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.

Association between weight-adjusted-waist index and chronic kidney disease: a cross-sectional study.

AIMS: We aimed to investigate the potential association between weight-adjusted-waist index (WWI) and chronic kidney disease (CKD). DESIGN AND METHODS: This research examined data collected from the National Health and Nutrition Examination Survey (NHANES) spanning from 1999 to 2020. CKD was defined as the low estimated glomerular filtration rate (eGFR) or the existence of albuminuria (urinary albumin-to-creatinine ratio (ACR) ≥ 30mg/g). Low-eGFR was described as eGFR < 60 mL/min/1.73m2. The associations between WWI with CKD, albuminuria, and low-eGFR were examined using generalized additive models and weighted multivariable logistic regression models. We also analyzed the associations of other obesity indicators with CKD, albuminuria, and low-eGFR, including body mass index (BMI), waist-to-height ratio (WHtR), waist circumference(WC), height, and weight. The receiver operating characteristic (ROC) curves were used to assess and compare their diagnostic abilities. RESULTS: Males made up 48.26% of the total 40,421 individuals that were recruited. The prevalences of CKD, albuminuria, and low-eGFR were 16.71%, 10.97%, and 7.63%, respectively. WWI was found to be positively linked with CKD (OR = 1.42; 95% CI: 1.26, 1.60). A nonlinear connection between WWI and CKD was found using smooth curve fitting. Additionally, a higher prevalence of albuminuria is linked to a higher level of WWI (OR = 1.60; 95% CI: 1.40, 1.82). Different stratifications did not substantially influence the connection between WWI and CKD, albuminuria, and low-eGFR, according to subgroup analysis and interaction tests. We observed higher height was related to higher low-eGFR prevalence (OR = 1.05; 95% CI: 1.03, 1.06). ROC analysis revealed that WWI had the best discrimination and accuracy for predicting CKD and albuminuria compared to other obesity indicators (BMI, WHTR, WC, height and weight). In addition, height had the highest area under the curve (AUC) value for predicting low-eGFR. CONCLUSION: WWI is the best obesity indicator to predict CKD and albuminuria compared to other obesity indicators (BMI, WHTR, WC, height, and weight). WWI and CKD and albuminuria were found to be positively correlated. Furthermore, height had the strongest ability to predict low-eGFR. Therefore, the importance of WWI and height in assessing kidney health in US adults should be emphasized.

Elevated phospholipid hydroperoxide glutathione peroxidase (GPX4) expression modulates oxylipin formation and inhibits age-related skeletal muscle atrophy and weakness.

Our previous studies support a key role for mitochondrial lipid hydroperoxides as important contributors to denervation-related muscle atrophy, including muscle atrophy associated with aging. Phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that directly reduces phospholipid hydroperoxides and we previously reported that denervation-induced muscle atrophy is blunted in a mouse model of GPX4 overexpression. Therefore, the goal of the present study was to determine whether GPX4 overexpression can reduce the age-related increase in mitochondrial hydroperoxides in skeletal muscle and ameliorate age-related muscle atrophy and weakness (sarcopenia). Male C57Bl6 WT and GPX4 transgenic (GPX4Tg) mice were studied at 3 to 5 and 23-29 months of age. Basal mitochondrial peroxide generation was reduced by 34% in muscle fibers from aged GPX4Tg compared to old WT mice. GPX4 overexpression also reduced levels of lipid peroxidation products: 4-HNE, MDA, and LOOHs by 38%, 32%, and 84% respectively in aged GPX4Tg mice compared to aged WT mice. Muscle mass was preserved in old GPX4 Tg mice by 11% and specific force generation was 21% higher in old GPX4Tg versus age matched male WT mice. Oxylipins from lipoxygenases (LOX) and cyclooxygenase (COX), as well as less abundant non-enzymatically generated isomers, were significantly reduced by GPX4 overexpression. The expression of cPLA2, 12/15-LOX and COX-2 were 1.9-, 10.5- and 3.4-fold greater in old versus young WT muscle respectively, and 12/15-LOX and COX-2 levels were reduced by 37% and 35%, respectively in muscle from old GPX4Tg mice. Our study suggests that lipid peroxidation products may play an important role in the development of sarcopenia, and their detoxification might be an effective intervention in preventing muscle atrophy.

Liproxstatin-1 Alleviates Lung Transplantation-induced Cold Ischemia-Reperfusion Injury by Inhibiting Ferroptosis.

BACKGROUND: Primary graft dysfunction, which is directly related to cold ischemia-reperfusion (CI/R) injury, is a major obstacle in lung transplantation (LTx). Ferroptosis, a novel mode of cell death elicited by iron-dependent lipid peroxidation, has been implicated in ischemic events. This study aimed to investigate the role of ferroptosis in LTx-CI/R injury and the effectiveness of liproxstatin-1 (Lip-1), a ferroptosis inhibitor, in alleviating LTx-CI/R injury. METHODS: LTx-CI/R-induced signal pathway alterations, tissue injury, cell death, inflammatory responses, and ferroptotic features were examined in human lung biopsies, the human bronchial epithelial (BEAS-2B) cells, and the mouse LTx-CI/R model (24-h CI/4-h R). The therapeutic efficacy of Lip-1 was explored and validated both in vitro and in vivo. RESULTS: In human lung tissues, LTx-CI/R activated ferroptosis-related signaling pathway, increased the tissue iron content and lipid peroxidation accumulation, and altered key protein (GPX4, COX2, Nrf2, and SLC7A11) expression and mitochondrial morphology. In BEAS-2B cells, the hallmarks of ferroptosis were significantly evidenced at the setting of both CI and CI/R compared with the control, and the effect of adding Lip-1 only during CI was much better than that of only during reperfusion by Cell Counting Kit-8. Furthermore, Lip-1 administration during CI markedly relieved LTx-CI/R injury in mice, as indicated by significant improvement in lung pathological changes, pulmonary function, inflammation, and ferroptosis. CONCLUSIONS: This study revealed the existence of ferroptosis in the pathophysiology of LTx-CI/R injury. Using Lip-1 to inhibit ferroptosis during CI could ameliorate LTx-CI/R injury, suggesting that Lip-1 administration might be proposed as a new strategy for organ preservation.

Correction: Dysferlin-deficiency has greater impact on function of slow muscles, compared with fast, in aged BLAJ mice.

[This corrects the article DOI: 10.1371/journal.pone.0214908.].

Along with cyclic electron flow and non-photochemical quenching, water-to-water cycle is involved uniquely in alleviating Zn stress-caused photodamage in Melia azedarach.

Zinc (Zn) is a widespread industrial pollutant that has detrimental effects on plant growth and development. Photoprotective properties ensure plant survival during stress by protecting the photosynthetic apparatus. This occurs via numerous mechanisms, including non-photochemical quenching (NPQ), cyclic electron flow (CEF) and the water-to-water cycle (WWC). However, whether and how Zn stress affects the photoprotective properties of plants to enhance the tolerance of Zn toxicity remains unknown. In this study, we treated Melia azedarach plants with different Zn concentrations ranging from 200 to 1000 mg kg-1. We then analyzed the activities of two leaf photosynthetic pigment components-photosystems I and II (PSI and PSII)-and the relative expression levels of their subunit genes. As expected, we found that Zn treatment decreases photosynthesis and increases photodamage in M. azedarach leaves. The Zn treatments exacerbated a variety of photodamage phenotypes in photosystem activities and altered the expression levels of key photosystem complex genes and proteins. Furthermore, our results demonstrated that PSI was more seriously damaged than PSII under Zn stress. Subsequently, we compared differences in photodamage in the NPQ, CEF and WWC photoprotection pathways under Zn stress and found that each exerted a protective function again photodamage under 200 mg kg-1 Zn stress. The NPQ and CEF may also play major protective roles in the avoidance of irreversible photodamage and helping to ensure survival under higher (i.e., 500 and 1000 mg kg-1) levels of Zn stress. Thus, our study revealed that NPQ- and CEF-based photoprotection mechanisms are more effective than WWC in M. azedarach upon Zn stress.

Concurrent chemoradiotherapy versus radiotherapy alone for stage II nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy.

BACKGROUND: Concurrent chemoradiotherapy has long been a standardized therapy for localized advanced nasopharyngeal cancer. It is widely used in clinical applications. In contrast, NCCN guidelines highlight that the efficacy of concurrent chemoradiotherapy for stage II nasopharyngeal cancer in the new era of intensity-modulated radiotherapy has not been defined. Thus, we systematically reviewed the significance of concurrent chemoradiotherapy for stage II nasopharyngeal cancer. METHODS: We searched the relevant literature in PubMed, EMBASE, and Cochrane, extracting relevant data from the searched literature. The main items extracted were hazard ratios (HRs), risk ratios (RRs) and 95% confidence intervals (CIs). When the HR could not be extracted from the literature, we used Engauge Digitizer software for extraction. Data analysis was accomplished using the Review Manager 5.4 tool. RESULTS: Our study included seven articles involving 1633 cases of stage II nasopharyngeal cancer. The survival outcomes were overall survival (OS) (HR = 1.03, 95% CI (0.71-1.49), P = 0.87), progression-free survival (PFS) (HR = 0.91, 95% CI (0.59-1.39), P = 0.66), distant metastasis-free survival (DMFS) (HR = 1.05, 95% CI (0.57-1.93), P = 0.87), local recurrence-free survival (LRFS) (HR = 0.87, 95% CI (0.41-1.84), P = 0.71, P > 0.05), and locoregional failure-free survival (LFFS) (HR = 1.18, 95% CI (0.52-2.70), P = 0.69). CONCLUSIONS: In the era of intensity-modulated radiotherapy, concurrent chemoradiotherapy and radiotherapy alone have the same survival benefits, and concurrent chemoradiotherapy increases acute hematological toxicity. Subgroup analysis showed that for people with N1 nasopharyngeal cancer at risk of distant metastases, concurrent chemoradiotherapy and radiotherapy alone also had equal survival benefits.

Impact of delayed veno-venous extracorporeal membrane oxygenation weaning on postoperative rehabilitation of lung transplantation: a single-center comparative study.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a reliable and effective extracorporeal life support during lung transplantation (LTx). However, the clinical benefit of delayed VV-ECMO weaning remains unclear. The current study aims to investigate whether delayed weaning of VV-ECMO is more beneficial to the rehabilitation for lung transplant patients. Patients who underwent LTx with VV-ECMO between January 2017 and January 2019 were included. Enrollment of patients was suitable for weaning off ECMO immediately after surgery. Randomization was performed in the operating room. Postoperative outcomes were compared between the two groups. Besides, univariate and multivariable logistic regressions were performed to estimate risk of postoperative complications. Compared to VV-ECMO weaning immediately after LTx, delayed weaning was associated with shorter hospital length of stay (days, 31 vs. 46; P < 0.05), lower incidence of noninvasive ventilation (4.3% vs. 24.4%; P < 0.05), primary graft dysfunction (PGD) (6.4% vs. 29.3%; P < 0.05), atrial fibrillation (AF) (4.3% vs. 22%, P < 0.05), and respiratory failure (4.3% vs. 19.5%; P < 0.05). Multivariable logistic regressions revealed that VV-ECMO weaning after LTx was independently correlated with increased risk of developing PGD [odds ratio (OR), 5.97, 95% CI 1.16-30.74], AF (OR, 6.87, 95% CI 1.66-28.47) and respiratory failure (OR, 6.02, 95% CI 1.12-32.49) by comparison of delayed VV-ECMO weaning. Patients with delayed VV-ECMO weaning are associated with lower complications and short hospital length of stay, while it relates to longer mechanical ventilation. These findings suggest that delayed VV-ECMO after LTx can facilitate rehabilitation.

Soil microbial communities and their co-occurrence networks in response to long-term Pb-Zn contaminated soil in southern China.

Mining causes extreme heavy metal (HM) contamination to surrounding environments and poses threats to soil microbial community. The effects of HMs on soil microbial communities are not only related to their total amounts but also associated with the distribution of chemical fractions. However, the effects of chemical fractions on soil microbes and their interactions remain largely unclear. Here we investigated soil physicochemical properties and bacterial and fungal communities of soil samples from the control area and lightly (L), moderately (M), and heavily (H) contaminated areas, respectively, which were collected from long-term Pb-Zn slag contamination area in the southern China. The results showed that bacterial and fungal community composition and structure were significantly affected by HMs, while community diversity was not significantly affected by HMs. The critical environmental factor affecting bacterial and fungal communities was pH, and the impacts of chemical fractions on their changes were more significant than the total amounts of HMs. Variance partitioning analysis (VPA) revealed fungal community changes were mostly driven by HM total amounts, but bacterial community changes were mostly driven by soil chemical properties. Co-occurrence network indicated that interactions among species of fungal network were sparser than that of bacterial network, but fungal network was more stable, due to a more significant number of keystone taxa and a lower percentage of positive associations. These illustrated that the fungal community might serve as indicator taxa for HM-contaminated status, and specific HM-responsive fungal species such as Triangularia mangenotii, Saitozyma podzolica, and Cladosporium endophytica, and genus Rhizophagus can be considered relevant bioindicators due to their less relative abundance in contaminated areas. Additionally, HM-responsive bacterial OTUs representing five genera within Sulfurifustis, Thiobacillus, Sphingomonas, Qipengyuania, and Sulfurirhabdus were found to be tolerant to HM stress due to their high relative abundance in contaminated levels.

Association between neutrophil-to-lymphocyte ratio and diabetic kidney disease in type 2 diabetes mellitus patients: a cross-sectional study.

Aims: This investigation examined the possibility of a relationship between neutrophil-to-lymphocyte ratio (NLR) and diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients. Methods: Adults with T2DM who were included in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2020 were the subjects of the current cross-sectional investigation. Low estimated glomerular filtration rate (eGFR) (< 60 mL/min/1.73 m2) or albuminuria (urinary albumin-to-creatinine ratio (ACR) ≥ 30 mg/g) in T2DM patients were the diagnostic criteria for DKD. Weighted multivariable logistic regression models and generalized additive models were used to investigate the independent relationships between NLR levels with DKD, albuminuria, and low-eGFR. Additionally, we examined the relationships between DKD, albuminuria, and low-eGFR with other inflammatory markers, such as the aggregate index of systemic inflammation (AISI), systemic immune-inflammation index (SII), system inflammation response index (SIRI), and platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR). Their diagnostic capabilities were evaluated and contrasted using receiver operating characteristic (ROC) curves. Results: 44.65% of the 7,153 participants who were recruited for this study were males. DKD, albuminuria, and low-eGFR were prevalent in 31.76%, 23.08%, and 14.55% of cases, respectively. Positive correlations were seen between the NLR with the prevalences of DKD, albuminuria, and low-eGFR. Subgroup analysis and interaction tests revealed that the associations of NLR with DKD, albuminuria, and low-eGFR were not significantly different across populations. In addition, MLR, SII and SIRI showed positive associations with the prevalence of DKD. ROC analysis discovered that when compared to other inflammatory markers (MLR, PLR, SII, SIRI, and AISI), NLR may demonstrate more discriminatory power and accuracy in assessing the risk of DKD, albuminuria, and low-eGFR. Conclusion: Compared to other inflammatory markers (MLR, PLR, SII, SIRI, and AISI), NLR may serve as the more effective potential inflammatory marker for identifying the risk of DKD, albuminuria, and low-eGFR in US T2DM patients. T2DM patients with elevated levels of NLR, MLR, SII, and SIRI should be closely monitored for their potential risk to renal function.

High MCM8 expression correlates with unfavorable prognosis and induces immune cell infiltration in hepatocellular carcinoma.

BACKGROUND: MCM8 has been reported highly expressed in several human malignancies. However, its role in HCC has not yet been researched. METHODS: The prognostic significance of MCM8 mRNA expression was analyzed using datasets from TCGA and GEO databases. Immunohistochemistry (IHC) assay was used to detect the MCM8 protein expression in HCC tissues. The Cox regression analysis was employed to determine the independent prognostic value of MCM8. Then, we established a nomogram for OS and RFS prediction based on MCM8 protein expression. We analyzed the DNA methylation and genetic alteration of MCM8 in HCC. Moreover, GO, KEGG and GSEA were utilized to explore the potential biological functions of MCM8. Subsequently, we evaluate the correlations between MCM8 expression and composition of the tumor microenvironment as well as immunocyte infiltration ratio in HCC. RESULTS: MCM8 mRNA and protein were significantly overexpressed in HCC tissues. High MCM8 protein expression was an independent risk factor for OS and RFS of HCC patients. MCM8 expression is altered in 60% of queried HCC patients. In addition, higher methylation of the CpG site cg03098629, cg10518808, and 17230679 correlated with lower MCM8 levels. MCM8 expression correlated with cell cycle and DNA replication signaling. Moreover, MCM8 may be correlated with different compositions of the tumor microenvironment and immunocyte infiltration ratio in HCC. CONCLUSIONS: MCM8 was highly expressed in HCC tissues and was associated with poor prognosis. Meanwhile, high expression of MCM8 may induce immune cell infiltration and may be a promising prognostic biomarker for HCC.

Association between soft drink consumption types and risk of lung cancer and all-cancer: A prospective study of PLCO data.

Diet/sugar-free soft drinks are considered to be healthier than regular soft drinks. However, few studies have examined the relationship between the types of soft drinks (regular and diet/sugar-free) and lung cancer (LC)/all-cancer (AC) risk. In this study, we comprehensively assessed the influence of the type of soft drink consumption on LC/AC risk based on the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Multivariable Cox proportional hazards and competing risks Fine-Gray regression models adjusted for relevant confounders were used to estimate hazard ratios (HRs) and subdistribution HRs for different types of soft drink consumption. In the PLCO population, female subgroup, and the ever/current smoker subgroup, consumption of both regular and diet soft drinks was associated with a significantly reduced risk of LC compared with no soft drinks at all. For the non-lung cancer (NLC) risk, consumption of only diet soft drinks had a significant positive association for the total population and female subgroup. Based on our findings, it was suggested that partial replacement of regular soft drinks with diet soft drinks might be beneficial to LC prevention, especially for females and ever/current smokers. Additionally, completely replacing regular soft drinks with diet soft drinks might be detrimental to NLC prevention, especially for females.

Is compromised intestinal barrier integrity responsible for the poor prognosis in critically ill patients with pre-existing hyperglycemia?

BACKGROUND: Compromised intestinal barrier integrity can be independently driven by hyperglycemia, and both hyperglycemia and intestinal barrier injury are associated with poor prognosis in critical illness. This study investigated the intestinal barrier biomarkers in critically ill patients, to explore the role of compromised intestinal barrier integrity on the prognosis of critically ill patients with pre-existing hyperglycemia. METHODS: This was a retrospective observational study. The relationships between intestinal barrier biomarkers and glycated hemoglobin A1c (HbA1c), fasting blood glucose (FBG), indicators of clinical characteristics, disease severity, and prognosis in critically ill patients were investigated. Then the metrics mentioned above were compared between survivors and non-survivors, the risk factors of 90-day mortality were investigated by logistic regression analysis. Further, patients were divided into HbA1c < 6.5% Group and HbA1c ≥ 6.5% Group, metrics mentioned above were compared between these two groups. RESULTS: A total of 109 patients with critical illness were included in the study. D-lactate and lipopolysaccharide (LPS) were associated with sequential organ failure assessment (SOFA) score and 90-day mortality. LPS was an independent risk factor of 90-day mortality. DAO, NEU (neutrophil) proportion, temperature, lactate were lower in HbA1c ≥ 6.5% Group while D-lactate, LPS, indicators of disease severity and prognosis showed no statistical difference between HbA1c < 6.5% Group and HbA1c ≥ 6.5% Group. CONCLUSIONS: Intestinal barrier integrity is associated with the disease severity and prognosis in critical illness. Compromised intestinal barrier integrity might be responsible for the poor prognosis in critically ill patients with pre-existing hyperglycemia.

Impact of aging and oxidative stress on specific components of excitation contraction coupling in regulating force generation.

Muscle weakness associated with sarcopenia is a major contributor to reduced health span and quality of life in the elderly. However, the underlying mechanisms of muscle weakness in aging are not fully defined. We investigated the effect of oxidative stress and aging on specific molecular mechanisms involved in muscle force production in mice and skinned permeabilized single fibers in mice lacking the antioxidant enzyme CuZnSod (Sod1KO) and in aging (24-month-old) wild-type mice. Loss of muscle strength occurs in both models, potentially because of reduced membrane excitability with altered NKA signaling and RyR stability, decreased fiber Ca2+ sensitivity and suppressed SERCA activity via modification of the Cys674 residue, dysregulated SR and cytosolic Ca2+ homeostasis, and impaired mitochondrial Ca2+ buffering and respiration. Our results provide a better understanding of the specific impacts of aging and oxidative stress on mechanisms related to muscle weakness that may point to future interventions for countering muscle weakness.