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Byline: Juan. Yang, Haijing. Sui, Haihan. Song, Ronghong. Jiao, Xiaohui. Zhao Conclusions: Increased RDW may be considered as a biomarker of MCI. Background and Objective: Previous literature has reported that [...]

Background: Acute respiratory distress syndrome (ARDS) / acute lung injury (ALI) is a serious medical disease characterized by pulmonary dysfunction and inflammation. This study aims to determine the main molecular modules linked to ARDS and investigate the role of Fibulin-1 (FBLN1) in regulating ferroptosis in ARDS. Methods: Weighted Gene Co-expression Network Analysis (WGCNA) was employed on the GSE263867 dataset to find key modules associated with ALI. Differentially expressed genes (DEGs) and protein-protein interaction (PPI) networks were analyzed. MLE-12 cells were treated with lipopolysaccharide (LPS) to induce ferroptosis. In vitro studies were conducted to investigate the effects of FBLN1 and Transforming Growth Factor Beta 1 (TGF-β) overexpression on cell viability, oxidative stress markers, and ferroptosis-related proteins. Results: WGCNA identified the turquoise module as significantly negatively correlated with ARDS. Five key overlapping genes (GRIA1, OGN, COL14A1, FBLN1, and COL6A3) were significantly downregulated in ARDS samples. LPS treatment induced ferroptosis in MLE-12 cells, indicated by increased malondialdehyde (MDA), lipid reactive oxygen species (ROS), and ferrous iron (Fe2⁺) levels, and decreased cell viability and glutathione (GSH) levels. FBLN1 overexpression partially reversed these effects. Additionally, FBLN1 inhibited the TGF-β/Smad signaling pathway, as shown by decreased TGF-β and p-Smad protein levels. TGF-β overexpression exacerbated LPS-induced oxidative stress and ferroptosis, reducing cell viability and GSH levels. FBLN1 overexpression counteracted this effect, suggesting antagonistic roles for FBLN1 and TGF-β in regulating ferroptosis. Conclusion: This study highlights FBLN1 as a critical regulator of ferroptosis in ARDS. Targeting the TGF-β/Smad pathway to modulate FBLN1 expression offers a potential therapeutic strategy to alleviate oxidative stress and mitigate pulmonary injury in inflammatory lung diseases. [ABSTRACT FROM AUTHOR]

Oxidative stress and inflammation are at the root of a multitude of diseases. Treatment of these conditions is often necessary but current standard therapies to fight excessive reactive oxygen species (ROS) and inflammation are often ineffective or complicated by substantial safety concerns. Nanozymes are emerging nanomaterials with intrinsic enzyme‐like properties that hold great promise for effective cancer treatment, bacterial elimination, and anti‐inflammatory/anti‐oxidant therapy. While there is rapid progress in tailoring their catalytic activities as evidenced by the recent integration of single‐atom catalysts (SACs) to create next‐generation nanozymes with superior activity, selectivity, and stability, a better understanding and tuning of their safety profile is imperative for successful clinical translation. This review outlines the current applied safety assessment approaches and provides a comprehensive summary of the safety knowledge of therapeutic nanozymes. Overall, nanozymes so far show good in vitro and in vivo biocompatibility despite considerable differences in their composition and enzymatic activities. However, current safety investigations mostly cover a limited set of basic toxicological endpoints, which do not allow for a thorough and deep assessment. Ultimately, remaining research gaps that should be carefully addressed in future studies are highlighted, to optimize the safety profile of therapeutic nanozymes early in their pre‐clinical development. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is one of the most common intestinal disorders, with increasing global incidence and prevalence. Numerous therapeutic drugs are available but require intravenous administration and are associated with high toxicity and insufficient patient compliance. Here, an oral liposome that entraps the activatable corticosteroid anti-inflammatory budesonide was developed for efficacious and safe IBD therapy. The prodrug was produced via the ligation of budesonide with linoleic acid linked by a hydrolytic ester bond, which was further constrained into lipid constituents to form colloidal stable nanoliposomes (termed budsomes). Chemical modification with linoleic acid augmented the compatibility and miscibility of the resulting prodrug in lipid bilayers to provide protection from the harsh environment of the gastrointestinal tract, while liposomal nanoformulation enables preferential accumulation to inflamed vasculature. Hence, when delivered orally, budsomes exhibited high stability with low drug release in the stomach in the presence of ultra-acidic pH but released active budesonide after accumulation in inflamed intestinal tissues. Notably, oral administration of budsomes demonstrated favorable anti-colitis effect with only ∼7% mouse body weight loss, whereas at least ∼16% weight loss was observed in other treatment groups. Overall, budsomes exhibited higher therapeutic efficiency than free budesonide treatment and potently induced remission of acute colitis without any adverse side effects. These data suggest a new and reliable approach for improving the efficacy of budesonide. Our in vivo preclinical data demonstrate the safety and increased efficacy of the budsome platform for IBD treatment, further supporting clinical evaluation of this orally efficacious budesonide therapeutic. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the work was to establish a prediction model of mild cognitive impairment (MCI) progression based on intestinal flora by machine learning method. Method: A total of 1,013 patients were recruited, in which 87 patients with MCI finished a two-year follow-up. To establish a prediction model, 61 patients were randomly divided into a training set and 26 patients were divided into a testing set. A total of 121 features including demographic characteristics, hematological indicators, and intestinal flora abundance were analyzed. Results: Of the 87 patients who finished a two-year follow-up, 44 presented rapid progression. Model 1 was established based on 121 features with the accuracy 85%, sensitivity 85%, and specificity 83%. Model 2 was based on the first fifteen features of model 1 (triglyceride, uric acid, alanine transaminase, F-Clostridiaceae, G-Megamonas, S-Megamonas, G-Shigella, G-Shigella, S-Shigella, average hemoglobin concentration, G-Alistipes, S-Collinsella, median cell count, average hemoglobin volume, low-density lipoprotein), with the accuracy 97%, sensitivity 92%, and specificity 100%. Model 3 was based on the first ten features of model 1, with the accuracy 97%, sensitivity 86%, and specificity 100%. Other models based on the demographic characteristics, hematological indicators, or intestinal flora abundance features presented lower sensitivity and specificity. Conclusion: The 15 features (including intestinal flora abundance) could establish an effective model for predicting rapid MCI progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Lactate (L-lactate and D-lactate) is the main production of the Warburg effect, which is vital for carcinoma cell metabolism. This review retrospects the lactate isomer metabolism in the cancer progress. The related enzyme and proteins have been listed as prognostic biomarkers for cancers, and the lactate down-streamed molecular cancerogenic signaling is also introduced. This review will provide a new strategy for anticancer therapy that targets lactate metabolism. Lactate mediates multiple cell-intrinsic effects in cancer metabolism in terms of development, maintenance, and metastasis and is often correlated with poor prognosis. Its functions are undertaken as an energy source for neighboring carcinoma cells and serve as a lactormone for oncogenic signaling pathways. Indeed, two isomers of lactate are produced in the Warburg effect: L-lactate and D-lactate. L-lactate is the main end-production of glycolytic fermentation which catalyzes glucose, and tiny D-lactate is fabricated through the glyoxalase system. Their production inevitably affects cancer development and therapy. Here, we systematically review the mechanisms of lactate isomers production, and highlight emerging evidence of the carcinogenic biological effects of lactate and its isomers in cancer. Accordingly, therapy that targets lactate and its metabolism is a promising approach for anticancer treatment. [ABSTRACT FROM AUTHOR]

The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we estab-lish a rationale for eliminating HIV-1-infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences in the human genome represent the remnants of ancient infectious retroviruses. We show that the infection of [CD4.sup.+] T cells with HIV-1 resulted in transcription of the HML-2 lineage of HERV type K [HERV-K(HML-2)] and the expression of Gag and Env proteins. HERV-K(HML-2)-specific CD8+ T cells obtained from HIV-1-infected human subjects responded to HIV-1-infected cells in a Vif-dependent manner in vitro. Consistent with the proposed mode of action, a HERV-K(HML-2)-specific [CD8.sup.+] T cell clone exhibited comprehensive elimination of cells infected with a panel of globally diverse HIV-1, HIV-2, and SIV isolates in vitro. We identified a second T cell response that exhibited cross-reactivity between homologous HIV-1-Pol and HERV-K(HML-2)-Pol determinants, raising the possibility that homology between HIV-1 and HERVs plays a role in shaping, and perhaps enhancing, the T cell response to HIV-1. This justifies the consideration of HERV-K(HML-2)-specific and cross-reactive T cell responses in the natural control of HIV-1 infection and for exploring HERV-K(HML-2)-targeted HIV-1 vaccines and immunotherapeutics., Introduction The genetic diversity of HIV-1 is considerable, with amino acids in Env differing by as much as 20% within a subtype and by more than 35% between subtypes and [...]

Nanozymes are nanomaterials with intrinsic natural enzyme-like catalytic properties. They have received extensive attention and have the potential to be an alternative to natural enzymes. Increasing the atom utilization rate of active centers in nanozymes has gradually become a concern of scientists. As the limit of designing nanozymes at the atomic level, single-atom nanozymes (SAzymes) have become the research frontier of the biomedical field recently because of their high atom utilization, well-defined active centers, and good natural enzyme mimicry. In this review, we first introduce the preparation of SAzymes through pyrolysis and defect engineering with regulated activity, then the characterization and surface modification methods of SAzymes are introduced. The possible influences of surface modification on the activity of SAzymes are discussed. Furthermore, we summarize the applications of SAzymes in the biomedical fields, especially in those of reactive oxygen species (ROS) scavenging and antibacterial. Finally, the challenges and opportunities of SAzymes are summarized and prospected. [ABSTRACT FROM AUTHOR]

Objective: The manuscript aims to explore the relationship between power performance and SNPs of Chinese elite athletes and to create polygenic models. Methods: One hundred three Chinese elite athletes were divided into the power group (n = 60) and endurance group (n = 43) by their sports event. Best standing long jump (SLJ) and standing vertical jump (SVJ) were collected. Twenty SNPs were genotyped by SNaPshot. Genotype distribution and allele frequency were compared between groups. Additional genotype data of 125 Chinese elite athletes were used to verify the screened SNPs. Predictive and identifying models were established by multivariate logistic regression analysis. Results: ACTN3 (rs1815739), ADRB3 (rs4994), CNTFR (rs2070802), and PPARGC1A (rs8192678) were significantly different in genotype distribution or allele frequency between groups (p < 0.05). The predictive model consisted of ACTN3 (rs1815739), ADRB3 (rs4994), and PPARGC1A (rs8192678), the area under curve (AUC) of which was 0.736. The identifying model consisted of body mass index (BMI), standing vertical jump (SVJ), ACTN3, ADRB3, and PPARGC1A, the area under curve (AUC) of which was 0.854. Based on the two models, nomograms were created to visualize the results. Conclusion: Two models can be used for talent identification in Chinese athletes, among which the predictive model can be used in adolescent athletes to predict development potential of power performance and the identifying one can be used in elite athletes to evaluate power athletic status. These can be applied quickly and visually by using nomograms. When the score is more than the 130 or 148 cutoff, it suggests that the athlete has a good development potential or a high level for power performance. [ABSTRACT FROM AUTHOR]

Abstract Background We previously reported that cynomolgus monkey (CM) TRIM5α could restrict human immunodeficiency virus type 2 (HIV-2) strains carrying a proline at the 120th position of the capsid protein (CA), but it failed to restrict those with a glutamine or an alanine. In contrast, rhesus monkey (Rh) TRIM5α could restrict all HIV-2 strains tested but not simian immunodeficiency virus isolated from macaque (SIVmac), despite its genetic similarity to HIV-2. Results We attempted to identify the viral determinant of SIVmac evasion from Rh TRIM5α-mediated restriction using chimeric viruses formed between SIVmac239 and HIV-2 GH123 strains. Consistent with a previous study, chimeric viruses carrying the loop between α-helices 4 and 5 (L4/5) (from the 82nd to 99th amino acid residues) of HIV-2 CA were efficiently restricted by Rh TRIM5α. However, the corresponding loop of SIVmac239 CA alone (from the 81st to 97th amino acid residues) was not sufficient to evade Rh TRIM5α restriction in the HIV-2 background. A single glutamine-to-proline substitution at the 118th amino acid of SIVmac239 CA, corresponding to the 120th amino acid of HIV-2 GH123, also increased susceptibility to Rh TRIM5α, indicating that glutamine at the 118th of SIVmac239 CA is necessary to evade Rh TRIM5α. In addition, the N-terminal portion (from the 5th to 12th amino acid residues) and the 107th and 109th amino acid residues in α-helix 6 of SIVmac CA are necessary for complete evasion from Rh TRIM5α-mediated restriction. A three-dimensional model of hexameric GH123 CA showed that these multiple regions are located on the CA surface, suggesting their direct interaction with TRIM5α. Conclusion We found that multiple regions of the SIVmac CA are necessary for complete evasion from Rh TRIM5α restriction.

Background: The Ebola virus causes an acute, serious illness which is often fatal if untreated. However, factors affecting the survival of the disease remain unclear. Here, we investigated the prognostic factors of Ebola virus disease (EVD) through various statistical models. Methodology/Principal Findings: Sixty three laboratory-confirmed EVD patients with relatively complete clinical profiles were included in the study. All the patients were recruited at Jui Government Hospital, Sierra Leone between October 1st, 2014 and January 18th, 2015. We first investigated whether a single clinical presentation would be correlated with the survival of EVD. Log-rank test demonstrated that patients with viral load higher than 106 copies/ml presented significantly shorter survival time than those whose viral load were lower than 106 copies/ml (P = 0.005). Also, using Pearson chi-square test, we identified that chest pain, coma, and viral load (>106 copies/ml) were significantly associated with poor survival of EVD patients. Furthermore, we evaluated the effect of multiple variables on the survival of EVD by Cox proportional hazards model. Interestingly, results revealed that patient’s age, symptom of confusion, and viral load were the significantly associated with the survival of EVD cases (P = 0.017, P = 0.002, and P = 0.027, respectively). Conclusions/Significance: These results suggest that age, chest pain, coma, confusion and viral load are associated with the prognosis of EVD, in which viral load could be one of the most important factors for the survival of the disease. [ABSTRACT FROM AUTHOR]

Fibroblast growth factors and their receptors (FGFRs) play important roles in blood system. FGFR4 rs351855 (Gly388Arg) polymorphism has shown to be a risk factor for many diseases. The aim of this study was to investigate the association between FGFR4 polymorphisms and the susceptibility to non-Hodgkin lymphoma (NHL) in the Chinese population. We identified two polymorphisms in the FGFR4 gene, rs351855G/A (Gly388Arg), and rs147603016G/A, by polymerase chain reaction-restriction fragment length polymorphism in 412 NHL cases and 476 healthy controls. Results showed that frequencies of AA genotype and A allele in rs351855 (Gly388Arg) polymorphism were significantly higher in patients than in controls (odds ratio (OR) 2.12, 95 % confidence intervals (CI) 1.99-3.48, P < 0.0001; OR 1.45, 95 % CI 1.21-1.88, P < 0.0001, respectively; data were adjusted for age and sex). The rs147603016G/A polymorphism did not show any correlation with NHL. When analyzing the survival time of NHL patients with FGFR4 rs351855G/A polymorphism, cases with AA genotype had significantly shorter survival time compared to the patients with GG and GA genotypes ( P = 0.002). These results suggested polymorphism in FGFR4 gene was associated with increased susceptibility to NHL and could be used as a prognostic marker for this malignancy. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a severe form of diffuse lung disease, which imposes a substantial health burden all over the world. The immune system plays a key role in the development of ALI. The aim of the study was to investigate the expression of cytotoxic T-lymphocyte antigen 4 (CTLA4) in ALI. Levels of CTLA4 were tested on CD4+ and CD8+ T cells in 62 ALI cases and 75 healthy controls by flow cytometry. Data revealed that prevalence of CTLA4 on CD4+ T cells was significantly increased in ALI patients (3.7%±2.1%) than in controls (0.7%±0.3%). Similarly, the proportion of CTLA4 on CD8+ T cells was also significantly elevated in cases (1.0%±0.4% versus 0.5%±0.1%, p<0.05). Further analysis showed that the frequency of CTLA4+CD4+ T cells was positively correlated with the score of Acute Physiology and Chronic Health Evaluation II (APACHE II) ( p=0.0005). In addition, when investigating CTLA4 expression with ALI patient mortality, we observed that the level of CTLA4+CD4+ T cells in patients was higher at the time before death than at the time of recruitment ( p=0.001). These data suggested that CTLA4 was involved in the pathogenesis and progression of ALI and could be used as a potential target for treating this disease. [ABSTRACT FROM AUTHOR]

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy worldwide. Interleukin-2 (IL-2) plays a key role in the proliferation of T cells and natural killer cells. It has been reported that polymorphisms in the IL-2 gene are associated with various cancers. The aim of this study was to examine the effect of polymorphisms in the IL-2 gene on the development of NHL in the Chinese population. IL-2-330T/G and +114T/G polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism in 438 NHL cases and 482 age-matched healthy controls. Data were analyzed using the Chi-square test. Results showed that individuals with −330TG genotype or −330GG genotype had significantly increased susceptibility to NHL (Odds ratio [OR]=1.40, 95% confidence interval [CI]: 1.05-1.85, p=0.020 and OR=2.04, 95%CI: 1.28-3.24, p=0.002). Meanwhile, the +114T/G polymorphism did not show any correlation with NHL. When analyzing the haplotypes of these two polymorphisms, the prevalence of −330G/+114T haplotype was significantly higher in NHL cases than in controls (OR=1.45, 95%CI: 1.12-1.88, p=0.005). These data indicate that IL-2 gene polymorphisms may be new risk factors for NHL. [ABSTRACT FROM AUTHOR]

Chemokines are potent proinflammatory cytokines that are implicated in numerous inflammatory diseases. Monocyte chemoattractant protein-1 (MCP-1) and its receptor CC chemokine receptor-2 (CCR2) play a major role in the recruitment of inflammatory cells to the lungs of patients with chronic obstructive pulmonary disease (COPD). We investigated a possible association between polymorphisms in MCP-1 and CCR2 genes ( MCP-1 −2518 A/G and CCR2 190G/A or V64I) and the development of COPD. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism in 386 COPD cases and 398 age-matched healthy controls. Frequency of MCP-1 2518GG genotype for cases and controls was 0.396 and 0.324, respectively; individuals who had the GG genotype had a 1.59-fold increased risk of COPD ( p=0.036). Frequency of CCR2 190AA (64I/64I) genotype for cases and controls was 0.285 and 0.21, respectively; subjects carrying the 64I/64I genotype had a 2.04-fold increased risk of COPD compared with the wild-type genotype ( p=0.001). When analyzing the allele combination of these two polymorphisms, the combinations MCP-1-A/ CCR2-A and MCP-1-G/ CCR2-A were detected in significantly higher numbers in COPD cases than in healthy controls (odds ratio [OR]=1.50, 95% confidence interval [CI]: 1.04-2.17, p=0.032; and OR=1.89, 95% CI: 1.38-2.60, p=7.38×10−5). These data suggest that MCP-1 −2518 A/G and CCR2 190G/A polymorphisms are new risk factors for COPD. [ABSTRACT FROM AUTHOR]