Cell-Penetrating Peptide TAT-HuR-HNS3 Suppresses Proinflammatory Gene Expression via Competitively Blocking Interaction of HuR with Its Partners.

Proinflammatory cytokines/chemokines are commonly regulated by RNA-binding proteins at posttranscriptional levels. Human Ag R (HuR)/embryonic lethal abnormal vision-like 1 (ELAVL1) is one of the well-characterized RNA-binding proteins that increases the stability of short-lived mRNAs, which encode proinflammatory mediators. HuR employs its nucleocytoplasmic shuttling sequence (HNS) domain, interacting with poly(ADP-ribose) polymerase 1 (PARP1), which accounts for the enhanced poly-ADP-ribosylation and cytoplasmic shuttling of HuR. Also by using its HNS domain, HuR undergoes dimerization/oligomerization, underlying the increased binding of HuR with proinflammatory cytokine/chemokine mRNAs and the disassociation of the miRNA-induced silencing complex from the targets. Therefore, competitively blocking the interactions of HuR with its partners may suppress proinflammatory mediator production. In this study, peptides derived from the sequence of the HuR-HNS domain were synthesized, and their effects on interfering HuR interacting with PARP1 and HuR itself were analyzed. Moreover, cell-penetrating TAT-HuR-HNS3 was delivered into human and mouse cells or administered into mouse lungs with or without exposure of TNF-α or LPS. mRNA levels of proinflammatory mediators as well as neutrophil infiltration were evaluated. We showed that TAT-HuR-HNS3 interrupts HuR-PARP1 interaction and therefore results in a lowered poly-ADP-ribosylation level and decreased cytoplasmic distribution of HuR. TAT-HuR-HNS3 also blocks HuR dimerization and promotes Argonaute 2-based miRNA-induced silencing complex binding to the targets. Moreover, TAT-HuR-HNS3 lowers mRNA stability of proinflammatory mediators in TNF-α-treated epithelial cells and macrophages, and it decreases TNF-α-induced inflammatory responses in lungs of experimental animals. Thus, TAT-HuR-HNS3 is a promising lead peptide for the development of inhibitors to treat inflammation-related diseases.

Structural effects of water clusters on viscosity at high shear rates.

In this study, we use molecular dynamics simulations of liquid water to investigate how shear thinning affects the viscosity of liquid water by structural changes of the hydrogen bond network. The effect of shear on viscosity can be divided into two parts: shear-induced destruction of the hydrogen bond network and the influence of the water structure on shear viscosity. First, strong shear destroys tetrahedral structures and thus reduces the connectivity of the hydrogen bond network. It is mainly because shear deformation, characterized by compression and expansion axes, respectively, triggers the destruction and formation of hydrogen bonds, resulting in anisotropic effects on water structures. At the same time, shear destroys large clusters and enhances the formation of small ones, resulting in a decrease in average cluster sizes. Second, the change of viscosity obeys a power law relationship with the change of hydrogen bond structures, highlighting a one-to-one correspondence between structure and property. Meanwhile, in order to explain why the structure affects viscosity, we define hydrogen-bond viscosity and find that the cooperative motion of the water structures can promote momentum transfer in the form of aggregations. Hydrogen-bond viscosity accounts for 5%-50% of the total viscosity. Our results elucidate that water structures are the important structural units to explain the change of water properties.

Chlordane exposure impairs the growth and behavior of Drosophila.

Chlordane, a previously extensively utilized insecticidal pesticide, has since been prohibited, however, owing to its limited degradability, it continues to persist significantly in soil and water reservoirs, subsequently accumulating within plant and animal organisms, representing a substantial threat to human health. Despite extensive research conducted over the past few decades to investigate the toxic effects of chlordane, there remains a notable dearth of studies focusing on its impact on sleep activity. Therefore, in this study, the effects of short-term and long-term exposure to chlordane on the activity and sleep of Drosophila were investigated. When exposed to chlordane at a concentration of 1 µM, Drosophila lost body weight, decreased body size and resulted in lipid metabolism disorders. In addition, chlordane exposure altered the arousal and sleep behaviors of Drosophila. Short-term exposure to chlordane resulted in an increase in night-time sleep duration, while long-term exposure to chlordane resulted in an increase in activity and a decrease in sleep, as evidenced by a decrease in the duration of each sleep session and the appearance of sleep fragmentation. Under conditions of long-term chlordane exposure, reactive oxygen species levels were significantly up-regulated in Drosophila. Our results suggest that long-term chlordane exposure triggers oxidative stress damage in Drosophila, leading to sleep disruption. This study offers novel insights into the harmful impacts of environmental pollutants on human sleep patterns and proposes that mitigating the presence of chlordane in the environment could potentially contribute to the reduction of global sleep disorder prevalence.

Femoral Tunnel Malposition, Increased Lateral Tibial Slope, and Decreased Notch Width Index Are Risk Factors for Non-Traumatic Anterior Cruciate Ligament Reconstruction Failure.

PURPOSE: To identify risk factors for patients who sustain nontraumatic anterior cruciate ligament reconstruction (ACLR) failure. METHODS: A retrospective analysis was performed on patients undergoing primary or revision ACLR in our institution between 2010 and 2018. Patients sustaining insidious-onset knee instability without history of trauma were identified as nontraumatic ACLR failure and assigned to the study group. The control group of subjects who showed no evidence of ACLR failure with minimum 48-month follow-up were matched in a 1:1 ratio based on age, sex, and body mass index. Anatomic parameters including tibial slope (lateral [LTS], medial [MTS]); tibial plateau subluxation (lateral [LTPsublx], medial [MTPsublx]); notch width index (NWI); and lateral femoral condyle ratio were measured with magnetic resonance imaging or radiography. Graft tunnel position was assessed using 3-dimensional computed tomography and reported in 4 dimensions: deep-shallow ratio (DS ratio) and high-low ratio for femoral tunnel, anterior-posterior ratio and medial-lateral ratio for tibial tunnel. Interobserver and intraobserver reliability were evaluated by the intraclass correlation coefficient (ICC). Patients' demographic data, surgical factors, anatomic parameters, and tunnel placements were compared between the groups. Multivariate logistic regression and receiver operating characteristic curve analysis was used to discriminate and assess the identified risk factors. RESULTS: A total of 52 patients who sustained nontraumatic ACLR failure were included and matched with 52 control subjects. Compared to patients with intact ACLR, those who sustained nontraumatic ACLR failure showed significantly increased LTS, LTPsublx, MTS, and deceased NWI (all P < .001). Moreover, the average tunnel position in the study group was significantly more anterior (P < .001) and superior (P = .014) at the femoral side and more lateral (P = .002) at the tibial side. Multivariate regression analysis identified LTS (odds ratio [OR] = 1.313; P = .028), DS ratio (OR = 1.091; P = .002), and NWI (OR = 0.813; P = .040) as independent predictors of nontraumatic ACLR failure. LTS appeared to be the best independent predictive factor (area under the curve [AUC] = 0.804; 95% confidence interval [CI], 0.721-0.887), followed by DS ratio (AUC = 0.803; 95% CI, 0.717-0.890), and NWI (AUC = 0.756; 95% CI, 0.664-0.847). The optimal cutoff values were 6.7° for increased LTS (sensitivity = 0.615, specificity = 0.923); 37.4% for increased DS ratio (sensitivity = 0.673, specificity = 0.885); and 26.4% for decreased NWI (sensitivity = 0.827, specificity = 0.596). Intraobserver and interobserver reliability was good to excellent, with ICCs ranging from 0.754 to 0.938 for all radiographical measurements. CONCLUSIONS: Increased LTS, decreased NWI, and femoral tunnel malposition are predictive risk factors for nontraumatic ACLR failure. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Trajectory and predictors of family function in caregivers of stroke survivors: A longitudinal study of the first 6 months after stroke.

AIMS: This study aimed to investigate the trajectory and predictors of family function in caregivers of stroke survivors during the first 6 months after the first episode of stroke. DESIGN: Longitudinal study. METHODS: A total of 288 primary caregivers of patients with first-time stroke were recruited from seven tertiary hospitals in China between July 2020 and March 2021. The following characteristics were assessed by caregivers at hospitalization (T0) and at 1 month (T1), 3 months (T2) and 6 months (T3) after the stroke: family function, general self-efficacy, social support, coping style, caregiver burden, and sociodemographic and clinical data. RESULTS: Family function scores among caregivers of stroke survivors were highest in the resolve dimension and lowest in the growth and adaptation dimensions within the first 6 months. The percentages of families with low functioning were 34.7%, 33.3%, 24.8% and 17.7% at T0, T1, T2 and T3, respectively. The generalized estimating equation model revealed that family function in caregivers increased over the first 6 months (Exp(B) = 1.415-2.689, p < .05). The following factors were identified as predictors of family functioning: caregiver's age, education, residential district, self-efficacy, social support utilization and caregiver burden. CONCLUSIONS: Family function of caregivers of stroke survivors gradually increased during the first 6 months after stroke. However, some families demonstrated poor functioning. Caregivers' age, education, caregiver burden, self-efficacy and social support utilization could predict family function over time. IMPACT: Empirical data on family function in families of stroke survivors are important for developing psychosocial interventions that can help families adapt to stroke. This study found that families of stroke survivors were likely to be dysfunctional in the first 6 months after stroke, particularly in family growth and adaptation. Therefore, reducing caregiver burden and promoting self-efficacy and social support utilization can help restore family functioning early after stroke. PATIENT OR PUBLIC CONTRIBUTION: Stroke caregivers from seven hospitals in China were involved in this study and had the right to be informed of the main findings. A few patients were informed of the research results, who contributed to the dissemination.

Nursing management of cognitive dysfunction in adults with brain injury: Summary of best evidence-practiced strategies.

OBJECTIVE: To summarize the best evidence-based strategies for the management of cognitive dysfunction in patients with brain injury and to provide a reference for clinical nursing practice. DESIGN: Review. METHODS: The review was presented using PRISMA guidelines. A systematic search of evidence on the management of cognitive dysfunction in patients with brain injury was conducted in computerized decision systems, guideline websites, professional association websites and comprehensive databases from the date of creation to 21 June 2023. The types of evidence included were clinical decision making, guidelines, evidence summaries, best practices, recommended practices, expert consensus, systematic reviews and meta-analyses. Two researchers trained in evidence-based methodological systems independently evaluated the quality of the literature and extracted, integrated and graded the evidence for inclusion. RESULTS: A total of 20 articles were selected, including nine guidelines, three expert consensus articles, one clinical practice article and seven systematic reviews, and the overall quality of the literature was high. Thirty pieces of evidence were summarized in seven areas: assessment, multidisciplinary team, rehabilitation program, cognitive intervention, exercise intervention, music intervention and medication management. CONCLUSIONS: This study summarizes the latest evidence on the management of cognitive dysfunction in the care of adults with brain injury and provides a reference for clinical nursing practice. The best evidence should be selected for localized and individualized application in clinical work, and the best evidence should be continuously updated to standardize nursing practice. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Patients with cognitive impairment after brain injury often suffer from memory loss, attention deficit and disorientation and are unable to have a normal life and experience much enjoyment, which seriously affects their physical and mental health and creates a great burden of care for their families and society. Best evidence-based strategies for the nursing management of cognitive impairment in brain injury are essential for standardizing clinical nursing practice and providing timely, professional, systematic and comprehensive nursing interventions for patients. REPORTING METHOD: This review is reported following the PRISMA 2020 statement guidelines, as applicable, to enhance transparency in reporting the evidence synthesis. TRIAL AND PROTOCOL REGISTRATION: This study has been registered with the Fudan University Centre for Evidence-based Nursing, a JBI Centre of Excellence under registration number ES20232566, http://ebn.nursing.fudan.edu.cn/myRegisterList. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

The efficacy of medial meniscal posterior Root tear Repair with or without high tibial osteotomy: a systematic review.

BACKGROUND: Medial meniscal posterior root tear (MMPRTs) is a common lesion of the knee joint, and repair surgery is a well-established treatment option. However, patients with obvious varus alignment are at an increased risk for MMPRT and can suffer from a greater degree of medial meniscus extrusion, which leads to the development of osteoarthritis following repair. The efficacy of high tibial osteotomy (HTO) as a means of correcting this malformation, and its potential benefits for MMPRT repair, remains unclear. PURPOSE: To explore whether HTO influenced the outcome of MMPRT repair in clinical scores and radiological findings. STUDY DESIGN: Systematic review. METHODS: According to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines, we searched PubMed, Embase, Web of Science, and the Cochrane Library databases for studies reporting the outcomes of MMPRT repair and extracted data about characteristics of patients, clinical functional scores and radiologic outcomes. One reviewer extracted the data and 2 reviewers assessed the risk of bias and performed a synthesis of the evidence. Articles were eligible if they reported the results of MMPRT repair with exact mechanical axis (registered in the International Prospective Register of Systematic Reviews, CRD42021292057). RESULTS: Fifteen studies with 625 cases of high methodological quality were identified. Eleven studies were assigned to the MMPRT repair group (M) with 478 cases performing MMPRT repair only, and others belonged to the MMPRT repair and HTO group (M and T) performing HTO and MMPRT repair. Most of the studies had significantly improved clinical outcome scores, especially in M groups. And the radiologic outcomes showed that the osteoarthritis deteriorated in both groups with similar degree in about 2-year follow-up. CONCLUSION: HTO is a useful supplement in treating MMPRT patients with severe osteoarthritis and the clinical and radiological outcomes were similar with MMPRT repair alone. Which would be better for patients' prognosis generally, performing MMPRT repair alone or a combination of HTO and MMPRT repair, was still controversial. We suggested taking K-L grade into account. Large-scale randomized control studies were called for in the future to help make better clinical decisions. LEVEL OF EVIDENCE: III.

Increased Lateral Femoral Condyle Ratio Measured by Magnetic Resonance Imaging Is Associated With Anterior Cruciate Ligament Rerupture.

PURPOSE: To investigate the association between lateral femoral condyle ratio (LFCR) measured by magnetic resonance imaging (MRI) and anterior cruciate ligament (ACL) rerupture after anatomic ACL reconstruction (ACLR) and to compare the diagnostic accuracy between MRI and radiograph measurements. METHODS: A retrospective review was conducted on patients who underwent anatomic ACLR in our institution between 2015 and 2018. Patients who experienced rerupture after ACLR were identified and matched 1:1 with control patients who showed no evidence of graft failure during a minimum 48-month follow-up. The matching criteria included age, sex, and body mass index. LFCR was measured on MRI scans and radiographs of the affected limb. Patients' characteristics, surgical features, and anatomic measurements were compared between groups. Conditional logistic regression was performed to investigate whether MRI-measured LFCR is a risk factor for ACL rerupture. The optimal cutoff value was determined by receiver operating characteristic curves (ROC). Delong's test was performed to compare the diagnostic accuracy between MRI and radiograph measurements. RESULTS: A total of 72 patients who sustained ACL rerupture were included and matched with 72 control subjects. Compared to patients with intact ACLR, those who sustained ACL rerupture showed a significant increase in LFCR on MRI scans (63.38% ± 2.26% [95% CI, 62.84%-63.91%] vs 61.10% ± 2.19% [95% CI, 60.59%-61.61%], P < .001). An MRI-measured LFCR >62.18% was set as the cutoff point to discern patients at a higher risk of graft failure after anatomic ACLR, with sensitivity and specificity of 75.0% and 70.8%, respectively. MRI-measured LFCR demonstrated superior diagnostic accuracy during ROC curve analysis, achieving a higher area under the curve compared to radiograph-measured LFCR (0.783 ± 0.051 vs 0.668 ± 0.060, P = .041). CONCLUSIONS: The study found that MRI-measured LFCR was associated with ACL rerupture. A cutoff value of 62.18% was determined, which can help identify patients at a higher risk of rerupture. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

There is no difference in the efficacy of anterior cruciate ligament reconstruction using autograft combined with or without ligament augmentation: a systematic review and meta-analysis.

PURPOSE: This study aims to determine the efficacy of anterior cruciate ligament reconstruction (ACLR) using autograft combined with or without ligament augmentation. METHODS: A computerized search of the databases was conducted, including PubMed, Web of Science, Embase, Scopus and the Cochrane Library. Only prospective or retrospective comparative studies with a minimum 2-year follow-up were considered for inclusion. Two independent reviewers performed data extraction and methodological quality assessment. A Mantel-Haenszel analysis was used for the pooling of results. Sensitivity analysis was performed to maintain the stability of results. The egger test was applied to assess the publication bias. RESULTS: Fourteen studies were included. The total cohort was 1353 patients (non-augmented group: 763 patients; augmented group: 590 patients). There were three Randomized Controlled Trials (RCTs, Level I), six retrospective comparative studies (Level III) and five case-control studies (Level III). The follow-up rate was ≥ 88% and the follow-up periods were ≥ 24 months in all included studies. The augmented graft used to compare with autograft included the Ligament Augmentation Device (LAD), the Ligament Advanced Reinforcement System (LARS) artificial ligament, FiberTape, hamstring tendon allograft, degradable poly (urethane urea). No significant differences were observed between the augmented and non-augmented groups regarding postoperative patient-reported outcomes (PROs), including the International Knee Documentation Committee score, Lysholm score and Tegner score, knee laxity, including KT-1000, side-to-side difference, Lachman test and pivot shift and rate of graft failure. CONCLUSIONS: ACLR using autografts combined with ligament augmentation shows no advantages in PROs, knee laxity and graft failure rate compared with using autografts only. LEVEL OF EVIDENCE: Level III. TRIAL REGISTRATION: The research protocol was registered at the PROSPERO database (CRD42022324784).

The apex of the deep cartilage is a stable landmark to position the femoral tunnel during remnant-preserving anterior cruciate ligament reconstruction.

PURPOSE: The aim of this retrospective cohort study was to investigate whether the apex of the deep cartilage (ADC) could help surgeons position the femoral tunnel accurately in remnant-preserving anterior cruciate ligament (ACL) reconstruction (ACLR). METHODS: In the current retrospective cohort study, a total of 134 patients who underwent ACLR between 2016 and 2020 were included. The femoral tunnel position was located using ADC as the landmark. The patients were divided into two groups: the remnant-preserving group (RP group, n = 68) underwent remnant-preserving ACLR, and the nonremnant group (NRP group, n = 66) underwent traditional ACLR with remnant removal. Postoperatively, the femoral tunnel position was evaluated on 3D-CT. The length from the ADC to the shallow cartilage margin (L) and to the centre of the femoral tunnel (l) and the length from the centre of the femoral tunnel to a low cartilage ratio in the direction from high to low (H) were measured. RESULTS: The l/L values of the RP and NRP groups were both 0.4 ± 0.1 after rounding (n.s.), and the H values were 9.3 ± 1.6 mm and 9.3 ± 1.7 mm, respectively (n.s.). There was no significant difference in l/L or H between the two groups. The estimation plot also showed high consistency of H and l/L of the two groups. The inter- and intraobserver reliability of I, L, l/L, and H were almost perfect. CONCLUSIONS: The apex of the deep cartilage is a good landmark for positioning the femoral tunnel in remnant-preserving ACL reconstruction. LEVEL OF EVIDENCE: Level III.

Hierarchical clustering analysis of hydrogen bond networks in aqueous solutions.

To understand the relation between the macroscopic properties and microscopic structure of hydrogen bond networks in solutions, we introduced a hierarchical clustering method to analyze the typical configurations of water clusters in this type of network. Regarding hydrogen bonds as frames, the rings, fragments and clusters are defined and analyzed to provide a comprehensive perspective for the distributional and dynamic characteristics of the hydrogen-bonding network in NaCl solution at different concentrations. The properties of the radial distribution function and hydrogen bonds are first analyzed. Destruction and shorter lifetimes of hydrogen bonds are observed in solutions. In further analysis of the two-dimensional configuration, i.e., ring, and three-dimensional configuration, i.e., fragment, the average number, size and lifetime of these structures consistently decrease as the concentration increases. Ionic effects on disrupting rings and fragments are significant in the first hydration shell, especially with sodium cations, and these effects weaken beyond the first hydration shell. Regarding the clusters obtained using the Louvain algorithm, our results indicate that clusters break and become smaller as the NaCl concentration increases. The presence of ions also leads to the isolation of clusters and therefore the inhibition of changes. The lifetime of clusters increases with NaCl concentration, indicating the slowed breakage and reformation of clusters in NaCl solutions. This method can be further applied to quantitatively characterize hydrogen bond networks to elucidate more properties of aqueous solutions.

Usability evaluation of mHealth apps for elderly individuals: a scoping review.

BACKGROUND: Usability is a key factor affecting the acceptance of mobile health applications (mHealth apps) for elderly individuals, but traditional usability evaluation methods may not be suitable for use in this population because of aging barriers. The objectives of this study were to identify, explore, and summarize the current state of the literature on the usability evaluation of mHealth apps for older adults and to incorporate these methods into the appropriate evaluation stage. METHODS: Electronic searches were conducted in 10 databases. Inclusion criteria were articles focused on the usability evaluation of mHealth apps designed for older adults. The included studies were classified according to the mHealth app usability evaluation framework, and the suitability of evaluation methods for use among the elderly was analyzed. RESULTS: Ninety-six articles met the inclusion criteria. Research activity increased steeply after 2013 (n = 92). Satisfaction (n = 74) and learnability (n = 60) were the most frequently evaluated critical measures, while memorability (n = 13) was the least evaluated. The ratios of satisfaction, learnability, operability, and understandability measures were significantly related to the different stages of evaluation (P < 0.05). The methods used for usability evaluation were questionnaire (n = 68), interview (n = 36), concurrent thinking aloud (n = 25), performance metrics (n = 25), behavioral observation log (n = 14), screen recording (n = 3), eye tracking (n = 1), retrospective thinking aloud (n = 1), and feedback log (n = 1). Thirty-two studies developed their own evaluation tool to assess unique design features for elderly individuals. CONCLUSION: In the past five years, the number of studies in the field of usability evaluation of mHealth apps for the elderly has increased rapidly. The mHealth apps are often used as an auxiliary means of self-management to help the elderly manage their wellness and disease. According to the three stages of the mHealth app usability evaluation framework, the critical measures and evaluation methods are inconsistent. Future research should focus on selecting specific critical measures relevant to aging characteristics and adapting usability evaluation methods to elderly individuals by improving traditional tools, introducing automated evaluation tools and optimizing evaluation processes.

[Progress on the design and optimization of antimicrobial peptides].

Antimicrobial peptides (AMPs) are a class of peptides widely existing in nature with broad-spectrum antimicrobial activity. It is considered as a new alternative to traditional antibiotics because of its unique mechanism of antimicrobial activity. The development and application of natural AMPs are limited due to their drawbacks such as low antimicrobial activity and unstable metabolism. Therefore, the design and optimization of derived peptides based on natural antimicrobial peptides have become recent research hotspots. In this paper, we focus on ribosomal AMPs and summarize the design and optimization strategies of some related derived peptides, which include reasonable primary structure modification, cyclization strategy and computer-aided strategy. We expect to provide ideas for the design and optimization of antimicrobial peptides and the development of anti-infective drugs through analysis and summary in this paper.

MiR-802 causes nephropathy by suppressing NF-κB-repressing factor in obese mice and human.

Obesity is associated with significant microvascular complications including renal injuries and may induce end-stage renal disease. Emerging studies have demonstrated microRNAs (miRNAs) are potential mediators in the pathophysiological process of nephropathy. The present study aimed to investigate the role of miR-802 in obesity-related nephropathy and potential molecular mechanisms. Through utilizing obese mouse model and human subjects, we explored the therapeutic benefits and clinical application of miR-802 in protecting against nephropathy. Renal miR-802 level was positively correlated with functional parameters, including blood urea nitrogen and creatinine in obese mice. Specific silencing of renal miR-802 improved high fat diet (HFD)-induced renal dysfunction, structural disorders and fibrosis. The up-regulated inflammatory response and infiltrated macrophages were also significantly decreased in miR-802 inhibitor-treated obese mice. Mechanistically, miR-802 directly bond to 3'-UTR of NF-κB-repressing factor (NRF) and suppressed its expression. In clinical study, the circulating miR-802 level was significantly increased in obese subjects, and positively correlated with plasma creatinine level but negatively correlated with creatinine clearance. Taken together, our findings provided evidence that miR-802/NRF signalling was an important pathway in mediating obesity-related nephropathy. It is a possible useful clinical approach of treating miR-802 inhibitor to combat nephropathy.

Immune response of interferon-γ-inducible lysosomal thiol reductase (GILT) from Chinese sturgeon (Acipenser sinensis) to microbial invasion and its antioxdative activity in lipopolysaccharides-treated mammalian dentritic cells.

Interferon-γ-inducible lysosomal thiol reductase (GILT) plays an important role in the major histocompatibility complex-restricted antigen processing of endocytosed proteins via catalyzing the disulfide bond reduction in the endocytic pathway. Here, the cDNA of Chinese sturgeon (Acipenser sinensis) GILT (CsGILT) was cloned. It contained an open reading frame of 762 nucleotides encoding a protein of 254 amino acids with an estimated molecular weight of 28.1 kDa. The characteristic structural features, including a signature sequence CQHGX2ECX2NX4C, a CXXC motif, two potential N-glycosylation sites, and eight conserved cysteines were detected in the deduced amino acid sequence of CsGILT. CsGILT was widely expressed in Chinese sturgeon with the highest expression in the spleen, and CsGILT mRNA expression was significantly up-regulated when Chinese sturgeons were challenged with polyinosinic polycytidylic acid or Vibrio anguillarum. The recombinant CsGILT displayed obvious thiol reductase activity demonstrated by catalyzing the reduction of mouse IgG(H+L) by dithiothreitol into heavy chain and light chain. CsGILT also displayed significant antioxidant activity in mouse dentritic cells as indicated by its increasing GSH level and GSH/GSSG ratio, decreasing intracellular reactive oxygen species and nitric oxide levels and lipid peroxidation, as well as enhancing the activities of the antioxidative redox enzymes including catalase and superoxide dismutase. Our results suggested an important role for CsGILT in the immune response in Chinese sturgeon to pathogen invasion possibly via a conserved functional mechanism throughout vertebrate evolution, contributing to our understanding the immune biology and protection of Chinese sturgeon.

Alpha- and gamma-mangostins exhibit anti-acne activities via multiple mechanisms.

Objective: Acne is a chronic skin disease that involves four key pathogenic factors: excess sebum production, ductal epidermal hyperproliferation, Propionibacterium acnes (P. acnes) colonization, and skin inflammation. Mangostins are well-known for their anti-bacterial and anti-inflammatory effects, suggesting that mangostins may have therapeutic potential for acne. The present study aimed to explore the anti-acne effects of mangostins from the perspective of multiple pathogenic mechanisms of acne. Methods: The effects of α- and γ-mangostins on the growth of P. acnes and lipase activity were analyzed. Their effects on P. acnes-induced keratinocyte proliferation were examined by CCK-8. The expression of inflammatory genes and activation of NF-κB and MAPK signaling pathways were detected by quantitative real-time PCR and western blotting, respectively. Results: Alpha- and γ-mangostins not only inhibited the growth of P. acnes, but also reduced the proliferation of keratinocytes induced by heat-killed P. acnes. Furthermore, α- and γ-mangostins were able to suppress P. acnes-induced expression of pro-inflammatory cytokines, including TNF-α, IL-1ß, and IL-6 in keratinocytes by inhibiting the activation of NF-κB and MAPK signaling pathways. Discussion and conclusions: Mangostins appeared to possess multiple anti-acne activities, including the inhibition of P. acnes growth, regulation of keratinocytes proliferation, and attenuation of skin inflammatory reaction. Hence, mangostins might be developed into a potential therapeutic agent for the treatment of acne.

A Combined Molecular Cloning and Mass Spectrometric Method to Identify, Characterize, and Design Frenatin Peptides from the Skin Secretion of Litoria infrafrenata.

Amphibian skin secretions are unique sources of bioactive molecules, particularly bioactive peptides. In this study, the skin secretion of the white-lipped tree frog (Litoria infrafrenata) was obtained to identify peptides with putative therapeutic potential. By utilizing skin secretion-derived mRNA, a cDNA library was constructed, a frenatin gene was cloned and its encoded peptides were deduced and confirmed using RP-HPLC, MALDI-TOF and MS/MS. The deduced peptides were identified as frenatin 4.1 (GFLEKLKTGAKDFASAFVNSIKGT) and a post-translationally modified peptide, frenatin 4.2 (GFLEKLKTGAKDFASAFVNSIK.NH2). Antimicrobial activity of the peptides was assessed by determining their minimal inhibitory concentrations (MICs) using standard model microorganisms. Through studying structure-activity relationships, analogues of the two peptides were designed, resulting in synthesis of frenatin 4.1a (GFLEKLKKGAKDFASALVNSIKGT) and frenatin 4.2a (GFLLKLKLGAKLFASAFVNSIK.NH2). Both analogues exhibited improved antimicrobial activities, especially frenatin 4.2a, which displayed significant enhancement of broad spectrum antimicrobial efficiency. The peptide modifications applied in this study, may provide new ideas for the generation of leads for the design of antimicrobial peptides with therapeutic applications.

Identification and Characterisation of the Antimicrobial Peptide, Phylloseptin-PT, from the Skin Secretion of Phyllomedusa tarsius, and Comparison of Activity with Designed, Cationicity-Enhanced Analogues and Diastereomers.

Antimicrobial peptides belonging to the phylloseptin family are mainly found in phyllomedusine frogs. These peptides not only possess potent antimicrobial activity but exhibit low toxicity against eukaryotic cells. Therefore, they are considered as promising drug candidates for a number of diseases. In a recent study, potent antimicrobial activity was correlated with the conserved structures and cationic amphiphilic characteristics of members of this peptide family. A phylloseptin peptide precursor was discovered here in the skin secretion of Phyllomedusa tarsius and the mature peptide was validated by MS/MS sequencing, and was subsequently named phylloseptin-PT. The chemically-synthesized and purified phylloseptin-PT displayed activity against Staphylococcus aureus and Candida albicans. Nevertheless, a range of cationicity-enhanced peptide analogues of phylloseptin-PT, which contained amino acid substitutions at specific sites, exhibited significant increases in antimicrobial activity compared to native phylloseptin-PT. In addition, alternative conformers which were designed and chemically-synthesized with d-lysine, showed potent antimicrobial activity and enhanced bioavailability. These data indicate that phylloseptins may represent potential candidates for next-generation antibiotics. Thus, rational design through modification of natural antimicrobial peptide templates could provide an accelerated path to overcoming obstacles en-route to their possible clinical applications.

Exploration of the factors influencing hearing disability in older adults of China: a nested case-control study.

Objective: As two line trends - aging disability and disability aging - continue to emerge, hearing disability is becoming increasingly prevalent among older adults in china. This study aimed to investigate the incidence of hearing disability among older adults and identify the various factors contributing to its development. Methods: In this matched nested case-control study, data from the China Health and Retirement Longitudinal Study from 2011 to 2018 were analyzed. A total of 4,523 older adults were recruited from a national sample database, of which 1,094 individuals were eligible for inclusion in the hearing disability cohort, while 3,429 older adults who had not been diagnosed with hearing disability were considered non-hearing disability controls. Hearing disability was assessed by a self-reported question. These controls were matched to hearing disability cases in a 1:1 ratio based on age and sex. The logistic regression models were used to find out various factors of hearing disability in the target population. Results: Totally 1,094 individuals (24.14%) developed hearing disability during the follow-up period. After 1:1 matching, 2,182 subjects were included in the study, with 1,091 cases in the case group. Factors that influenced the incidence of hearing disability in older adults included annual per capita household income (OR = 0.985, p = 0.003), cognitive function (OR = 0.982, p = 0.015), depression level (OR = 1.027, p < 0.001), somatic mobility (OR = 0.946, p = 0.007), history of kidney disease (OR = 1.659, p < 0.001), history of asthma (OR = 1.527, p = 0.008), history of accidental injuries (OR = 1.348, p = 0.015), whether there is a place for recreational and fitness activities in the community (OR = 0.672, p < 0.001), and whether there is a health service center/health center in the community (OR = 0.882, p = 0.006). Conclusion: The incidence of hearing disabilities among older adults in China is high. The protective and risk factors that contribute to the incidence of disability should be fully considered in the care of older adults.

Understanding Care Needs of Older Adults with Disabilities: A Scoping Review.

Purpose: To conducted a scoping review of care needs of older adults with disabilities at home and in the community and provide a comprehensive understanding of the essential needs of older adults with disabilities. Methods: Eight databases were searched for relevant Chinese and English studies (supplemented by retrospective references of the included studies) from the establishment of the database to February 13, 2023. An thematic synthesis approach was used to qualitatively integrate the retrieved studies and identify need-related themes. Results: A total of 6239 studies were retrieved, 2557 were de-weighted and excluded, and 56 were obtained after the double screening. Studies were from 11 countries. Thirty-three studies used a self-prepared survey instrument to investigate needs, and the other research tools commonly used were secondary databases and the Long-Term Care Needs of the Disabled Scale. A total of 78 specific need items were identified and summarized into three need themes based on the ICF framework: physical functioning needs, activity and participation needs, and environment needs. Conclusion: The complex physical and mental health conditions faced by older adults with disabilities result in multifaceted, integrated needs that are difficult to identify and meet. Current research on older adults with disabilities is limited to common care. Future research should focus on the specificities of the older disabled population and understand the diverse care needs of people with disabilities in order to better target care services for this group. Policymakers should formulate more operational and strategic measures based on the actual needs of older adults with disabilities to expand the coverage of services and to pinpoint care services.