Developing oxaliplatin and IL-15 Co-carried gels as drug depots to enable triple-interlocked combination therapy for colorectal cancer.

Chemo-immunotherapy, which involves the simultaneous use of chemotherapy drug and immunotherapeutic agent to achieve synergistic effects, plays a crucial role in cancer treatment. However, the immunosuppressive microenvironment, insufficient tumor specificity, and serious systemic side effects hinder their synergistic therapeutic effects and clinical applications. Herein, T cell and natural killer (NK) cell, which are the most important immune effector cells, were both activated to reverse the immunosuppressive microenvironment. To simplify drug carriers, oxaliplatin was selected as the chemotherapy drug which can both induce the ICD effect and activate T cells. IL-15 was selected to activate NK cells. To enhance the productivity of the carrier and reduce side effects, the easy-prepared thermosensitive hydrogel (OXL/IL-15 TG) was developed to co-load oxaliplatin-loaded liposomes (OXL) and IL-15. Colorectal cancer, suitable for in situ administration, was selected as model cancer. The resulting novel triple-interlocked combination therapy could directly kill the tumor cells, induces ICD effect and activate NK cells. After administration, OXL/IL-15 TG was formed serving as a drug depot, slowing releasing OXL and IL-15 non-interferencely. OXL around 165.47±7.04 nm was passively delivered to tumor tissue, killing tumor cells and inducing ICD effect. The results demonstrated that IL-15 stimulated the activation of NK cells. In tumor-bearing mice models, OXL/IL-15 TG exhibited a remarkable and noteworthy anti-tumor efficacy, and expanded survival rate. Notably, OXL/IL-15 TG led to an enhanced infiltration of CD3+CD8+ T cells and CD3-CD49+ NK cells within the tumor tissue. Overall, the triple-interlocked combination therapy provided a new idea for colorectal cancer therapy.

Decoding CLU (Clusterin): Conquering cancer treatment resistance and immunological barriers.

One major obstacle in the treatment of cancer is the presence of proteins resistant to cancer therapy, which can impede the effectiveness of traditional approaches such as radiation and chemotherapy. This resistance can lead to disease progression and cause treatment failure. Extensive research is currently focused on studying these proteins to create tailored treatments that can circumvent resistance mechanisms. CLU (Clusterin), a chaperone protein, has gained notoriety for its role in promoting resistance to a wide range of cancer treatments, including chemotherapy, radiation therapy, and targeted therapy. The protein has also been discovered to have a role in regulating the immunosuppressive environment within tumors. Its ability to influence oncogenic signaling and inhibit cell death bolster cancer cells resistant against treatments, which poses a significant challenge in the field of oncology. Researchers are actively investigating to the mechanisms by which CLU exerts its resistance-promoting effects, with the ultimate goal of developing strategies to circumvent its impact and enhance the effectiveness of cancer therapies. By exploring CLU's impact on cancer, resistance mechanisms, tumor microenvironment (TME), and therapeutic strategies, this review aims to contribute to the ongoing efforts to improve cancer treatment outcomes.

Mechanisms and translational applications of regeneration in limbs: From renewable animals to humans.

BACKGROUND: The regenerative capacity of organisms declines throughout evolution, and mammals lack the ability to regenerate limbs after injury. Past approaches to achieving successful restoration through pharmacological intervention, tissue engineering, and cell therapies have faced significant challenges. OBJECTIVES: This review aims to provide an overview of the current understanding of the mechanisms behind animal limb regeneration and the successful translation of these mechanisms for human tissue regeneration. RESULTS: Particular attention was paid to the Mexican axolotl (Ambystoma mexicanum), the only adult tetrapod capable of limb regeneration. We will explore fundamental questions surrounding limb regeneration, such as how amputation initiates regeneration, how the limb knows when to stop and which parts to regenerate, and how these findings can apply to mammalian systems. CONCLUSIONS: Given the urgent need for regenerative therapies to treat conditions like diabetic foot ulcers and trauma survivors, this review provides valuable insights and ideas for researchers, clinicians, and biomedical engineers seeking to facilitate the regeneration process or elicit full regeneration from partial regeneration events.

Serum metabolomics analysis of patients with chronic obstructive pulmonary disease and 'frequent exacerbator' phenotype.

Chronic obstructive pulmonary disease (COPD) exacerbations accelerate loss of lung function and increased mortality. The complex nature of COPD presents challenges in accurately predicting and understanding frequent exacerbations. The present study aimed to assess the metabolic characteristics of the frequent exacerbation of COPD (COPD­FE) phenotype, identify potential metabolic biomarkers associated with COPD­FE risk and evaluate the underlying pathogenic mechanisms. An internal cohort of 30 stable patients with COPD was recruited. A widely targeted metabolomics approach was used to detect and compare serum metabolite expression profiles between patients with COPD­FE and patients with non­frequent exacerbation of COPD (COPD­NE). Bioinformatics analysis was used for pathway enrichment analysis of the identified metabolites. Spearman's correlation analysis assessed the associations between metabolites and clinical indicators, while receiver operating characteristic (ROC) analysis evaluated the ability of metabolites to distinguish between two groups. An external cohort of 20 patients with COPD validated findings from the internal cohort. Out of the 484 detected metabolites, 25 exhibited significant differences between COPD­FE and COPD­NE. Metabolomic analysis revealed differences in lipid, energy, amino acid and immunity pathways. Spearman's correlation analysis demonstrated associations between metabolites and clinical indicators of acute exacerbation risk. ROC analysis demonstrated that the area under the curve (AUC) values for D­fructose 1,6­bisphosphate (AUC=0.871), arginine (AUC=0.836), L­2­hydroxyglutarate (L­2HG; AUC=0.849), diacylglycerol (DG) (16:0/20:5) (AUC=0.827), DG (16:0/20:4) (AUC=0.818) and carnitine­C18:2 (AUC=0.804) were >0.8, highlighting their discriminative capacity between the two groups. External validation results demonstrated that DG (16:0/20:5), DG (16:0/20:4), carnitine­C18:2 and L­2HG were significantly different between patients with COPD­FE and those with COPD­NE. In conclusion, the present study offers insights into early identification, mechanistic understanding and personalized management of the COPD­FE phenotype.

U-shaped association between serum calcium and in-hospital mortality in diabetes patients with congestive heart failure: a cohort study.

Previous studies have reported that the significant association between serum calcium and mortality substantially in patients, especially among those with intensive care unit (ICU). And In diabetes mellitus, congestive heart failure (CHF) is a significant comorbidity. We aim to evaluate the association between serum calcium levels and in-hospital mortality among patients with diabetes and congestive heart failure. The participants in this study were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. To scrutinize potential associations between serum calcium levels and in-hospital mortality, a comprehensive analysis encompassing multivariate logistic regression, cubic spline function model, threshold effect analysis, and subgroup analysis was performed. This retrospective cohort study encompassed 7063 patients, among whom the in-hospital mortality stood at 12.2%. In the multivariate logistic regression, adjusted odds ratios (ORs) were contrasted with the reference category Q6 (8.8-9.1 mg/dL) for serum calcium levels and in-hospital mortality. The adjusted ORs for Q1 (≤ 7.7 mg/dL), Q2 (7.7-8 mg/dL), and Q7 (≥ 9.1 mg/dL) were 1.69 (95% CI 1.17-2.44, p = 0.005), 1.62 (95% CI 1.11-2.36, p = 0.013), and 1.57 (95% CI 1.1-2.24, p = 0.012) respectively. The dose-response analysis uncovered a U-shaped relationship between serum calcium levels and in-hospital mortality in diabetic patients with heart failure. Subgroup analyses confirmed result stability notwithstanding the influence of diverse factors. Our investigation revealed a U-shaped correlation between serum calcium levels and in-hospital mortality in diabetes patients with congestive heart failure, pinpointing a significant inflection point at 9.05 mg/dL.

Syntaxin5 is essential for survival by ensuring midgut epithelial homeostsis and regulating feeding in Locusta migratoria.

Syntaxin5 (Syx5) belongs to SNAREs family, which play important roles in fusion of vesicles to target membranes. Most of what we know about functions of Syx5 originates from studies in fungal or vertebrate cells, how Syx5 operates during the development of insects is poorly understood. In this study, we investigated the role of LmSyx5 in the gut development of the hemimetabolous insect Locusta migratoria. LmSyx5 was expressed in many tissues, with higher levels in the gut. Knockdown of LmSyx5 by RNA interference (RNAi) considerably suppressed feeding in both nymphs and adults. The dsLmSyx5-injected locusts lost body weight and finally died at a mortality of 100%. Furthermore, hematoxylin-eosin staining indicated that the midgut is deformed in dsLmSyx5-treated nymphs and the brush border in midgut epithelial cells is severely damaged, suggesting that LmSyx5 is involved in morphogenesis of the midgut. TEM further showed that the endoplasmic reticulum of midgut cells have a bloated appearance. Taken together, these results suggest that LmSyx5 is essential for midgut epithelial homeostsis that affects growth and development of L. migratoria. Thus, Syx5 is a promising RNAi target for controlling L. migratoria, and even other pests.

Differential associations of fine and coarse particulate air pollution with cause-specific pneumonia mortality: A nationwide, individual-level, case-crossover study.

BACKGROUND: The connections between fine particulate matter (PM2.5) and coarse particulate matter (PM2.5-10) and daily mortality of viral pneumonia and bacterial pneumonia were unclear. OBJECTIVES: To distinguish the connections between PM2.5 and PM2.5-10 and daily mortality due to viral pneumonia and bacterial pneumonia. METHODS: Using a comprehensive national death registry encompassing all areas of mainland China, we conducted a case-crossover investigation from 2013 to 2019 at an individual level. Residential daily particle concentrations were evaluated using satellite-based models with a spatial resolution of 1 km. To analyze the data, we employed the conditional logistic regression model in conjunction with polynomial distributed lag models. RESULTS: We included 221,507 pneumonia deaths in China. Every interquartile range (IQR) elevation in concentrations of PM2.5 (lag 0-2 d, 37.6 µg/m3) was associated with higher magnitude of mortality for viral pneumonia (3.03%) than bacterial pneumonia (2.14%), whereas the difference was not significant (p-value for difference = 0.38). An IQR increase in concentrations of PM2.5-10 (lag 0-2 d, 28.4 µg/m3) was also linked to higher magnitude of mortality from viral pneumonia (3.06%) compared to bacterial pneumonia (2.31%), whereas the difference was not significant (p-value for difference = 0.52). After controlling for gaseous pollutants, their effects were all stable; however, with mutual adjustment, the associations of PM2.5 remained, and those of PM2.5-10 were no longer statistically significant. Greater magnitude of associations was noted in individuals aged 75 years and above, as well as during the cold season. CONCLUSION: This nationwide study presents compelling evidence that both PM2.5 and PM2.5-10 exposures could increase pneumonia mortality of viral and bacterial causes, highlighting the more robust effects of PM2.5 and somewhat higher sensitivity of viral pneumonia.

Cohort profile of an early life observational cohort in China: Bone and MicroBiOme onset (BAMBOO) study.

PURPOSE: The Bone And MicroBiOme Onset (BAMBOO) study is an ongoing prospective observational cohort study conducted in Tianjin, China, aiming to determine age-appropriate trajectories for microbiome maturation and bone development and to identify the influence of dietary factors in the process. PARTICIPANTS: The recruitment started in September 2021 and was completed in February 2023. A total of 1380 subjects were recruited, 690 at birth (group 1) and 690 at 6 months of age (group 2). Groups 1 and 2 will be followed up for 12 months and 36 months, respectively. FINDINGS TO DATE: The age of the mothers was 31.1±3.7 (mean±SD), and the birth weight of infants was 3.3±0.5 kg with an incidence of caesarean section 50.4%. Food diary information of the first 100 subjects showed that 64 food items were introduced by 6 months. A pilot microbiome analysis revealed that at the species level, bacterial communities were composed of mostly Bacteroides dorei, Bacteroides vulgatus and Escherichia coli, which were consistent with that of previous reports. Feasibility assessments of breast milk vitamin D and human milk oligosaccharides were validated through certified reference measurements. The early data assessment showed a high reliability of the data generated from this study. FUTURE PLANS: Data collection will be completed in August 2025. Four stage-statistical analyses will be performed as the cohort reaches certain age thresholds before the final report. Analysis of BAMBOO data will be used to develop age-appropriate trajectories for microbiome maturation and bone development for children aged 0-3 years and investigate the contribution of dietary factors in the process. TRIAL REGISTRATION NUMBER: ChiCTR2100049972.

Salvianolic acid B protects against UVB-induced skin aging via activation of NRF2.

BACKGROUND: Prolonged exposure to sun radiation may result in harmful skin photoaging. Therefore, discovering novel anti-photoaging treatment modalities is critical. An active component isolated from Salvia miltiorrhiza (SM), Salvianolic acid B (Sal-B), is a robust antioxidant and anti-inflammatory agent. This investigation aimed to discover the therapeutic impact and pathways of salvianolic acid B for UVB-induced skin photoaging, an area that remains unexplored. METHODS: We conducted in vitro experiments on human dermal fibroblasts (HDFs) exposed to UVB radiation, assessing cellular senescence, superoxide dismutase (SOD) activity, cell viability, proliferation, migration, levels of reactive oxygen species (ROS), and mitochondrial health. The potential mechanism of Sal-B was analyzed using RNA sequencing, with further validation through Western blotting, PCR, and nuclear factor erythroid 2-related factor 2 (NRF2) silencing methods. In vivo, a model of skin photoaging induced by UVB in nude mice was employed. The collagen fiber levels were assessed utilizing hematoxylin and eosin (H&E), Masson, and Sirus red staining. Additionally, NRF2 and related gene and protein expression levels were identified utilizing PCR and Western blotting. RESULTS: Sal-B was found to significantly counteract photoaging in UVB-exposed skin fibroblasts, reducing aging-related decline in fibroblast proliferation and an increase in apoptosis. It was observed that Sal-B aids in protecting mitochondria from excessive ROS production by promoting NRF2 nuclear translocation. NRF2 knockdown experiments established its necessity for Sal-B's anti-photoaging effects. The in vivo studies also verified Sal-B's anti-photoaging efficacy, surpassing that of tretinoin (Retino-A). These outcomes offer novel insights into the contribution of Sal-B in developing clinical treatment modalities for UVB-induced photodamage in skin fibroblasts. CONCLUSION: In this investigation, we identified the Sal-B protective impact on the senescence of dermal fibroblasts and skin photoaging induced by radiation of UVB. The outcomes suggest Sal-B as a potential modulator of the NRF2 signaling pathway.

Omics analysis revealed the intestinal toxicity induced by aflatoxin B1 and aflatoxin M1.

Aflatoxin B1 (AFB1), a common mycotoxin, can occur in agricultural products. As a metabolite of AFB1, aflatoxin M1 (AFM1) mainly exist in dairy products. These two mycotoxins threaten human health, although it is unclear how they affect the function of the intestinal barrier. In this study, mice were exposed to AFB1 (0.3 mg/kg body b.w.) and AFM1(3.0 mg/kg b.w.) either individually or in combination for 28 days to explore the main differentially expressed proteins (DEPs) and the associated enriched pathways. These findings were preliminarily verified by the transcriptomic and proteomic analyses in differentiated Caco-2 cells. The results revealed that AFB1 and AFM1 exposure in mice disrupted the function of the intestinal barrier, and the combined toxicity was greater than that of each toxin alone. Further proteomic analysis in mice demonstrated that the mechanisms underlying these differences could be explained as follows: (i) lipid metabolism was enriched by AFB1-induced DEPs. (ii) protein export pathway was stimulated by AFM1-induced DEPs. (iii) cell metabolic ability was inhibited (as evidenced by changes in UDP-GT1, UDP-GT2, and Gatm6), apoptosis was induced (MAP4K3), and epithelial cell integrity was disrupted (Claudin7 and IQGAP2), resulting in more extensive intestinal damage after combined treatment. In conclusion, the hazardous impact of co-exposure to AFB1 and AFM1 from proteomic perspectives was demonstrated in the present study.

Association between the triglyceride glucose index and length of hospital stay in patients with heart failure and type 2 diabetes in the intensive care unit: a retrospective cohort study.

Background: The coexistence of heart failure and diabetes is prevalent, particularly in Intensive Care Units (ICU). However, the relationship between the triglyceride-glucose (TyG) index, heart failure, diabetes, and the length of hospital stay (LHS) in patients with cerebrovascular disease in the ICU remains uncertain. This study aims to investigate the association between the TyG index and LHS in patients with heart failure and diabetes. Methods: This retrospective study utilized the Medical Information Mart for Intensive Care (MIMIC)-IV database to analyze patients with diabetes and heart failure. Participants were categorized into quartiles based on the TyG index, and the primary outcome was LHS. The association between the TyG index at ICU admission and LHS was examined through multivariable logistic regression models, restricted cubic spline regression, and subgroup analysis. Results: The study included 635 patients with concurrent diabetes and heart failure. The fully adjusted model demonstrated a positive association between the TyG index and LHS. As a tertile variable (Q2 and Q3 vs Q1), the beta (ß) values were 0.88 and 2.04, with a 95% confidence interval (95%CI) of -0.68 to 2.44 and 0.33 to 3.74, respectively. As a continuous variable, per 1 unit increment, the ß (95% CI) was 1.13 (0.18 to 2.08). The TyG index's relationship with LHS showed linearity (non-linear p = 0.751). Stratified analyses further confirmed the robustness of this correlation. Conclusion: The TyG index exhibited a linearly positive association with the LHS in patients with both heart failure and diabetes. Nevertheless, prospective, randomized, controlled studies are imperative to substantiate and validate the findings presented in this investigation.

Comparative Mitogenome of Phylogenetic Relationships and Divergence Time Analysis within Potamanthidae (Insecta: Ephemeroptera).

Potamanthidae belongs to the superfamily Ephemeroidea but has no complete mt genome released in the NCBI (except for two unchecked and one partial mt genome). Since the sister clade to Potamanthidae has always been controversial, we sequenced seven mt genomes of Potamanthidae (two species from Rhoenanthus and five species from Potamanthus) in order to rebuild the phylogenetic relationships of Potamanthidae in this study. The divergence time of Potamanthidae was also investigated by utilizing five fossil calibration points because of the indeterminate origin time. In addition, because Rhoenanthus coreanus and Potamanthus luteus are always in low-temperature environments, we aimed to explore whether these two species were under positive selection at the mt genome level. Amongst the 13 PCGs, CGA was used as the start codon in COX1, whereas other genes conformed to initiating with an ATN start codon. From this analysis, UUA (L), AUU (I), and UUU (F) had the highest usage. Furthermore, the DHU arm was absent in the secondary structure of S1 in all species. By combining the 13 PCGs and 2 rRNAs, we reconstructed the phylogenetic relationship of Potamanthidae within Ephemeroptera. The monophyly of Potamanthidae and the monophyly of Rhoenanthus and Potamanthus were supported in the results. The phylogenetic relationship of Potamanthidae + (Ephemeridae + Polymitarcyidae) was also recovered with a high prior probability. The divergence times of Potamanthidae were traced to be 90.44 Mya (95% HPD, 62.80-121.74 Mya), and the divergence times of Rhoenanthus and Potamanthus originated at approximately 64.77 Mya (95% HPD, 43.82-88.68 Mya), thus belonging to the late Pliocene Epoch or early Miocene Epoch. In addition, the data indicated that R. coreanus was under negative selection and that ATP8 and ND2 in Potamanthidae had a high evolutionary rate.

Efficacy of Danzhixiaoyao tablets combined with methylcobalamin tablets in the treatment of burning mouth syndrome: an open-label, randomized controlled trial.

OBJECTIVES: This randomized controlled trial compared the efficacy and tolerability of danzhixiaoyao pills in the accurate treatment of patients with burning mouth syndrome (BMS). METHOD: Collect a total of 78 patients (75 female patients and 3 male patients) from the oral mucosa department who were considered eligible fromOctober 2020 to October 2022.The patients were randomized and divided into trial group and control group.The trail group received danzhixiaoyao pills and mecobalamine tablets while the control group was given mecobalamine tablets.The Visual Analogue Scale (VAS), Beck Anxiety Inventory(BAI), Beck Depression Inventory (BDI), Oral Health Impact Profile (OHIP-14), Traditional Chinese medicine(TCM) syndrome integral and adverse reactions were performed at baseline and after 2, 4, and 6 weeks of treatment. Descriptive statistics, including the Wilcoxon rank-sum test and the Chi-square test for median comparisons between different times, were used. RESULT: 1.After treatment, the VAS, BDI,OHIP-14, and TCM syndrome integral in the trial group had a significant decrease than the control group(P< 0.05).However, there was no statistical difference in the BAI scores between the two groups (P> 0.05). 2.According to the efficacy determination criteria , the total effective rate of the test group was 73.68% , the control group was 52.94% and the recurrence rate was 0. There was a significant difference between the two groups (Z=-2.688, P < 0.05). The results showed that the curative effect of test group was better than that of control group.3. No adverse effects occurred in patients in either group. CONCLUSION: Danzhixiaoyao pills has demonstrated to have a positive effect in relieving BMS symptoms and in improving a patient's overall quality of life with no AEs compared with the control group. The efficacy evaluation systems that can be verified and complementary in this study provide a perfect, effective and referential evaluation system for the use of Chinese patent medicine in the treatment of oral mucosal diseases. TRIAL REGISTRATION: Registry name: Chinese Clinical trail Registry Registration number: ChiCTR2000038189 Date of Registration: 2020-09-13 Please visit ( https://www.chictr.org.cn/showproj.html?proj=61462 ) to the protocol.

Increasing expression of dual-specificity phosphatase 12 mitigates oxygen-glucose deprivation/reoxygenation-induced neuronal apoptosis and inflammation through inactivation of the ASK1-JNK/p38 MAPK pathway.

Dual-specificity phosphatase 12 (DUSP12) is abnormally expressed under various pathological conditions and plays a crucial role in the pathological progression of disorders. However, the role of DUSP12 in cerebral ischaemia/reperfusion injury has not yet been investigated. This study explored the possible link between DUSP12 and cerebral ischaemia/reperfusion injury using an oxygen-glucose deprivation/reoxygenation (OGD/R) model. Marked decreases in DUSP12 levels have been observed in cultured neurons exposed to OGD/R. DUSP12-overexpressed neurons were resistant to OGD/R-induced apoptosis and inflammation, whereas DUSP12-deficient neurons were vulnerable to OGD/R-evoked injuries. Further investigation revealed that DUSP12 overexpression or deficiency affects the phosphorylation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) in neurons under OGD/R conditions. Moreover, blockade of ASK1 diminished the regulatory effect of DUSP12 deficiency on JNK and p38 MAPK activation. In addition, DUSP12-deficiency-elicited effects exacerbating neuronal OGD/R injury were reversed by ASK1 blockade. In summary, DUSP12 protects against neuronal OGD/R injury by reducing apoptosis and inflammation through inactivation of the ASK1-JNK/p38 MAPK pathway. These findings imply a neuroprotective function for DUSP12 in cerebral ischaemia/reperfusion injury.

Long-term efficacy, safety and biocompatibility of a novel sirolimus eluting iron bioresorbable scaffold in a porcine model.

Iron is considered as an attractive alternative material for bioresorbable scaffolds (BRS). The sirolimus eluting iron bioresorbable scaffold (IBS), developed by Biotyx Medical (Shenzhen, China), is the only iron-based BRS with an ultrathin-wall design. The study aims to investigate the long-term efficacy, safety, biocompatibility, and lumen changes during the biodegradation process of the IBS in a porcine model. A total of 90 IBSs and 70 cobalt-chromium everolimus eluting stents (EES) were randomly implanted into nonatherosclerotic coronary artery of healthy mini swine. The multimodality assessments including coronary angiography, optical coherence tomography, micro-computed tomography, magnetic resonance imaging, real-time polymerase chain reaction (PCR), and histopathological evaluations, were performed at different time points. There was no statistical difference in area stenosis between IBS group and EES group at 6 months, 1year, 2 years and 5 years. Although the scaffolded vessels narrowed at 9 months, expansive remodeling with increased mean lumen area was found at 3 and 5 years. The IBS struts remained intact at 6 months, and the corrosion was detectable at 9 months. At 5 years, the iron struts were completely degraded and absorbed in situ, without in-scaffold restenosis or thrombosis, lumen collapse, aneurysm formation, and chronic inflammation. No local or systemic toxicity and abnormal histopathologic manifestation were found in all experiments. Results from real-time PCR indicated that no sign of iron overload was reported in scaffolded segments. Therefore, the IBS shows comparable efficacy, safety, and biocompatibility with EES, and late lumen enlargement is considered as a unique feature in the IBS-implanted vessels.

Testis specific protein, Y-encoded-like 2 activates JAK2/STAT3 pathway in hypothalamic paraventricular nucleus to sustain hypertension.

BACKGROUND: In the hypothalamic paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHRs), the expression of Testis specific protein, Y-encoded-like 2 (TSPYL2) and the phosphorylation level of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) are higher comparing with the normotensive Wistar-Kyoto rats (WKY). But how they are involved in hypertension remains unclear. TSPYL2 may interact with JAK2/STAT3 in PVN to sustain the high blood pressure during hypertension. METHODS: Knockdown of TSPYL2 via adeno-associated virus (AAV) carrying shRNA was conducted through bilateral micro-injection into the PVN of SHR and WKY rats. JAK2/STAT3 inhibition was achieved by intraperitoneally or PVN injection of AG490 into the SHRs. Blood pressure (BP), plasma norepinephrine (NE), PVN inflammatory response, and PVN oxidative stress were measured. RESULTS: TSPYL2 knock-down in the PVN of SHRs but not WKYs led to reduced BP and plasma NE, and deactivation of JAK2/STAT3, decreased expression of pro-inflammatory cytokine IL-1ß, and increased expression of anti-inflammatory cytokine IL-10 in the PVN. Meanwhile, AG490 administrated in both ways reduced the blood pressure in the SHRs and deactivated JAK2/STAT3 but failed to change the expression of TSPYL2 in PVN. AG490 also downregulated expression of IL-1ß and upregulated expression of IL-10. Both knockdown of TSPYL2 and inhibition of JAK2/STAT3 can reduce the oxidative stress in the PVN of SHRs. CONCLUSION: JAK2/STAT3 is regulated by TSPYL2 in the PVN of SHRs, and PVN TSPYL2/JAK2/STAT3 is essential for maintaining high blood pressure in the hypertensive rats, making it a potential therapeutic target for hypertension.

Quantification of the Heat-Related Risk and Burden of Hospitalizations for Cause-Specific Injuries and Contribution of Human-Induced Climate Change: A Time-Stratified Case-Crossover Study in China.

BACKGROUND: Although ambient temperature has been linked with injury incidence, there have been few nationwide studies to quantify the temperature-related risk and burden of cause-specific injury hospitalizations. Additionally, the impact of human-induced climate change to injury burden remains unknown. OBJECTIVES: Our objectives are to examine the associations between ambient temperature and injury hospitalizations from various causes and to quantify the contribution of human-induced warming to the heat-related burden. METHODS: We collected injury hospitalization data from a nationwide hospital-based registry in China during 2000-2019. Using a time-stratified case-crossover design, we investigated the associations between daily mean temperature (°C) and cause-specific injury hospitalizations. We also quantified the burden of heat-related injuries under the scenarios with and without anthropogenic forcing, using the Detection and Attribution Model Intercomparison Project to assess the contribution of human-induced warming. RESULTS: Our study included a total of 988,087 patients with hospitalization records for injuries. Overall, compared to the temperature at minimum risk of hospitalization (-12.1°C), the relative risk of hospitalization at extreme hot temperature (30.8°C, 97.5th percentile) was 1.18 [95% confidence interval (CI): 1.14, 1.22], with an approximately linear association between temperature and hospitalization. Vulnerability to heat-related injuries was more pronounced among males, young (<18 years of age) or middle-aged (45-64 years of age) individuals, and those living in the North. The heat-related attributable fraction increased from 23.2% in the 2000s to 23.6% in the 2010s, with a corresponding increase in the contribution of human-induced change over time. In the 2010s, the heat-related attributable fractions for specific causes of injury ranged from 12.4% to 54.4%, with human-induced change accounting for 6.7% to 10.6% of the burden. DISCUSSION: This nationwide study presents new evidence of significant associations between temperature and cause-specific injury hospitalizations in China and highlights the increasing contribution of human-induced warming to the injury burden. https://doi.org/10.1289/EHP14057.

Effects of the quorum sensing related luxS gene and lsr operon on Klebsiella michiganensis resisting copper stress.

Industrial wastewater is a major environmental concern due to its high copper content, which poses significant toxicity to microbial life. Autoinducer-2 (AI-2) can participate in the inter- and intra-species communication and regulate the physiological functions of different bacterial species by producing AI-2 signal molecules. However, there are few research reports on the luxS gene and lsr operon functions for AI-2 in bacteria with a certain tolerance to copper. This study delves into the potential of quorum sensing mechanisms, particularly the AI-2 system, for enhancing microbial resistance to copper toxicity in Klebsiella michiganensis (KM). We detail the critical roles of the luxS gene in AI-2 synthesis and the lsr operon in AI-2 uptake, demonstrating their collective impact on enhancing copper resistance. Our findings show that mutations in the lsr operon, alongside the knockout of the luxS gene in KM strain (KMΔluxSΔlsr), significantly impair the strain's motility (p<0.0001) and biofilm formation (p<0.01), underscoring the operon's role in AI-2 transport. These genetic insights are pivotal for developing bioremediation strategies aimed at mitigating copper pollution in wastewater. By elucidating the mechanisms through which KM modulates copper resistance, this study highlights the broader ecological significance of leveraging microbial quorum sensing pathways for sustainable wastewater management.

EPA and DHA promote cell proliferation and enhance activity of the Akt-TOR-S6K anabolic signaling pathway in primary muscle cells of turbot (Scophthalmus maximus L.).

Fish growth and health are predominantly governed by dietary nutrient supply. Although the beneficial effects of omega-3 polyunsaturated fatty acids supplementation have been shown in a number of fish species, the underlying mechanisms are still mostly unknown. In this study, we conducted an investigation into the effects of EPA and DHA on cell proliferation, nutrient sensing signaling, and branched-chain amino acids (BCAA) transporting in primary turbot muscle cells. The findings revealed that EPA and DHA could stimulate cell proliferation, promote protein synthesis and inhibit protein degradation through activation of target of rapamycin (TOR) signaling pathway, a pivotal nutrient-sensing signaling cascade. While downregulating the expression of myogenin and myostatin, EPA and DHA increased the level of myogenic regulatory factors, such as myoD and follistatin. Furthermore, we observed a significant increase in the concentrations of intracellular BCAAs following treatment with EPA or DHA, accompanied by an upregulation of the associated amino acid transporters. Our study providing valuable insights into the mechanisms underlying the growth-promoting effects of omega-3 fatty acids in fish.