employed. The impact of ALDH9A1 in ccRCC progression and metabolic programming was assessed through both in vitro and in vivo. Here, this study revealed ALDH9A1 as a tumor suppressor gene in ccRCC. The fat mass and obesity associated protein (FTO) was identified as a demethylase for ALDH9A1 mRNA, resulting in its reduced stability and expression levels in ccRCC. Functional experiments demonstrated that the deficiency of ALDH9A1 in ccRCC promoted tumor proliferation, invasion, migration and lipid accumulation. Mechanistic insights illustrated that the diminished levels of ALDH9A1 resulted in the failure to sequester nucleophosmin 1 (NPM1) within cytoplasm, thereby suppressing the transcription of IQ motif containing the GTPase-activating protein 2 (IQGAP2), subsequently activating the AKT-mTOR signaling, ultimately fostering tumor progression and lipid accumulation. In conclusion, the present study highlights the robust prognostic significance of ALDH9A1 and delivers a comprehensive understanding of ALDH9A1-NPM1-IQGAP2-AKT axis in ccRCC. These findings established a solid research foundation for novel therapeutic strategies for ccRCC patients.

NAT10-mediated ac4C-modified ANKZF1 promotes tumor progression and lymphangiogenesis in clear-cell renal cell carcinoma by attenuating YWHAE-driven cytoplasmic retention of YAP1.

BACKGROUND: Lymphatic metastasis is one of the most common metastatic routes and indicates a poor prognosis in clear-cell renal cell carcinoma (ccRCC). N-acetyltransferase 10 (NAT10) is known to catalyze N4-acetylcytidine (ac4C) modification of mRNA and participate in many cellular processes. However, its role in the lymphangiogenic process of ccRCC has not been reported. This study aimed to elucidate the role of NAT10 in ccRCC lymphangiogenesis, providing valuable insights into potential therapeutic targets for intervention. METHODS: ac4C modification and NAT10 expression levels in ccRCC were assessed using public databases and clinical samples. Functional investigations involved manipulating NAT10 expression in cellular and mouse models to study its role in ccRCC. Mechanistic insights were gained through a combination of RNA sequencing, mass spectrometry, co-immunoprecipitation, RNA immunoprecipitation, immunofluorescence, and site-specific mutation analyses. RESULTS: We found that ac4C modification and NAT10 expression levels increased in ccRCC. NAT10 promoted tumor progression and lymphangiogenesis of ccRCC by enhancing the nuclear import of Yes1-associated transcriptional regulator (YAP1). Subsequently, we identified ankyrin repeat and zinc finger peptidyl tRNA hydrolase 1 (ANKZF1) as the functional target of NAT10, and its upregulation in ccRCC was caused by NAT10-mediated ac4C modification. Mechanistic analyses demonstrated that ANKZF1 interacted with tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE) to competitively inhibit cytoplasmic retention of YAP1, leading to transcriptional activation of pro-lymphangiogenic factors. CONCLUSIONS: These results suggested a pro-cancer role of NAT10-mediated acetylation in ccRCC and identified the NAT10/ANKZF1/YAP1 axis as an under-reported pathway involving tumor progression and lymphangiogenesis in ccRCC.

miR-1182-mediated ALDH3A2 inhibition affects lipid metabolism and progression in ccRCC by activating the PI3K-AKT pathway.

In clear cell renal cell carcinoma (ccRCC), dysregulated lipid metabolism plays a pivotal role in tumor initiation and progression. This study delves into the unexplored landscape of Dysregulated Aldehyde Dehydrogenase 3 Family Member A2 (ALDH3A2) in ccRCC. Using a combination of "fatty acid metabolism" dataset analysis and differentially expressed genes (DEGs) derived from Gene Expression Omnibus (GEO) database, potential metabolic regulators in ccRCC were identified. Subsequent investigations utilizing public databases, clinical samples, and in vitro experiments revealed that ALDH3A2 was down-regulated in ccRCC, mediated by miR-1182, highlighting its role as an independent prognostic factor for patient survival. Functionally, ALDH3A2 exhibited tumor-suppressive properties, impacting ccRCC cell phenotypes and influencing epithelial-mesenchymal transition. Mechanistically, silencing ALDH3A2 promoted lipid accumulation in ccRCC cells by activating the PI3K-AKT pathway, thereby promoting tumor progression. These findings shed light on the critical role of the miR-1182/ALDH3A2 axis in ccRCC tumorigenesis, emphasizing the potential for targeting lipid metabolism as a promising anti-cancer strategy.

A Rift Valley fever mRNA vaccine elicits strong immune responses in mice and rhesus macaques.

Rift Valley fever virus (RVFV) is listed as a priority pathogen by the World Health Organization (WHO) because it causes serious and fatal disease in humans, and there are currently no effective countermeasures. Therefore, it is urgent to develop a safe and efficacious vaccine. Here, we developed six nucleotide-modified mRNA vaccines encoding different regions of the Gn and Gc proteins of RVFV encapsulated in lipid nanoparticles, compared their ability to induce immune responses in mice and found that mRNA vaccine encoding the full-length Gn and Gc proteins had the strongest ability to induce cellular and humoral immune responses. IFNAR(-/-) mice vaccinated with mRNA-GnGc were protected from lethal RVFV challenge. In addition, mRNA-GnGc induced high levels of neutralizing antibodies and cellular responses in rhesus macaques, as well as antigen-specific memory B cells. These data demonstrated that mRNA-GnGc is a potent and promising vaccine candidate for RVFV.

N6-methyladenosine-modified DBT alleviates lipid accumulation and inhibits tumor progression in clear cell renal cell carcinoma through the ANXA2/YAP axis-regulated Hippo pathway.

BACKGROUND: The mechanism of metabolism reprogramming is an unsolved problem in clear cell renal cell carcinoma (ccRCC). Recently, it was discovered that the Hippo pathway altered tumor metabolism and promoted tumor progression. Thus, this study aimed at identifying key regulators of metabolism reprogramming and the Hippo pathway in ccRCC and pinpointing potential therapeutic targets for ccRCC patients. METHODS: Hippo-related gene sets and metabolic gene sets were used to screen potential regulators of the Hippo pathway in ccRCC. Public databases and samples from patients were applied to investigate the association of dihydrolipoamide branched chain transacylase E2 (DBT) with ccRCC and Hippo signaling. The role of DBT was confirmed by gain or loss of function assays in vitro and in vivo. Mechanistic results were yielded by luciferase reporter assay, immunoprecipitation, mass spectroscopy, and mutational studies. RESULTS: DBT was confirmed as a Hippo-related marker with significant prognostic predictive value, and its downregulation was caused by methyltransferase-like-3 (METTL3)-mediated N6-methyladenosine (m6 A) modification in ccRCC. Functional studies specified DBT as a tumor suppressor for inhibiting tumor progression and correcting the lipid metabolism disorder in ccRCC. Mechanistic findings revealed that annexin A2 (ANXA2) interacted with the lipoyl-binding domain of DBT to activate Hippo signaling which led to decreased nuclear localization of yes1-associated transcriptional regulator (YAP) and transcriptional repression of lipogenic genes. CONCLUSIONS: This study demonstrated a tumor-suppressive role for the DBT/ANXA2/YAP axis-regulated Hippo signaling and suggested DBT as a potential target for pharmaceutical intervention in ccRCC.

AIM2 promotes renal cell carcinoma progression and sunitinib resistance through FOXO3a-ACSL4 axis-regulated ferroptosis.

Renal cell carcinoma (RCC) is a serious threat to people's health due to its rapid progression, and patients easily develop resistance to targeted therapy. The absent in melanoma 2 (AIM2) is a receptor protein that has recently been proposed to play an important role in various diseases. In this study, AIM2 was identified as a new biomarker of RCC and promoted RCC progression and sunitinib resistance in an inflammasome-independent manner. Mechanistically, AIM2 promoted FOXO3a phosphorylation and proteasome degradation, thereby reducing its transcriptional effect on ACSL4 and inhibiting ferroptosis. In summary, AIM2 promoted RCC progression and sunitinib resistance through FOXO3a-ACSL4 axis-regulated ferroptosis, which could provide new ideas and therapeutic targets for RCC diagnosis and treatment.

An adenovirus-vectored RVF vaccine confers complete protection against lethal RVFV challenge in A129 mice.

Instruction: Rift valley fever virus (RVFV) is a mosquito-transmitted bunyavirus that causes severe disease in animals and humans. Nevertheless, there are no vaccines applied to prevent RVFV infection for human at present. Therefore, it is necessary to develop a safe and effective RVFV vaccine. Methods: We generated Ad5-GnGcopt, a replication-deficient recombinant Ad5 vector (human adenovirus serotype 5) expressing codon-optimized RVFV glycoproteins Gn and Gc, and evaluated its immunogenicity and protective efficacy in mice. Results and Discussion: Intramuscular immunization of Ad5-GnGcopt in mice induces strong and durable antibody production and robust cellular immune responses. Additionally, a single vaccination with Ad5-GnGcopt vaccination can completely protect interferon-α/ß receptor-deficient A129 mice from lethal RVFV infection. Our work indicates that Ad5-GnGcopt might represent a potential vaccine candidate against RVFV. However, further research is needed, first to confirm its efficacy in a natural animal host, and ultimately escalate as a potential vaccine candidate for humans.

Comprehensive analyses of A 12-metabolism-associated gene signature and its connection with tumor metastases in clear cell renal cell carcinoma.

BACKGROUND: The outcomes of patients with clear cell renal cell carcinoma (ccRCC) were dreadful due to lethal local recurrence and distant metastases. Accumulating evidence suggested that ccRCC was considered a metabolic disease and metabolism-associated genes (MAGs) exerted essential functions in tumor metastases. Thus, this study intends to seek whether the dysregulated metabolism promotes ccRCC metastases and explores underlying mechanisms. METHOD: Weighted gene co-expression network analysis (WGCNA) was employed based on 2131 MAGs to select genes mostly associated with ccRCC metastases for subsequent univariate Cox regression. On this basis, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression were employed to create a prognostic signature based on the cancer genome atlas kidney renal clear cell carcinoma (TCGA-KIRC) cohort. The prognostic signature was confirmed using E-MTAB-1980 and GSE22541 cohorts. Kaplan-Meier, receiver operating characteristic (ROC) curve, and univariate and multivariate Cox regression were applied to detect the predictability and independence of the signature in ccRCC patients. Functional enrichment analyses, immune cell infiltration examinations, and somatic variant investigations were employed to detect the biological roles of the signature. RESULT: A 12-gene-metabolism-associated prognostic signature, termed the MAPS by our team, was constructed. According to the MAPS, patients were divided into low- and high-risk subgroups and high-risk patients displayed inferior outcomes. The MAPS was validated as an independent and reliable biomarker in ccRCC patients for forecasting the prognosis and progression of ccRCC patients. Functionally, the MAPS was closely associated with metabolism dysregulation, tumor metastases, and immune responses in which the high-risk tumors were in an immunosuppressive status. Besides, high-risk patients benefited more from immunotherapy and held a higher tumor mutation burden (TMB) than low-risk patients. CONCLUSION: The 12-gene MAPS with prominent biological roles could independently and reliably forecast the outcomes of ccRCC patients, and provide clues to uncover the latent mechanism in which dysregulated metabolism controlled ccRCC metastases.

Diabetes and Risks of Right-Sided and Left-Sided Colon Cancer: A Meta-Analysis of Prospective Cohorts.

Background and Aims: Diabetes is associated with an increased risk of colon cancer (CC). Epidemiologic studies previously reported a higher risk for right-sided colon cancer (RCC) compare to left-sided colon cancer (LCC), although data are conflicting. We performed a meta-analysis to investigate this issue. Methods: We systematically searched the PubMed, EMBASE, Web of Science and Cochrane Library database for prospective cohort studies published up to June 2021. Studies were included if they reported site-specific estimates of the relative risk (RR) between diabetes and the risks of RCC and LCC. Random effects meta-analyses with inverse variance weighting were used to estimate the pooled site-specific RRs and the RCC-to-LCC ratio of RRs (RRRs). Results: Data from 10 prospective cohort studies, representing 1,642,823 individuals (mainly white) and 17,624 CC patients, were included in the analysis. Diabetes was associated with an increased risk of both RCC (RR =1.35, 95% CI = 1.24-1.47) and LCC (RR = 1.18, 95% CI = 1.08-1.28). After adjusting for major risk factors, individuals with diabetes had a greater risk for RCC than for LCC (RRR = 1.13, 95% CI = 1.02-1.26), with no significant heterogeneity between studies (I2 = 0%). Conclusions: This meta-analysis indicates that diabetes is associated with a higher risk for RCC than for LCC. Our findings suggest that colonoscopic surveillance in diabetic patients with careful examination of the right colon is warranted.

UPLC-ESI-QTOF-MS/MS Analysis of the Phytochemical Compositions From Chaenomeles speciosa (Sweet) Nakai Fruits.

Chaenomeles speciosa (Sweet) Nakai (C. speciosa Nakai) is a popular fruit widely used in China for its health-promoting properties. The presences of phytochemical compositions in the plants play an important role in the health benefits. Nevertheless, the detailed information of these ingredients is still unknown. Therefore, in this work, an untargeted analytical method based on ultra-high-performance liquid chromatography-quadrupole-time of flight coupled to mass spectrometry in two different ionization modes was used to qualitative the phytochemicals in C. speciosa Nakai, meanwhile, the anti-inflammatory activity of these phytochemicals was researched through detecting the inhibition of nitric oxide (NO) that was induced by lipopolysaccharide in RAW 264.7 murine macrophage cells. The results showed that there were totally 175 primary and secondary metabolites were identified in the fruit of C. speciosa Nakai, including phenols, terpenoids, flavonoids and other phyto-constituents. Actually, most compounds were described in C. speciosa Nakai fruits for the first time. Besides, the anti-inflammatory activity was measured by the result of NO inhibition rate, the consequence showed that the value of half-inhibitory concentration (IC50) was 365.208 µg/mL. These results indicate that C. speciosa Nakai is an efficient medicinal fruit, which owns various bioactivities and has the potential to treat various diseases.

Anti-hypertensive and cardioprotective activities of traditional Chinese medicine-derived polysaccharides: A review.

Cardiovascular diseases (CVDs), a leading cause of death in modern society, have become a major public health issue globally. Although numerous approaches have been proposed to reduce morbidity and mortality, the pursuit of pharmaceuticals with more preventive and/or therapeutic value remains a focus of attention. Being a vast treasure trove of natural drug molecules, Traditional Chinese Medicine (TCM) has a long history of clinical use in the prophylaxis and remedy of CVDs. Increasing lines of preclinical evidence have demonstrated the effectiveness of TCM-derived polysaccharides on hindering the progression of CVDs, e.g. hypertension, myocardial infarction. However, to the best of our knowledge, there are few reviews on the application of TCM-derived polysaccharides in combating CVDs. Hence, we provide an overview of primary literature on the anti-hypertensive and cardioprotective activities of herbal polysaccharides. Additionally, we also discuss the current limitations and propose a new hypothesis about how polysaccharides exert cardiovascular effects based on the metabolism of polysaccharides.

The Analyses of Chemical Components From Oldenlandia hedyotidea (DC.) Hand.-Mazz and Anticancer Effects in vitro.

Oldenlandia hedyotidea (DC.) Hand.-Mazz (OH), also known as sweet tea, is a valuable functional food with medicinal properties and is used for the treatment of cold, cough, gastroenteritis, heatstroke, herpes zoster, and rheumatoid arthritis. The phytochemicals in plant-based foods are responsible for the occurrence of these diseases to some extent. However, there is a scarcity of information on the chemical components of OH. We, therefore, aimed to investigate the phytochemical components of OH using ultra high-performance liquid chromatography-mass spectrometry (UHPLC-MS) and UHPLC triple time-of-flight mass spectrometry (UHPLC-Triple-TOF-MS). The main component of the OH extract, asperulosidic acid, was additionally quantified using UHPLC with ultraviolet detection (UHPLC-UV). The anticancer activity of the OH extract was assessed by a cell proliferation assay and a scratch assay using an esophageal cancer cell line. Ten compounds were tentatively identified in the aqueous extract of OH, including five iridoids, two anthraquinones, and one phenolic acid. The content of asperulosidic acid in the aqueous extract of OH was approximately 42 µg ml-1, and the extract exerted definite in vitro anticancer effects. The results can be used for quality control and assessment of the OH extract, which can serve as a promising source of functional ingredients for potential use in the food and drug industries.

Synthesis and anti-inflammatory activity of novel steroidal chalcones with 3ß-pregnenolone ester derivatives in RAW 264.7 cells in vitro.

To identify new potential anti-inflammatory agents, we herein report the synthesis of novel steroidal chalcones with 3ß-pregnenolone esters of cinnamic acid derivatives using pregnenolone as the starting material. The structures of the newly synthesised compounds were confirmed by 1H NMR, 13C NMR, HRMS and infrared imaging. All the derivatives were examined to determine their in vitro anti-inflammatory profiles against LPS-induced inflammation in RAW 264.7 cells; the derivates were evaluated by the quantification of the pro-inflammatory mediator nitric oxide (NO) in the cell culture supernatant based on the Griess reaction, which measures nitrite levels, followed by an in vitro cytotoxicity study. Among these novel derivatives, compound 11e [3ß-3-phenyl acrylate-pregn-5-en-17ß-yl-3' -(p-fluoro)-phenylprop-2'-en-1'-one] was identified as the most potent anti-inflammatory agent, which showed significant anti-inflammatory activity by inhibiting the LPS-induced pro-inflammatory mediator NO in a dose-dependent manner without any cytotoxicity. Moreover, compound 11e markedly inhibited the expression of pro-inflammatory cytokines, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2), in LPS-induced RAW 264.7 cells. Further studies confirmed that compound 11e significantly suppressed the transcriptional activity of NF-κB in activated RAW 264.7 cells. Molecular docking study revealed the strong binding affinity of compound 11e to the active site of the pro-inflammatory proteins, which confirmed that compound 11e acted as an anti-inflammatory mediator. These results indicated that steroidal chalcones with 3ß-pregnenolone esters of cinnamic acid derivatives might be considered for further research in the design of anti-inflammatory drugs, and compound 11e might be a promising therapeutic anti-inflammatory drug candidate.