A novel antidiuretic hormone governs tumour-induced renal dysfunction.

Maintenance of renal function and fluid transport are essential for vertebrates and invertebrates to adapt to physiological and pathological challenges. Human patients with malignant tumours frequently develop detrimental renal dysfunction and oliguria, and previous studies suggest the involvement of chemotherapeutic toxicity and tumour-associated inflammation1,2. However, how tumours might directly modulate renal functions remains largely unclear. Here, using conserved tumour models in Drosophila melanogaster3, we characterized isoform F of ion transport peptide (ITPF) as a fly antidiuretic hormone that is secreted by a subset of yki3SA gut tumour cells, impairs renal function and causes severe abdomen bloating and fluid accumulation. Mechanistically, tumour-derived ITPF targets the G-protein-coupled receptor TkR99D in stellate cells of Malpighian tubules-an excretory organ that is equivalent to renal tubules4-to activate nitric oxide synthase-cGMP signalling and inhibit fluid excretion. We further uncovered antidiuretic functions of mammalian neurokinin 3 receptor (NK3R), the homologue of fly TkR99D, as pharmaceutical blockade of NK3R efficiently alleviates renal tubular dysfunction in mice bearing different malignant tumours. Together, our results demonstrate a novel antidiuretic pathway mediating tumour-renal crosstalk across species and offer therapeutic opportunities for the treatment of cancer-associated renal dysfunction.

Identification of ribosomal protein family as immune-cell-related biomarkers of NAFLD by bioinformatics and experimental analyses.

Background: Immune cells play an integral role in the development and progression of non-alcoholic fatty liver disease (NAFLD). This study was to identify immune-cell-related biomarkers for the diagnosis and treatment of NAFLD. Methods and findings: First, we introduced human liver transcriptome data from the GEO database (GSE48452 and GSE126848) and performed a weighted gene co-expression network analysis (WGCNA) to screen out the modules related to immune cell infiltration and to identify immune-cell-related differentially expressed genes (ICR-DEGs) associated with NAFLD progression. Further, the protein-protein interaction (PPI) network of ICR-DEGs was established to obtain hub genes and subsequently, the expression trend analysis was conducted to identify immune-cell-related biomarkers of NAFLD. Finally, the mRNA expression of biomarkers was validated in a NAFLD mouse model induced by high-fat diet (HFD) feeding. In total, we identified 66 ICR-DEGs and 13 hub genes associated with NAFLD. Among them, 9 hub genes (CD247, CD74, FCGR2B, IL2RB, INPP5D, MRPL16, RPL35, RPS3A, RPS8) were correlated with the infiltrating immune cells by the Pearson correlation analysis. Subsequently, 4 immune-cell-related biomarkers (RPL35, RPS3A, RPS8, and MRPL16) with the same expression trends in GSE48452 and GSE126848 datasets were identified. These biomarkers were enriched in immune-related pathways and had a good ability to distinguish between NASH and healthy samples. Moreover, we constructed a competing endogenous RNA (ceRNA) network of biomarkers and predicted twenty potential therapeutic drugs targeting RPS3A such as taxifolin and sitagliptin. Finally, experimental validation indicated that the hepatic mRNA expression of Rpl35, Rps3A, and Rps8 was significantly decreased in NAFLD mice. Conclusions: This study identified four ribosomal protein genes (RPL35, RPS3A, RPS8, and MRPL16) as immune-cell-related biomarkers of NAFLD, which may actively participate in the immune processes during NAFLD progression and could serve as potential targets for the diagnosis and treatment of NAFLD.

Bidirectional Association between Hypertension and NAFLD: A Systematic Review and Meta-Analysis of Observational Studies.

An increasing body of evidence connects non-alcoholic fatty liver disease (NAFLD) to hypertension. The objective of this systematic review and meta-analysis was to estimate the nature and magnitude of the association between NAFLD and hypertension. We systematically searched PubMed, Embase, Cochrane Library, and Web of Science for observational studies published up to May 1, 2021. Cohort studies that reported data on the association between NAFLD and incident hypertension or between hypertension and incident NAFLD were included. We used random-effects models to conduct meta-analysis on the measures of association from individual studies. A total of 11 studies were eligible for inclusion, among which 4 studies including 25,260 participants reported the association between hypertension and new-onset NAFLD. The presence of hypertension was significantly associated with an increased risk of incident NAFLD (HR 1.63, 95% CI: 1.41-1.88; I 2 = 37.6%). On the other hand, 9 studies with data on 46,487 participants analyzed the effects of NAFLD on incident hypertension. Pooled analysis showed that the presence of NAFLD was significantly associated with an increased incidence of hypertension (HR 1.55, 95% CI: 1.29-1.87; I 2 = 80.5%). There was significant heterogeneity among the studies in this analysis (p < 0.01). Sensitivity analyses showed that the magnitude of the association was significantly different in subgroups stratified by a mean age of participants and geographical location, which explains part of the heterogeneity. In conclusion, this meta-analysis indicates the existence of a bidirectional relationship between NAFLD and hypertension independent of traditional cardiometabolic risk factors.

Diabetes Mellitus and COVID-19: Associations and Possible Mechanisms.

Coronavirus disease 2019 (COVID-19) is a recently emerged disease with formidable infectivity and high mortality. Emerging data suggest that diabetes is one of the most prevalent comorbidities in patients with COVID-19. Although their causal relationship has not yet been investigated, preexisting diabetes can be considered as a risk factor for the adverse outcomes of COVID-19. Proinflammatory state, attenuation of the innate immune response, possibly increased level of ACE2, along with vascular dysfunction, and prothrombotic state in people with diabetes probably contribute to higher susceptibility for SARS-CoV-2 infection and worsened prognosis. On the other hand, activated inflammation, islet damage induced by virus infection, and treatment with glucocorticoids could, in turn, result in impaired glucose regulation in people with diabetes, thus working as an amplification loop to aggravate the disease. Therefore, glycemic management in people with COVID-19, especially in those with severe illness, is of considerable importance. The insights may help to reduce the fatality in the effort against COVID-19.

Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78).

Abnormal cardiac fibrosis indicates cardiac dysfunction and poor prognosis in myocardial infarction (MI) patients. Many studies have demonstrated that the ubiquitin proteasome system (UPS) plays a significant role in the pathogenesis of fibrosis. Ubiquitin C-terminal hydrolase L1 (UCHL1), a member of the UPS, is related to fibrosis in several heart diseases. However, whether UCHL1 regulates cardiac fibrosis following MI has yet to be determined. In the present study, we found that UCHL1 was dramatically increased in infarct hearts and TGF-ß1-stimulated cardiac fibroblasts (CFs). Inhibition of UCHL1 with LDN57444 (LDN) reversed the myocardial fibrosis in post-MI heart and improved cardiac function. Treatment of LDN or UCHL1 siRNA abolished the TGF-ß1-induced fibrotic response of CFs. We further identified GRP78 as an interactor of UCHL1 through screening using immunoprecipitation-mass spectrometer. We determined that UCHL1 interacted with glucose-regulated protein of 78 kDa (GRP78) and prompted GRP78 degradation via ubiquitination. Furthermore, we found that GRP78 was upregulated after UCHL1 knockdown and that the GRP78 inhibitor HA15 diminished the antifibrotic function exerted by UCHL1 knockdown in CFs stimulated with TGF-ß1. This suggests that UCHL1 regulates cardiac fibrosis post MI through interactions with GRP78. This work identifies that the UCHL1-GRP78 axis is involved in cardiac fibrosis after MI.

Sodium-Glucose Co-Transporter 2 Inhibitors Compared with Sulfonylureas in Patients with Type 2 Diabetes Inadequately Controlled on Metformin: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND OBJECTIVE: When metformin is insufficient for patients with type 2 diabetes mellitus (T2DM), the optimal adjunctive therapy is unclear. This meta-analysis was to compare the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors with sulfonylureas (SUs) as second-line therapy in patients with T2DM inadequately controlled on metformin. METHODS: We systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for randomized controlled trials comparing SGLT2 inhibitors with SUs as add-on to metformin. Our primary endpoints were glycemic control, hypoglycemia, and change in weight. We assessed pooled data using a random-effects model. RESULTS: Five trials involving 4300 participants were included in our meta-analysis. Compared with SUs, SGLT2 inhibitors led to no significant reduction in changes in HbA1c (mean difference [MD] - 0.06; 95% confidence interval [CI] [- 0.12, 0.08]), but less hypoglycemia as add-on to metformin (odds ratio [OR] 0.12; 95% CI [0.07, 0.21]). SGLT2 inhibitors led to a reduction in weight by about 3.5 kg; however, SUs caused a gain in weight by about 1 kg (MD - 4.39; 95% CI [- 4.64, - 4.14]). SGLT2 inhibitors also showed a reduction in blood pressure, but increased the incidence of genital tract infections compared with SUs. Interestingly, subgroup analysis by duration of interventions showed that reduction of HbA1c from baseline was similar between the two groups at 12-52 weeks, but SGLT2 inhibitors led to a greater reduction in HbA1c at 104-208 weeks. CONCLUSIONS: Despite similar glycemic efficacy in a relatively short term, SGLT2 inhibitors are more effective in the longer term than SUs as add-on to metformin. In addition, SGLT2 inhibitors produce less hypoglycemic events and lead to greater reductions in weight and blood pressure compared with SUs.

The influence of land urbanization on landslides: An empirical estimation based on Chinese provincial panel data.

This study used panel data for 28 provinces and municipalities in China from 2003 to 2014 to investigate the relationship between land urbanization and landslides by building panel models for a national sample and subsamples from the three regions of China and studied the problems of landslide prevention measures based on the relationship. The results showed that 1) at the national level, the percentage of built-up area and road density are respectively negative and positive for landslides. 2) At the regional level, the improvement of landslide prevention measures with increasing economic development only appears in built-up areas. The percentage of built-up areas increases the number of landslides in the western region and decreases the number in the central and eastern regions; the degree of decrease in the eastern region is larger than in the central region. Road density increases the number of landslides in each region, and the degree increases gradually from the west to the east. 3) The effect of landslide prevention funding is not obvious. Although the amount of landslide prevention funds decreases the number of landslides at the national level, the degree of increase is too small. Except in the central region, the amount of landslide prevention funding did not decrease the number of landslides effectively in the western and eastern regions. We propose a series of policy implications based on these test results that may help to improve landslide prevention measures.

The Empirical Relationship between Mining Industry Development and Environmental Pollution in China.

This study uses a vector autoregression (VAR) model to analyze changes in pollutants among different mining industries and related policy in China from 2001 to 2014. The results show that: (1) because the pertinence of standards for mining waste water and waste gas emissions are not strong and because the maximum permissible discharge pollutant concentrations in these standards are too high, ammonia nitrogen and industrial sulfur dioxide discharges increased in most mining industries; (2) chemical oxygen demand was taken as an indicator of sewage treatment in environmental protection plans; hence, the chemical oxygen demand discharge decreased in all mining industries; (3) tax reduction policies, which are only implemented in coal mining and washing and extraction of petroleum and natural gas, decreased the industrial solid waste discharge in these two mining industries.