Identification of two repurposed drugs targeting GSDMD oligomerization interface I to block pyroptosis.

As an executor of pyroptosis, gasdermin D (GSDMD) plays a critical role in inflammatory diseases and cancer. Thus, GSDMD is currently being widely explored as a drug target. Existing inhibitors targeting GSDMD, such as necrosulfonamide, disulfiram, and fumarate, primarily prevent pyroptosis by modifying human/mouse C191/C192 in the N-terminal fragment of GSDMD. However, cysteine modification can prevent the function of important proteins or enzymes, thereby leading to adverse reactions. Here, we chose an alternative key intervention site for GSDMD activation, which is located at the oligomerization interface I of its pore-forming structure. Through high-throughput virtual and experimental screening and in combination with efficacy and pharmacological validation, we have identified two safe, specific "repurposed drugs" that potently suppress GSDMD-mediated pyroptosis. Moreover, the candidates exhibited synergistic therapeutic effects of "1 + 1>2" in murine sepsis and tumorigenesis models. These recently identified GSDMD inhibitors hold great promise for clinical translation in the development of anti-inflammatory and anti-cancer immunotherapies.

Cu-UiO-66 Catalyzed Synthesis of Imines via Acceptorless Dehydrogenative Coupling of Alcohols and Amines.

Herein, the Cu-UiO-66 catalyst was developed for acceptorless dehydrogenative coupling (ADC) between alcohols and amines to produce imines. The Cu-UiO-66 catalyst was synthesized by installing Cu2+ onto Zr-oxo clusters in UiO-66, and the catalyst efficiently catalyzes the ADC reaction under mild and environmentally friendly conditions with excellent selectivity. Mechanistic studies reveal that the O2·- radicals and porosity of formed in Cu-UiO-66 participate cooperatively during the catalytic cycle. Meanwhile, the only by-product of the system is environmentally benign water. Cycling tests and hot filtration tests showed that the Cu-UiO-66 catalyst exhibited excellent stability and catalytic activity during the reaction. Importantly, the Cu-UiO-66 catalyst might provide a promising strategy for the ADC reaction between alcohols and amines to produce imines.

Stress hyperglycemia is associated with poor prognosis in critically ill patients with cardiogenic shock.

Background: Stress hyperglycemia is now more common in intensive care unit (ICU) patients and is strongly associated with poor prognosis. Whether this association exists in critically ill patients with cardiogenic shock (CS) is unknown. This study investigated the prognostic relationship of stress hyperglycemia on critically ill patients with CS. Methods: We included 393 critically ill patients with CS from the MIMIC IV database in this study and categorized the patients into four groups based on quartiles of Stress hyperglycemia ratio (SHR). We assessed the correlation between SHR and mortality using restricted cubic spline analysis and Cox proportional hazards models. The primary outcomes observed were ICU mortality and hospitalization mortality. Results: The mean age of the entire study population was 68 years, of which 30% were male (118 cases). There was no significant difference between the four groups in terms of age, gender, BMI, and vital signs (P>0.05). There was an increasing trend in the levels of lactate (lac), white blood cell count (WBC), glutamic oxaloacetic transaminase (AST), glucose and Hemoglobin A1C (HbA1c) from group Q1 to group Q2, with the greatest change in patients in group Q4 (P<0.05) and the patients in group Q4 had the highest use of mechanical ventilation, the longest duration of mechanical ventilation, ICU stay and hospital stay. After adjusting for confounders, SHR was found to be strongly associated with patient ICU mortality, showing a U-shaped relationship. Conclusion: In critically ill patients with CS, stress hyperglycemia assessed by SHR was significantly associated with patient ICU mortality.

Association between waist triglyceride index, body mass index, dietary inflammatory index, and triglyceride- glucose index with chronic kidney disease: the 1999-2018 cohort study from NHANES.

Purpose: To compare the dietary inflammatory index (DII), triglyceride glucose index (TyG), waist triglyceride index (WTI), and body mass index (BMI) in predicting the survival of chronic kidney disease (CKD). Methodology: Inclusion of 23,099 participants from the NHANES database who met specific criteria. Baseline was established using quartiles of DII index. The relationship between DII index, WTI index, TyG index, and BMI index with mortality rate in CKD patients was evaluated using Kaplan-Meier curves. Univariate and multivariate COX regression risk models were used to study the relationship between DII index, WTI index, and TyG index with mortality risk in CKD patients. Stratification of eGFR by age and gender was conducted to investigate the association between DII index, WTI index, and TyG index with mortality risk in CKD patients. Restricted cubic spline analysis was used to study the correlation between DII index, WTI index, and TyG index with mortality risk in CKD patients. Results: The incidence of CKD increased with the increase of DII index, WTI index and TyG index. After multivariable adjustment, the fourth quartile of DII index, TyG index and WTI index showed the highest risk for CKD [DII: hazard ratio (HR) 1.36, 95% confidential interval (CI) (1.23-1.51); TyG: HR 1.21; 95% CI (1.07-1.37); WTI: HR 1.29; 95% CI (1.13-1.46)]. There was no difference in the risk of developing CKD between the obese group (BMI ≥24 kg/m2) and the normal weight group (P>0.05). Conclusion: This study has identified a significant association between elevated DII index, WTI index, and TyG index with the risk of CKD. Furthermore, the DII index demonstrated superior prognostic capability in predicting CKD compared to other indicators.

Comparison of thyroid surgery techniques: a retrospective cohort study and meta-analysis of traditional electric knife vs. straight bipolar electrocoagulation forceps.

Background: In recent years, advancements in surgical techniques for thyroidectomy have led to varying outcomes and efficiencies. Understanding these differences is crucial to optimize patient care and surgical success. This study compared intra- and postoperative parameters of thyroid surgery for thyroidectomy or thyroid cancer. One approach involved the traditional electric knife, employing traditional clamp-ligation skills and an electric knife. The other approach utilized straight bipolar electrocoagulation forceps for micro-hemostasis and micro-cutting. Methods: Data were analyzed retrospectively for 228 patients who underwent thyroidectomy at the Third Affiliated Hospital of Kunming Medical University from January 2014 to November 2018. Surgery was performed either as traditional open surgery (n=150) or as a meticulous anatomical procedure involving bipolar electrocoagulation (n=78). In addition, data from published studies comparing the two surgical procedures were meta-analyzed. Results: The bipolar electrocoagulation procedure was associated with significantly shorter total operation time, lower intraoperative blood loss and lower rate of hypocalcemia. The two procedures were associated with similar rates of hoarseness. Meta-analysis of eight studies involving 2,080 patients showed that bipolar electrocoagulation was associated with significantly shorter total operation time than the traditional approach (mean difference =-21.29 min, 95% CI: -26.32 to -16.27) and with less intraoperative bleeding (mean difference =-12.87 min, 95% CI: -23.81 to -1.93). Conclusions: Straight bipolar electrocoagulation forceps can be used to perform fine dissection during thyroid surgery. Performing "micro-hemostasis" and "micro-cutting" manipulations with these straight bipolar forceps can smoothly dissect nerves and parathyroid glands and may reduce intraoperative bleeding, operation time and rates of postoperative complications, might accelerate recovery after surgery.

Capillary-driven microchip integrated with nickel phosphide hybrid-modified electrode for the electrochemical detection of glucose.

BACKGROUND: Transition metal phosphides with properties similar to platinum metal have received increasing attention for the non-enzymatic detection of glucose. However, the requirement of highly corrosive reagent during sample pretreatment would impose a potential risk to the human body, limiting their practical applications. RESULTS: In this study, we report a self-powered microfluidic device for the non-enzymatic detection of glucose using nickel phosphide (Ni2P) hybrid as the catalyst. The Ni2P hybrid is synthesized by pyrolysis of metal-organic framework (MOF)-based precursor and in-situ phosphating process, showing two linear detection ranges (1 µM-1 mM, 1 mM-6 mM) toward glucose with the detection limit of 0.32 µM. The good performance of Ni2P hybrid for glucose is attributed to the synergistic effect of Ni2P active sites and N-doped porous carbon matrix. The microchip is integrated with a NaOH-loaded paper pad and a capillary-based micropump, enabling the automatic NaOH redissolution and delivery of sample solution into the detection chamber. Under the optimized condition, the Ni2P hybrid-based microchip realized the detection of glucose in a user-friendly way. Besides, the feasibility of using this microchip for glucose detection in real serum samples has also been validated. SIGNIFICANCE: This article presents a facile fabrication method utilizing a MOF template to synthesize a Ni2P hybrid catalyst. By leveraging the synergy between the Ni2P active sites and the N-doped carbon matrix, an exceptional electrochemical detection performance for glucose has been achieved. Additionally, a self-powered chip device has been developed for convenient glucose detection based on the pre-established high pH environment on the chip.

Spicy food consumption and risk of vascular disease: Evidence from a large-scale Chinese prospective cohort of 0.5 million people.

BACKGROUND: Spicy food consumption has been reported to be inversely associated with mortality from multiple diseases. However, the effect of spicy food intake on the incidence of vascular diseases in the Chinese population remains unclear. This study was conducted to explore this association. METHODS: This study was performed using the large-scale China Kadoorie Biobank (CKB) prospective cohort of 486,335 participants. The primary outcomes were vascular disease, ischemic heart disease (IHD), major coronary events (MCEs), cerebrovascular disease, stroke, and non-stroke cerebrovascular disease. A Cox proportional hazards regression model was used to assess the association between spicy food consumption and incident vascular diseases. Subgroup analysis was also performed to evaluate the heterogeneity of the association between spicy food consumption and the risk of vascular disease stratified by several basic characteristics. In addition, the joint effects of spicy food consumption and the healthy lifestyle score on the risk of vascular disease were also evaluated, and sensitivity analyses were performed to assess the reliability of the association results. RESULTS: During a median follow-up time of 12.1 years, a total of 136,125 patients with vascular disease, 46,689 patients with IHD, 10,097 patients with MCEs, 80,114 patients with cerebrovascular disease, 56,726 patients with stroke, and 40,098 patients with non-stroke cerebrovascular disease were identified. Participants who consumed spicy food 1-2 days/week (hazard ratio [HR] = 0.95, 95% confidence interval [95% CI] = [0.93, 0.97], P <0.001), 3-5 days/week (HR = 0.96, 95% CI = [0.94, 0.99], P = 0.003), and 6-7 days/week (HR = 0.97, 95% CI = [0.95, 0.99], P = 0.002) had a significantly lower risk of vascular disease than those who consumed spicy food less than once a week (Ptrend <0.001), especially in those who were younger and living in rural areas. Notably, the disease-based subgroup analysis indicated that the inverse associations remained in IHD (Ptrend = 0.011) and MCEs (Ptrend = 0.002) risk. Intriguingly, there was an interaction effect between spicy food consumption and the healthy lifestyle score on the risk of IHD (Pinteraction = 0.037). CONCLUSIONS: Our findings support an inverse association between spicy food consumption and vascular disease in the Chinese population, which may provide additional dietary guidance for the prevention of vascular diseases.

Assembly processes and co-occurrence of bacterial communities in tree rhizosphere under Pb-Zn contamination.

Rhizosphere bacteria are critical for supporting plant performance in stressful environments. Understanding the assembly and co-occurrence of rhizosphere bacterial communities contributes significantly to both plant growth and heavy metal accumulation. In this study, Ligustrum lucidum and Melia azedarach were planted in soils with simulated varying levels of Pb-Zn contamination. The Rhizosphere bacterial communities were investigated by using 16S rRNA gene sequencing. The impacts of Pb-Zn contamination on the diversity and structure of the rhizosphere bacterial community were found to be greater than those of both tree species. The variation in bacterial community structure in both trees was mainly driven by the combinations of Pb-Zn and soil properties. Deterministic processes (non-planted, 82 %; L. lucidum, 73 %; M. azedarach, 55 %) proved to be the most important assembly processes for soil bacterial communities, but both trees increased the importance of stochastic processes (18 %, 27 %, 45 %). The rhizosphere co-occurrence networks exhibited greater stability compared to the non-planted soil networks. Rare taxa played a dominant role in maintaining the stability of rhizosphere networks, as most of the keystone taxa within rhizosphere networks belonged to rare taxa. Dissimilarities in the structure and network complexity of rhizosphere bacterial communities were significantly associated with differences in tree biomass and metal accumulation. These variations in response varied between both trees, with L. lucidum exhibiting greater potential for phytoremediation in its rhizosphere compared to M. azedarach. Our results offer valuable insights for designing effective microbe-assisted phytoremediation systems.

PGC-1α regulates endoplasmic reticulum stress in IPF-derived fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is considered to be associated with aging. Both ER stress and the unfolded protein response (UPR) have been associated with pulmonary fibrosis via key mechanisms including AEC apoptosis, EMT, altered myofibroblast differentiation, and M2 macrophage polarization. A relationship between ER stress and aging has also been demonstrated in vitro, with increased p16 and p21 levels seen in lung epithelial cells of older IPF patients. The mechanism underlying ER stress regulation of IPF fibroblasts is still unclear. In this study, we aimed to delineate ER stress regulation in IPF-derived fibroblasts. Here, we found that ER stress markers (p-eIF2α, p-IREα, ATF6) and fibrosis markers (α-SMA and Collagen-I) were significantly increased in lung tissues of IPF patients and bleomycin-induced mouse models. Notably, the expression of PGC-1α was decreased in fibroblasts. In vivo experiments were designed using an AAV-6 vector mediated conditional PGC-1α knockout driven by a specific α-SMA promoter. Ablation of PGC-1α expression in fibroblasts promoted ER stress and supported the development of pulmonary fibrosis in a bleomycin-induced mouse model. In another experimental group, mice with conditional knockout of PGC-1α in fibroblasts and injected intraperitoneally with 4-PBA (an endoplasmic reticulum stress inhibitor) were protected from lung fibrosis. We further constructed an AAV-6 vector mediated PGC-1α overexpression model driven by a specific Collagen-I promoter. Overexpression of PGC-1α in fibroblasts suppressed ER stress and attenuated development of pulmonary fibrosis in bleomycin-induced mouse models. Taken together, this study identified PGC-1α as a promising target for developing novel therapeutic options for the treatment of lung fibrosis.

Driving pressure association with mortality in post-lung transplant patients: A prospective observational study.

OBJECTIVE: To investigate the association between driving pressure (ΔP) and 90-day mortality in patients following lung transplantation (LTx) in patients who developed primary graft dysfunction (PGD). METHODS: This prospective, observational study involved consecutive patients who, following LTx, were admitted to our intensive care unit (ICU) from January 2022 to January 2023. Patients were separated into two groups according to ΔP at time of admission (i.e., low, ≤15 cmH2O or high, >15 cmH2O). Postoperative outcomes were compared between groups. RESULTS: In total, 104 patients were involved in the study, and of these, 69 were included in the low ΔP group and 35 in the high ΔP group. Kaplan-Meier analysis of 90-day mortality showed a statistically significant difference between groups with survival better in the low ΔP group compared with the high ΔP group. According to Cox proportional regression model, the variables independently associated with 90-day mortality were ΔP and pneumonia. Significantly more patients in the high ΔP group than the low ΔP group had PGD grade 3 (PGD3), pneumonia, required tracheostomy, and had prolonged postoperative extracorporeal membrane oxygenation (ECMO) time, postoperative ventilator time, and ICU stay. CONCLUSIONS: Driving pressure appears to have the ability to predict PGD3 and 90-day mortality of patients following LTx. Further studies are required to confirm our results.

Association between triglyceride-glucose index and chronic kidney disease: results from NHANES 1999-2020.

AIMS: Examining the connection between the triglyceride-glucose (TyG) index and chronic kidney disease (CKD) was the aim of this investigation. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) covering the years 1999-2020 were analyzed in this study. The TyG index was calculated as Ln (triglycerides (mg/dl) * fasting glucose (mg/dl)/2). The two criteria used to diagnose CKD were low estimated glomerular filtration rate (eGFR) (eGFR < 60 mL/min/1.73m2) or albuminuria (urine albumin-to-creatinine ratio (ACR) ≥ 30 mg/g). To look into the independent associations between TyG index levels with CKD, albuminuria, and low-eGFR, weighted multivariable logistic regression and generalized additive models were employed. To assess and contrast the diagnostic ability, receiver operating characteristic (ROC) curves were employed. RESULTS: Out of 18,078 total participants recruited, 48.54% were male. 8.48 + 0.68 was the mean value of the TyG index. CKD, albuminuria, and low-eGFR were common, with respective prevalences of 17.06%, 11.26%, and 8.03%, respectively. The TyG index and CKD were observed to positively correlate (OR = 4.03; 95% CI 1.81, 8.96). In US adults between the ages of 41 and 60, a J-shaped connection was found between the two. Furthermore, a higher TyG index is associated with a higher prevalence of albuminuria (OR = 6.11; 95% CI 2.64, 14.14). Subgroup analyses and interaction tests revealed that different stratifications did not significantly affect the relationship between TyG index and CKD, albuminuria, and low-eGFR. Comparing the TyG index to other indicators [lipid accumulation product (LAP), Visceral adiposity index (VAI), and the triglyceride glucose-body mass index (TyG-BMI)], it may be more accurate and discriminative in predicting CKD and albuminuria. CONCLUSION: When predicting CKD and albuminuria, the TyG index may be a more useful marker when compared to other markers (LAP, VAI, and TyG-BMI index). In addition, in American adults aged 41-60, the TyG index shows a J-shaped relationship with CKD. As a result, when assessing the kidney health of US adults, we must pay close attention to the significance of the TyG index.

[Outcomes of idiopathic pulmonary fibrosis patients with high body mass index undergoing extracorporeal membrane oxygenation support].

OBJECTIVE: To evaluate the extracorporeal membrane oxygenation (ECMO) related outcomes during hospitalization during the intensive care unit (ICU) in idiopathic pulmonary fibrosis (IPF) patients with high body mass index (BMI, > 25 kg/m2) undergoing lung transplantation with ECMO support. METHODS: A retrospective observational study was conducted. IPF patients who received ECMO during lung transplantation admitted to the Affiliated Wuxi People's Hospital of Nanjing Medical University from 2019 to 2020 were enrolled. Preoperative indicators including, demographics, comorbidities, arterial blood gas, and laboratory indicators; intraoperative indicators, such as lung lobe volume reduction, surgical type, surgical time, cold ischemia time, blood loss and transfusion volume; immediate indicators upon admission to the ICU, such as blood gas analysis and laboratory indicators; ECMO related outcomes, such as ECMO mode, ECMO support time, ECMO related complications (bleeding at the catheterization site, intraductal thrombosis, lower limb ischemia), and the length of ICU stay, duration of mechanical ventilation, and 30-day survival rate were collected. According to BMI, patients were divided into three groups: light weight group (BMI < 18.5 kg/m2), normal weight group (BMI 18.5-24.9 kg/m2), and overweight group (BMI ≥ 25.0 kg/m2). Mainly to compare the relevant outcomes of ECMO among patients during ICU. RESULTS: A total of 114 IPF patients who received ECMO support during lung transplantation were collected, including 23 cases in the light weight group, 63 cases in the normal weight group, and 28 cases in the overweight group. Compared with patients with underweight and normal weight, overweight patients were more likely to have hypertension (46.4% vs. 8.7%, 23.8%, P < 0.01) and coronary heart disease (32.1% vs. 4.3%, 20.6%, P < 0.05) before surgery, which was consistent with international guidelines for obesity. Other clinical data (preoperative, intraoperative, ICU characteristics) showed no statistically significant differences and were comparable. There was no statistically significant difference in terms of ECMO related outcomes, such as ECMO related complications [veno-venous (V-V) mode: 78.3%, 77.8%, 78.6%, veno-arterial (V-A) mode: 21.7%, 22.2%, 21.4%], ECMO support time (hours: 61.70±20.03, 44.57±5.76, 41.77±7.26), ECMO related complications (bleeding at the catheterization site: 4.3%, 7.9%, 14.3%; intraductal thrombosis: 8.7%, 12.7%, 17.9%; lower limb ischemia: 8.7%, 12.7%, 14.3%), and the length of ICU stay (days: 11±3, 7±1, 9±1), duration of mechanical ventilation [days: 2 (2, 11), 2 (2, 6), 3 (2, 8)] among the light weight group, normal weight group, and overweight group (all P > 0.05). Kaplan-Meier survival curve analysis showed that there was no statistically significant difference in the 30-day cumulative survival rate among the three groups (Log-Rank test: χ 2 = 0.919, P = 0.632). CONCLUSIONS: High BMI does not worsen ECMO-related outcomes or adversely affect early prognosis in IPF patients undergoing lung transplantation. BMI as a single parameter should not be a contraindication for the use of ECMO in lung transplantation surgery for IPF patients.

ppGpp is a dual-role regulator involved in balancing iron absorption and prodiginine biosynthesis in Pseudoalteromonas.

Iron is an essential element for microbial survival and secondary metabolism. However, excess iron availability and overloaded secondary metabolites can hinder microbial growth and survival. Microorganisms must tightly control iron homeostasis and secondary metabolism. Our previous studies have found that the stringent starvation protein A (SspA) positively regulates prodiginine biosynthesis by activating iron uptake in Pseudoalteromonas sp. strain R3. It is believed that the interaction between SspA and the small nucleotide ppGpp is important for iron to exert regulation functions. However, the roles of ppGpp in iron absorption and prodiginine biosynthesis, and the underlying relationship between ppGpp and SspA in strain R3 remain unclear. In this study, we found that ppGpp accumulation in strain R3 could be induced by limiting iron. In addition, ppGpp not only positively regulated iron uptake and prodiginine biosynthesis via increasing the SspA level but also directly repressed iron uptake and prodiginine biosynthesis independent of SspA, highlighting the finding that ppGpp can stabilize both iron levels and prodiginine production. Notably, the abolishment of ppGpp significantly increased prodiginine production, thus providing a theoretical basis for manipulating prodiginine production in the future. This dynamic ppGpp-mediated interaction between iron uptake and prodiginine biosynthesis has significant implications for understanding the roles of nutrient uptake and secondary metabolism for the survival of bacteria in unfavorable environments.

A novel nomogram for predicting prolonged mechanical ventilation in lung transplantation patients using extracorporeal membrane oxygenation.

Prolonged mechanical ventilation (PMV) is commonly associated with increased post-operative complications and mortality. Nevertheless, the predictive factors of PMV after lung transplantation (LTx) using extracorporeal membrane oxygenation (ECMO) as a bridge remain unclear. The present study aimed to develop a novel nomogram for PMV prediction in patients using ECMO as a bridge to LTx. A total of 173 patients who used ECMO as a bridge following LTx from January 2022 to June 2023 were divided into the training (122) and validation sets (52). A mechanical ventilation density plot of patients after LTx was then performed. The training set was divided in two groups, namely PMV (95) and non-prolonged ventilation (NPMV) (27). For the survival analysis, the effect of PMV was assessed using the log-rank test. Univariate and multivariate logistic regression analyses were performed to assess factors associated with PMV. A risk nomogram was established based on the multivariate analysis, and model performance was further assessed in terms of calibration, discrimination, and clinical usefulness. Internal validation was additionally conducted. The difference in survival curves in PMV and NPMV groups was statistically significant (P < 0.001). The multivariate analysis and risk factors in the nomogram revealed four factors to be significantly associated with PMV, namely the body mass index (BMI), operation time, lactic acid at T0 (Lac), and driving pressure (DP) at T0. These four factors were used to develop a nomogram, with an area under the curve (AUC) of 0.852 and good calibration. After internal validation, AUC was 0.789 with good calibration. Furthermore, goodness-of-fit test and decision-curve analysis (DCA) indicated satisfactory performance in the training and internal validation sets. The proposed nomogram can reliably and accurately predict the risk of patients to develop PMV after LTx using ECMO as a bridge. Four modifiable factors including BMI, operation time, Lac, and DP were optimized, which may guide preventative measures and improve prognosis.

Neuroprotective treatment with the nitrone compound OKN-007 mitigates age-related muscle weakness in aging mice.

Despite the universal impact of sarcopenia on compromised health and quality of life in the elderly, promising pharmaceutical approaches that can effectively mitigate loss of muscle and function during aging have been limited. Our group and others have reported impairments in peripheral motor neurons and loss of muscle innervation as initiating factors in sarcopenia, contributing to mitochondrial dysfunction and elevated oxidative stress in muscle. We recently reported a reduction in α motor neuron loss in aging mice in response to the compound OKN-007, a proposed antioxidant and anti-inflammatory agent. In the current study, we asked whether OKN-007 treatment in wildtype male mice for 8-9 months beginning at 16 months of age can also protect muscle mass and function. At 25 months of age, we observed a reduction in the loss of whole-body lean mass, a reduced loss of innervation at the neuromuscular junction and well-preserved neuromuscular junction morphology in OKN-007 treated mice versus age matched wildtype untreated mice. The loss in muscle force generation in aging mice (~ 25%) is significantly improved with OKN-007 treatment. In contrast, OKN-007 treatment provided no protection in loss of muscle mass in aging mice. Mitochondrial function was improved by OKN-007 treatment, consistent with its potential antioxidative properties. Together, these exciting findings are the first to demonstrate that interventions through neuroprotection can be an effective therapy to counter aging-related muscle dysfunction.

Association between systemic inflammation response index and chronic kidney disease: a population-based study.

Introduction: Our objective was to explore the potential link between systemic inflammation response index (SIRI) and chronic kidney disease (CKD). Methods: The data used in this study came from the National Health and Nutrition Examination Survey (NHANES), which gathers data between 1999 and 2020. CKD was diagnosed based on the low estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 or albuminuria (urinary albumin-to-creatinine ratio (ACR) of more than 30 mg/g). Using generalized additive models and weighted multivariable logistic regression, the independent relationships between SIRI and other inflammatory biomarkers (systemic immune-inflammation index (SII), monocyte/high-density lipoprotein ratio (MHR), neutrophil/high-density lipoprotein ratio (NHR), platelet/high-density lipoprotein ratio (PHR), and lymphocyte/high-density lipoprotein ratio (LHR)) with CKD, albuminuria, and low-eGFR were examined. Results: Among the recruited 41,089 participants, males accounted for 49.77% of the total. Low-eGFR, albuminuria, and CKD were prevalent in 8.30%, 12.16%, and 17.68% of people, respectively. SIRI and CKD were shown to be positively correlated in the study (OR = 1.24; 95% CI: 1.19, 1.30). Furthermore, a nonlinear correlation was discovered between SIRI and CKD. SIRI and CKD are both positively correlated on the two sides of the breakpoint (SIRI = 2.04). Moreover, increased SIRI levels were associated with greater prevalences of low-eGFR and albuminuria (albuminuria: OR = 1.27; 95% CI: 1.21, 1.32; low-eGFR: OR = 1.11; 95% CI: 1.05, 1.18). ROC analysis demonstrated that, compared to other inflammatory indices (SII, NHR, LHR, MHR, and PHR), SIRI exhibited superior discriminative ability and accuracy in predicting CKD, albuminuria, and low-eGFR. Discussion: When predicting CKD, albuminuria, and low-eGFR, SIRI may show up as a superior inflammatory biomarker when compared to other inflammatory biomarkers (SII, NHR, LHR, MHR, and PHR). American adults with elevated levels of SIRI, SII, NHR, MHR, and PHR should be attentive to the potential risks to their kidney health.

BitterDB database analysis plus cell stiffness screening identify flufenamic acid as the most potent TAS2R14-based relaxant of airway smooth muscle cells for therapeutic bronchodilation.

Rationale: Bitter taste receptors (TAS2Rs) are abundantly expressed in airway smooth muscle cells (ASMCs), which have been recognized as promising targets for bitter agonists to initiate relaxation and thereby prevent excessive airway constriction as the main characteristic of asthma. However, due to the current lack of tested safe and potent agonists functioning at low effective concentrations, there has been no clinically approved TAS2R-based drug for bronchodilation in asthma therapy. This study thus aimed at exploring TAS2R agonists with bronchodilator potential by BitterDB database analysis and cell stiffness screening. Methods: Bitter compounds in the BitterDB database were retrieved and analyzed for their working subtype of TAS2R and effective concentration. Compounds activating TAS2R5, 10, and 14 at < 100 µM effective concentration were identified and subsequently screened by cell stiffness assay using optical magnetic twisting cytometry (OMTC) to identify the most potent to relax ASMCs. Then the compound identified was further characterized for efficacy on various aspects related to relaxation of ASMCs, incl. but not limited to traction force by Fourier transform traction force microscopy (FTTFM), [Ca2+]i signaling by Fluo-4/AM intensity, cell migration by scratch wound healing, mRNA expression by qPCR, and protein expressing by ELISA. The compound identified was also compared to conventional ß-agonist (isoproterenol and salbutamol) for efficacy in reducing cell stiffness of cultured ASMCs and airway resistance of ovalbumin-treated mice. Results: BitterDB analysis found 18 compounds activating TAS2R5, 10, and 14 at < 100 µM effective concentration. Cell stiffness screening of these compounds eventually identified flufenamic acid (FFA) as the most potent compound to rapidly reduce cell stiffness at 1 µM. The efficacy of FFA to relax ASMCs in vitro and abrogate airway resistance in vivo was equivalent to that of conventional ß-agonists. The FFA-induced effect on ASMCs was mediated by TAS2R14 activation, endoplasmic reticulum Ca2+ release, and large-conductance Ca2+-activated K+ (BKCa) channel opening. FFA also attenuated lipopolysaccharide-induced inflammatory response in cultured ASMCs. Conclusions: FFA as a potent TAS2R14 agonist to relax ASMCs while suppressing cytokine release might be a favorite drug agent for further development of TAS2R-based novel dual functional medication for bronchodilation and anti-inflammation in asthma therapy.

Enhanced exclusive enteral nutrition delivery during the first 7 days is associated with decreased 28-day mortality in critically ill patients with normal lactate level: a post hoc analysis of a multicenter randomized trial.

BACKGROUND AND AIMS: Exclusive enteral nutrition (EN) is often observed during the first week of ICU admission because of the extra costs and safety considerations for early parenteral nutrition. This study aimed to assess the association between nutrition intake and 28-day mortality in critically ill patients receiving exclusive EN. METHODS: This is a post hoc analysis of a cluster-randomized clinical trial that assesses the effect of implementing a feeding protocol on mortality in critically ill patients. Patients who stayed in the ICUs for at least 7 days and received exclusive EN were included in this analysis. Multivariable Cox hazard regression models and restricted cubic spline models were used to assess the relationship between the different doses of EN delivery and 28-day mortality. Subgroups with varying lactate levels at enrollment were additionally analyzed to address the potential confounding effect brought in by the presence of shock-related hypoperfusion. RESULTS: Overall, 1322 patients were included in the analysis. The median (interquartile range) daily energy and protein delivery during the first week of enrollment were 14.6 (10.3-19.6) kcal/kg and 0.6 (0.4-0.8) g/kg, respectively. An increase of 5 kcal/kg energy delivery was associated with a significant reduction (approximately 14%) in 28-day mortality (adjusted hazard ratio [HR] = 0.865, 95% confidence interval [CI]: 0.768-0.974, P = 0.016). For protein intake, a 0.2 g/kg increase was associated with a similar mortality reduction with an adjusted HR of 0.868 (95% CI 0.770-0.979). However, the benefits associated with enhanced nutrition delivery could be observed in patients with lactate concentration ≤ 2 mmol/L (adjusted HR = 0.804 (95% CI 0.674-0.960) for energy delivery and adjusted HR = 0.804 (95% CI 0.672-0.962) for protein delivery, respectively), but not in those > 2 mmol/L. CONCLUSIONS: During the first week of critical illness, enhanced nutrition delivery is associated with reduced mortality in critically ill patients receiving exclusive EN, only for those with lactate concentration ≤ 2 mmol/L. TRIAL REGISTRATION: ISRCTN12233792, registered on November 24, 2017.

Elaborate tree-like Cu-Ag clusters from green electrodeposition for efficiently electrocatalyzing CO2 conversion into syngas.

The electrocatalytic carbon dioxide reduction (CO2RR) is one of the emerging technologies that can effectively transform carbon dioxide (CO2) into valuable products. Electrocatalysts deriving from green synthesis methods will significantly help to establish a new green carbon cycle. Herein, a green electrodeposition method without additional reducing agents was used to synthesize Cu-Ag bimetallic catalysts, and it is shown that the combination of Cu and Ag obviously affects the morphology of the Cu-Ag catalysts, resulting in the formation of elaborate tree-like Cu-Ag clusters. An as-deposited Cu-Ag/carbon fiber (Cu-Ag/CF) catalyst exhibits high activity, selectivity and stability toward the CO2RR; in particular, the elaborate dendritic Cu-Ag/CF can efficiently reduce CO2 to syngas with high selectivity (Faradaic efficiency (FE) > 95%) at a low onset potential (-0.5 V). This work provides a rational strategy to overcome the significantly different reaction capacities during the reduction of Ag+ and Cu2+, leading to the formation of a controlled morphology of Cu-Ag, which is favourable for the design and development of highly efficient Cu or Ag catalysts via green methods for electrocatalyzing the CO2RR.

Modulation of sarcopenia phenotypes by glutathione peroxidase 4 overexpression in mice.

Our laboratory previously showed lipid hydroperoxides and oxylipin levels are elevated in response to loss of skeletal muscle innervation and are associated with muscle pathologies. To elucidate the pathological impact of lipid hydroperoxides, we overexpressed glutathione peroxidase 4 (GPx4), an enzyme that targets reduction of lipid hydroperoxides in membranes, in adult CuZn superoxide dismutase knockout (Sod1KO) mice that show accelerated muscle atrophy associated with loss of innervation. The gastrocnemius muscle from Sod1KO mice shows reduced mitochondrial respiration and elevated oxidative stress (F2 -isoprostanes and hydroperoxides) compared to wild-type (WT) mice. Overexpression of GPx4 improved mitochondrial respiration and reduced hydroperoxide generation in Sod1KO mice, but did not attenuate the muscle loss that occurs in Sod1KO mice. In contrast, contractile force generation is reduced in EDL muscle in Sod1KO mice relative to WT mice, and overexpression of GPx4 restored force generation to WT levels in Sod1KO mice. GPx4 overexpression also prevented loss of muscle contractility at the single fibre level in fast-twitch fibres from Sod1KO mice. Muscle fibres from Sod1KO mice were less sensitive to both depolarization and calcium at the single fibre level and exhibited a reduced activation by S-glutathionylation. GPx4 overexpression in Sod1KO mice rescued the deficits in both membrane excitability and calcium sensitivity of fast-twitch muscle fibres. Overexpression of GPx4 also restored the sarco/endoplasmic reticulum Ca2+ -ATPase activity in Sod1KO gastrocnemius muscles. These data suggest that GPx4 plays an important role in preserving excitation-contraction coupling function and Ca2+ homeostasis, and in maintaining muscle and mitochondrial function in oxidative stress-induced sarcopenia. KEY POINTS: Knockout of CuZn superoxide dismutase (Sod1KO) induces elevated oxidative stress with accelerated muscle atrophy and weakness. Glutathione peroxidase 4 (GPx4) plays a fundamental role in the reduction of lipid hydroperoxides in membranes, and overexpression of GPx4 improves mitochondrial respiration and reduces hydroperoxide generation in Sod1KO mice. Muscle contractile function deficits in Sod1KO mice are alleviated by the overexpression of GPx4. GPx4 overexpression in Sod1KO mice rescues the impaired muscle membrane excitability of fast-twitch muscle fibres and improves their calcium sensitivity. Sarco/endoplasmic reticulum Ca2+ -ATPase activity in Sod1KO muscles is decreased, and it is restored by the overexpression of GPx4. Our results confirm that GPx4 plays an important role in preserving excitation-contraction coupling function and Ca2+ homeostasis, and maintaining muscle and mitochondrial function in oxidative stress-induced sarcopenia.