Effect and Potential Mechanism of Immunotherapy on Cognitive Deficits in Animal Models of Alzheimer's Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Immunotherapy has been reported to ameliorate Alzheimer's disease (AD) in the animal model; however, the immunologic approaches and mechanisms have not been specifically described. Thus, the systematic review and meta-analysis were conducted to explore the effect and potential mechanism of immunotherapy on AD animal experiments based on behavioral indicators. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Cochrane Collaboration guidelines and the inclusion/exclusion criteria of immunotherapy in animal studies, 15 studies were systematically reviewed after extraction from a collected database of 3,742 publications. Finally, the effect and mechanism of immunotherapy on AD models were described by performing multiple subgroup analyses. RESULTS: After immunotherapy, the escape latency was reduced by 18.15 seconds and the number of crossings over the platform location was increased by 1.60 times in the Morris Water Maze. Furthermore, compared to the control group, active and passive immunization could markedly ameliorate learning and memory impairment in 3 × Tg AD animal models, and active immunization could ameliorate the learning and memory ability of the APPswe/PS1ΔE9 AD animal model. Meanwhile, it could be speculated that cognitive dysfunction was improved by immunotherapy, perhaps mainly via reducing Aß40, Aß42, and Tau levels, as well as increasing IL-4 levels. CONCLUSION: Immunotherapy significantly ameliorated the cognitive dysfunction of AD animal models by assessing behavioral indicators.

Triglyceride-glucose index is strongly associated with all-cause mortality in elderly females with diabetic foot ulcers: A 9-year follow-up study.

This study aims to explore the association between the triglyceride-glucose (TyG) index and all-cause mortality in patients with diabetic foot ulcers (DFUs) through an ambispective cohort study. A total of 555 inpatients with DFUs were qualified to participate in the trial study from 2013 to 2022. Throughout a median 63-month period, all subjects were followed up every 6 months. According to the three quantiles of the TyG index, participants were divided into three groups: low-level (≤8.75, n = 185), moderate-level (8.76-9.33, n = 185) and high-level (≥9.34, n = 185). The association between the TyG index and all-cause mortality in patients with DFUs was then assessed. During the follow-up period, out of 555 patients with DFUs, 116 died (20.9%). After adjusting for confounding factors, the TyG index was positively associated with all-cause mortality in patients with DFUs (HR = 1.733; 95% CI = 1.341-2.241; p < 0.001). Compared with the low-level TyG index, the moderate-level TyG index (HR = 1.685; 95% CI = 1.011-2.810; p = 0.045) and the high-level TyG index (HR = 2.769; 95% CI = 1.678-4.568; p < 0.001) were positively correlated with all-cause mortality in patients with DFUs. Additionally, in subgroup analysis, both females (HR = 1.905; 95% CI = 1.250-2.904; p = 0.003), males (HR = 1.729; 95% CI = 1.240-2.409; p = 0.001), younger (<65 years old) (HR = 1.467; 95% CI = 1.008-2.135; p = 0.046) and elderly (≥ 65) (HR = 1.933; 95% CI = 1.339-2.791; p < 0.001) showed a positive correlation between TyG index and all-cause mortality rate in patients with DFUs. Furthermore, in the high-level TyG index group compared, males (HR = 2.699; 95% CI = 1.457-4.998) and participants aged <65 years (HR = 2.031; 95% CI = 0.972-4.242), with the TyG index level increase by 1.0, the risk for all-cause mortality increased 3.277-fold in females (HR = 4.277; 95% CI = 1.645-11.124) and 1.909-fold in elderly aged ≥65 years (HR = 2.909; 95% CI = 1.486-5.695), respectively. Kaplan-Meier survival curve analysis showed that the higher the TyG index level, the higher risk of all-cause mortality in patients with DFUs (log-rank, all p < 0.001). Briefly, this study implies a strong positive correlation between the TyG index and all-cause mortality in patients with DFUs, especially in older women. Therefore, special attention should be paid to elderly females with DFUs because they have a higher TyG index level and risk of all-cause mortality than other populations in daily clinical practice.

Metabolic dysfunction-associated fatty liver disease in the elderly with diabetic foot ulcers: A longitudinal cohort study.

This study aimed to explore the association between metabolic-associated fatty liver disease (MAFLD) and ulcer recurrence risk in patients with diabetic foot ulcers (DFUs) through an ambispective longitudinal cohort. From December 2013 to December 2022, a total of 482 inpatients with DFUs (PEDIS grade 3 and above with a severe infection) were eligible for inclusion in this study. This was an ambispective longitudinal cohort study. All participants were followed up every 6 months for 9 years with a median of 36 months. According to whether having MAFLD or not, all subjects were placed into two groups: non-MAFLD (n = 351) and MAFLD (n = 131). The association between MAFLD and ulcer recurrence in patients with DFUs was then evaluated through multivariate Cox regression analysis, stratified analyses and Kaplan-Meier survival analysis. Throughout the follow-up period, out of 482 subjects with DFUs, 68 had ulcer recurrence (14.1%). Three Cox regression models were established for data analyses. In the model I (unadjusted), MAFLD was significantly associated with the ulcer recurrence rate in patients with DFUs (HR = 1.79; 95% CI = 1.097-2.92; p = 0.02). Model II (adjusted model I with gender and age) (HR = 1.781; 95% CI = 1.09-2.912; p = 0.021) and model III (adjusted model II with CVD, duration of diabetes and Cr.) (HR = 1.743; 95% CI = 1.065-2.855; p = 0.027) also showed that MAFLD was significantly related to the ulcer recurrence risk in patients with DFUs, respectively. Stratified analysis indicated that subjects aged ≥60 had a greater risk of ulcer recurrence in MAFLD than in non-MAFLD (HR = 2.31; 95% CI = 1.268-4.206; p = 0.006). Kaplan-Meier survival curve analysis showed that ulcer recurrence rate had a significant association with MAFLD (log-rank, p = 0.018). This study indicated a close association between ulcer recurrence risk and MAFLD in patients with DFUs, especially in the elderly (aged ≥60). Therefore, special attention should be paid to the elderly with both DFUs and MAFLD because they have a higher ulcer recurrence rate than other general populations in routine clinical practice.

The triglyceride glucose index as a sensitive predictor for the risk of MACCEs in patients with diabetic foot ulcers: An ambispective longitudinal cohort study.

The triglyceride glucose (TyG) index has been confirmed a predictive value for type 2 diabetes mellitus (T2DM). However, no research has yet confirmed whether there is a linear correlation between the TyG index and MACCEs in DFUs. The present study aimed to delve into the association between the TyG index and the risk of MACCEs in patients with DFUs. A total of 960 inpatients with DFUs were recruited. All participants were followed up every 6 months for 11 years with a median of 83 months. According to the cut-off value of the TyG index acquired from receiver operating characteristic (ROC) analysis, the subjects were divided into two groups: low-level (<9.12, n = 480) and high-level (≥9.12, n = 480). The relationship between the TyG index and MACCEs was evaluated by the multivariable Cox regression model, restricted cubic spline (RCS) model, stratified analysis and the Kaplan-Meier survival analysis. Out of 960 participants, 271 experienced MACCEs (28.22%), of whom 79 (29.15%) died. ROC analysis got the optimal TyG index cut-off value of 9.12. Multivariable Cox regression analysis combined with the RCS model showed that the TyG index was positively associated with MACCEs in an S-shaped non-linear dose-dependent manner within the range of TyG index 7.5-9.5 (p < 0.001). The Kaplan-Meier survival analysis indicated the higher the TyG index, the greater the cumulative incidence of MACCEs (log-rank, p < 0.001). The study first confirmed an S-shaped non-linear dose-dependent positive relationship between the TyG index and the risk of MACCEs in DFUs. Consequently, lowering the TyG index level aids in improving the prognosis of patients with DFUs.

Autologous wound margin point columnar full-thickness skin grafting combined with negative pressure wound therapy improves wound healing in refractory diabetic foot ulcers.

Diabetic lower extremity ulcers (DLEUs) are a severe complication of diabetes mellitus (DM) and are difficult to heal. This study aimed to explore the efficacy of autologous point columnar full-thickness skin graft taken from the ulcer wound margin combined with negative pressure wound therapy (NPWT) in refractory DLEUs. This is a prospective cohort study. A total of 40 inpatients with refractory DLEUs were recruited in the Diabetes Foot Center of Guangxi Zhuang Autonomous Region People's Hospital from October 2019 to November 2021. According to the doctors' professional suggestions and the patients' personal wishes, these enrolled patients were divided into two groups based on different topical wound management: the graft group (n = 18) and the conventional wound therapeutic (CWT) group (n = 22). The efficacy evaluations included the time to complete re-epithelialization of the wound and healing speed within 14 days of graft treatment or after 14 days of graft treatment in the two groups. Before the treatment, the graft group had a significantly larger ulcer area than the CWT group [27.22 (15.28, 46.59) versus 10.92 (7.00, 24.93) cm2 , P < .01]. However, the time to complete wound re-epithelialization in the graft group was shorter than in the CWT group [58.22 ± 30.60 versus 86.09 ± 49.54 d, P < .05]. Meanwhile, the healing speed in graft group was markedly faster than in CWT group, whether within 14 days [0.60 (0.40, 0.92) versus 0.16 (0.07, 0.34) cm2 /d, P < .01] or after 14 days of graft treatment [0.57 (0.45, 0.91) versus 0.13 (0.08, 0.27) cm2 /d, P < .01]. However, the total treatment cost in the graft group was lower than in the CWT group [419.59 ± 137.20 versus 663.97 ± 497.02 $, P < .05]. The novel treatment modality of autologous full-thickness skin graft taken from the ulcer wound margin combined with NPWT has hereby proposed for the first time, and is a safe, effective, and reliable method with a good performance-to-cost ratio to promote wound healing and shorten the healing time for DLEUs.

Effect and Mechanism of Rapamycin on Cognitive Deficits in Animal Models of Alzheimer's Disease: A Systematic Review and Meta-analysis of Preclinical Studies.

Background: Alzheimer's disease (AD), the most common form of dementia, remains long-term and challenging to diagnose. Furthermore, there is currently no medication to completely cure AD patients. Rapamycin has been clinically demonstrated to postpone the aging process in mice and improve learning and memory abilities in animal models of AD. Therefore, rapamycin has the potential to be significant in the discovery and development of drugs for AD patients. Objective: The main objective of this systematic review and meta-analysis was to investigate the effects and mechanisms of rapamycin on animal models of AD by examining behavioral indicators and pathological features. Methods: Six databases were searched and 4,277 articles were retrieved. In conclusion, 13 studies were included according to predefined criteria. Three authors independently judged the selected literature and methodological quality. Use of subgroup analyses to explore potential mechanistic effects of rapamycin interventions: animal models of AD, specific types of transgenic animal models, dosage, and periodicity of administration. Results: The results of Morris Water Maze (MWM) behavioral test showed that escape latency was shortened by 15.60 seconds with rapamycin therapy, indicating that learning ability was enhanced in AD mice; and the number of traversed platforms was increased by 1.53 times, indicating that the improved memory ability significantly corrected the memory deficits. CONCLUSIONS: Rapamycin therapy reduced age-related plaque deposition by decreasing AßPP production and down-regulating ß-secretase and γ-secretase activities, furthermore increased amyloid-ß clearance by promoting autophagy, as well as reduced tau hyperphosphorylation by up-regulating insulin-degrading enzyme levels.

Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and MACCEs in Patients with Diabetic Foot Ulcers: An Ambispective Longitudinal Cohort Study.

Aim: Metabolic dysfunction-related fatty liver disease (MAFLD) is closely related to metabolic disorders. However, the relationship between MAFLD and the prognosis in diabetic foot ulcers (DFUs) remains unclear. This study aimed to explore the association between MAFLD and the risk of major adverse cardiac and cerebral events (MACCEs) in patients with DFUs. Methods: 889 inpatients with DFUs (PEDIS/TEXAS mild and above) were included in this study from 2013 to 2023. All participants were placed into non-MAFLD (n = 643) and MAFLD (n = 246) groups and followed up every 6 months for 10.9 years with a median of 63 months through in-person outpatient interviews and family fixed-line telephone visits. The association between MAFLD and the risk of MACCEs was evaluated through Multivariate Cox regression analyses, Stratified analyses and Kaplan-Meier survival analyses. Results: Of the 889 subjects, 214 (24.07%) experienced MACCEs. Multivariate Cox regression analysis showed that MAFLD was independently associated with MACCEs (P < 0.001), of which with non-fatal myocardial infarction (P = 0.04), non-fatal stroke (P = 0.047), coronary artery revascularization (P = 0.002), heart failure (P = 0.029), and all-cause mortality (P = 0.021), respectively. The stratified analysis revealed that compared with non-MAFLD (HR=1), DFUs with MAFLD had a 2.64-fold increased risk for MACCEs (P <0.001; P for interaction = 0.001) in peripheral arterial disease (PAD) subgroup. Kaplan-Meier analysis evidenced that the MAFLD group had a higher cumulative incidence of MACCEs (log-rank, all P < 0.05). Conclusion: MAFLD is a high-risk factor for MACCEs in patients with DFUs. The findings will remind clinicians to pay more attention to MAFLD in patients with DFUs, especially in patients with DFUs combined with PAD as early as possible in clinical practice and adopt timely effective intervention strategies to prevent the occurrence of MACCEs to improve the clinical prognosis in patients with DFUs.

The Ratio of Red Blood Cell Distribution Width to Albumin as a Predictor for Rehospitalization Risk and Rehospitalization All-Cause Mortality in Middle-Aged and Elderly Survivors with Sepsis: An Ambispective ICU Cohort Study.

Objective: To explore the relationship between red blood cell distribution width to albumin (RDW/ALB) ratio (RAR) and the risk of rehospitalization and rehospitalization all-cause mortality in middle-aged and elderly survivors with sepsis based on an ambispective longitudinal cohort from the Intensive Care Unit (ICU). Methods: Between 2017 and 2022, 455 adults who survived the first-episode severe sepsis without recurrence for at least 3 months were included in this study. All participants were followed up every 4 weeks for 12 months. According to the tertiles of RAR, participants were divided into three groups: low-level (≤0.36, n = 152), moderate-level (0.37-0.44, n = 152), and high-level (≥0.45, n = 151). The relationship between RAR and the risk of rehospitalization and rehospitalization all-cause mortality was evaluated. Results: Out of 455 participants, 156 experienced rehospitalization (34.3%), of which 44 (28.2%) died. Receiver operating characteristic (ROC) analysis showed that the RAR cut-off values for rehospitalization and rehospitalization all-cause mortality were 0.4251 and 0.4743, respectively. Multivariate Cox regression analysis indicated that the RAR was positively associated with rehospitalization (P = 0.011) and all-cause mortality (P = 0.006). Compared with the low-level, the high-level RAR presented a higher dose-dependent rehospitalization risk (P = 0.02) and rehospitalization all-cause mortality (P = 0.044). The stratified analysis displayed that compared to the low-level, with the RAR increasing by 1.0, the risk for rehospitalization increased 3.602-fold in aged <65 patients (P = 0.002) and 1.721-fold in female patients (P = 0.014). Kaplan-Meier survival analysis implied a significant positive association between the RAR and the cumulative incidence of rehospitalization and rehospitalization all-cause mortality (log-rank, all P < 0.001). Conclusion: RAR has a reliable predictive value for the risk of rehospitalization and rehospitalization all-cause mortality in patients with sepsis. Consequently, monitoring RAR for at least 1 year after surviving sepsis in female patients aged <65 in clinical practice is critical.

Knowledge domains and emerging trends of Genome-wide association studies in Alzheimer's disease: A bibliometric analysis and visualization study from 2002 to 2022.

OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive and behavioral function. Studies have shown that genetic factors are one of the main causes of AD risk. genome-wide association study (GWAS), as a novel and effective tool for studying the genetic risk of diseases, has attracted attention from researchers in recent years and a large number of studies have been conducted. This study aims to summarize the literature on GWAS in AD by bibliometric methods, analyze the current status, research hotspots and future trends in this field. METHODS: We retrieved articles on GWAS in AD published between 2002 and 2022 from Web of Science. CiteSpace and VOSviewer software were applied to analyze the articles for the number of articles published, countries/regions and institutions of publication, authors and cited authors, highly cited literature, and research hotspots. RESULTS: We retrieved a total of 2,751 articles. The United States had the highest number of publications in this field, and Columbia University was the institution with the most published articles. The identification of AD-related susceptibility genes and their effects on AD is one of the current research hotspots. Numerous risk genes have been identified, among which APOE, CLU, CD2AP, CD33, EPHA1, PICALM, CR1, ABCA7 and TREM2 are the current genes of interest. In addition, risk prediction for AD and research on other related diseases are also popular research directions in this field. CONCLUSION: This study conducted a comprehensive analysis of GWAS in AD and identified the current research hotspots and research trends. In addition, we also pointed out the shortcomings of current research and suggested future research directions. This study can provide researchers with information about the knowledge structure and emerging trends in the field of GWAS in AD and provide guidance for future research.

Radioactive Iodine-131 Therapy Reduced the Risk of MACEs and All-Cause Mortality in Elderly with Hyperthyroidism Combined with Type 2 Diabetes.

Aim: This study aimed to assess the efficacy of antithyroid drugs (ATDs) and radioactive iodine-131 (RAI) therapies in reducing the risk of major adverse cardiovascular events (MACEs) and all-cause mortality in patients with hyperthyroidism complicated with type 2 diabetes mellitus (T2DM). Methods: Between January 2013 and December 2021, 540 subjects were included in the analysis. All participants were followed up for 9 years, with a median of 54 months (2451 person-years). The subjects were categorized into two groups: the ATDs group (n = 414) and the RAI group (n = 126). According to the free triiodothyronine (FT3) tertiles, the patients receiving RAI were further grouped as follows: low-level (≤ 4.70 pmol/L, n = 42), moderate-level (4.70-12.98 pmol/L, n = 42), and high-level (≥ 12.98 pmol/L, n = 42). The efficacy of ATDs and RAI therapies in reducing the risk of MACEs and all-cause mortality was assessed. Results: Of the 540 participants, 163 experienced MACEs (30.19%), 25 (15.34%) of whom died. Multivariate Cox regression analyses revealed that RAI was associated with a 38.5% lower risk of MACEs (P = 0.016) and a 77.1% lower risk of all-cause mortality (P = 0.046). Stratified analyses indicated that RAI had a protective effect on MACEs in patients aged ≥ 60 years (P = 0.001, P for interaction = 0.031) and patients with a duration of diabetes mellitus ≥ 6 years (P = 0.013, P for interaction = 0.002). Kaplan‒Meier analysis revealed a lower cumulative incidence of MACEs and all-cause mortality in the RAI group (log-rank, all P < 0.05). Moreover, the ROC curve suggested an optimal FT3 cut-off value of 5.4 pmol/mL for MACE (P < 0.001). Conclusion: Our findings suggested that RAI therapy effectively reduced the risk of MACEs and all-cause mortality in elderly patients with hyperthyroidism combined with T2DM.

Water extract of moschus alleviates erastin-induced ferroptosis by regulating the Keap1/Nrf2 pathway in HT22 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Moschus, first described in the Shennong's Classic of the Materia medicine, is a scarce and precious animal medicine. Modern pharmacological researches have suggested that Moschus has neuroprotective actions, and its mechanism is related to anti-inflammatory, antioxidant, and anti-apoptosis effects. Ferroptosis is one of the major pathologies of Alzheimer's disease (AD) and is widely implicated in the pathogenesis and progression of AD. Although previous studies have suggested that Moschus possesses neuroprotective effect, whether Moschus could mitigate neuronal damages by inhibiting the onset of ferroptosis is unknown in model cells of AD. AIM OF THE STUDY: The aim of study was to explore the water extract of Moschus (WEM) on ferroptosis caused by erastin and the potential mechanism. MATERIALS AND METHODS: Erastin was used to stimulate HT22 cells to form ferroptosis model to evaluate the anti-ferroptosis effect of WEM by cell counting kit-8 and lactic dehydrogenase (LDH) tests. The malondialdehyde (MDA) and glutathione (GSH) kits are used for detection of MDA and GSH levels, and 2',7'-dichlorofluorescein diacetate and C11 BODIPY 581/591 fluorescence probe are used for evaluation of reactive oxygen species (ROS) and lipid peroxide (LOOH) levels. And Western blot was used to test nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), and ferroptosis associated proteins including glutathione peroxidase 4 (GPX4), cystine/glutamate antiporter subunit (SLC7A11), ferritin heavy chain 1 (FTH1), ferroportin1 (FPN1), transferrin receptor (TFRC). In addition, the Nrf2 inhibitor ML385 was applied to verify whether WEM prevents erastin-induced ferroptosis by activating the Keap1/Nrf2 pathway. RESULTS: After WEM treatment, erastin-induced HT22 cell survival was significantly elevated, the accumulation of intracellular MDA, ROS, and LOOH were significantly reduced, the level of GSH and expressions of ferroptosis inhibitors GPX4 and SLC7A11 were significantly increased, and iron metabolism-related proteins TFRC, FPN1, and FTH1 were regulated. These effects of WEM are implemented by activating the Keap1/Nrf2 pathway. CONCLUSIONS: This study demonstrated that WEM could perform neuroprotective effects by alleviating ferroptosis, verified that WEM treatment of AD can be mediated by the Keap1/Nrf2 pathway, and provided theoretical support for the application of WEM in the treatment of AD.

Geriatric nutritional risk index as a predictor for fragility fracture risk in elderly with type 2 diabetes mellitus: A 9-year ambispective longitudinal cohort study.

BACKGROUND & AIMS: The elderly are prone to fragility fractures, especially those suffering from type 2 diabetes mellitus (T2DM) combined with osteoporosis. Although studies have confirmed the association between GNRI and the prevalence of osteoporosis, the relationship between GNRI and fragility fracture risk and the individualized 10-year probability of osteoporotic fragility fractures estimated by FRAX remains unclear. This study aims to delve into the association between the GNRI and a fragility fracture and the 10-year probability of hip fracture (HF) and major osteoporotic fracture (MOF) evaluated by FRAX in elderly with T2DM. METHODS: A total of 580 patients with T2DM aged ≥60 were recruited in the study from 2014 to 2023. This research is an ambispective longitudinal cohort study. All participants were followed up every 6 months for 9 years with a median of 3.8 years through outpatient services, medical records, and home fixed-line telephone interviews. According to the tertiles of GNRI, all subjects were divided into three groups: low-level (59.72-94.56, n = 194), moderate-level (94.56-100.22, n = 193), and high-level (100.22-116.45, n = 193). The relationship between GNRI and a fragility fracture and the 10-year probability of HF and MOF calculated by FRAX was assessed by receiver operating characteristic (ROC) analysis, Spearman correlation analyses, restricted cubic spline (RCS) analyses, multivariable Cox regression analyses, stratified analyses, and Kaplan-Meier survival analysis. RESULTS: Of 580 participants, 102 experienced fragile fracture events (17.59%). ROC analysis demonstrated that the optimal GNRI cut-off value was 98.58 with a sensitivity of 75.49% and a specificity of 47.49%, respectively. Spearman partial correlation analyses revealed that GNRI was positively related to 25-hydroxy vitamin D [25-(OH) D] (r = 0.165, P < 0.001) and bone mineral density (BMD) [lumbar spine (LS), r = 0.088, P = 0.034; femoral neck (FN), r = 0.167, P < 0.001; total hip (TH), r = 0.171, P < 0.001]; negatively correlated with MOF (r = -0.105, P = 0.012) and HF (r = -0.154, P < 0.001). RCS analyses showed that GNRI was inversely S-shaped dose-dependent with a fragility fracture event (P < 0.001) and was Z-shaped with the 10-year MOF (P = 0.03) and HF (P = 0.01) risk assessed by FRAX, respectively. Multivariate Cox regression analysis demonstrated that compared with high-level GNRI, moderate-level [hazard ratio (HR) = 1.950; 95% confidence interval (CI) = 1.076-3.535; P = 0.028] and low-level (HR = 2.538; 95% CI = 1.378-4.672; P = 0.003) had an increased risk of fragility fracture. Stratified analysis exhibited that GNRI was negatively correlated with the risk of fragility fracture, which the stratification factors presented in the forest plot were not confounding factors and did not affect the prediction effect of GNRI on the fragility fracture events in this overall cohort population (P for interaction > 0.05), despite elderly females aged ≥70, with body mass index (BMI) ≥24, hypertension, and with or without anemia (all P < 0.05). Kaplan-Meier survival analysis identified that the lower-level GNRI group had a higher cumulative incidence of fragility fractures (log-rank, all P < 0.001). CONCLUSION: This study confirms for the first time that GNRI is negatively related to a fragility fracture and the 10-year probability of osteoporotic fragility fractures assessed by FRAX in an inverse S-shaped and Z-shaped dose-dependent pattern in elderly with T2DM, respectively. GNRI may serve as a valuable predictor for fragility fracture risk in elderly with T2DM. Therefore, in routine clinical practice, paying attention to the nutritional status of the elderly with T2DM and giving appropriate dietary guidance may help prevent a fragility fracture event.

Glucagon-like peptide 1 (GLP-1) receptor agonists in experimental Alzheimer's disease models: a systematic review and meta-analysis of preclinical studies.

Alzheimer's disease (AD) is a degenerative disease of the nervous system. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug used to treat type 2 diabetes, have been shown to have neuroprotective effects. This systematic review and meta-analysis evaluated the effects and potential mechanisms of GLP-1 RAs in AD animal models. 26 studies were included by searching relevant studies from seven databases according to a predefined search strategy and inclusion criteria. Methodological quality was assessed using SYRCLE's risk of bias tool, and statistical analysis was performed using ReviewManger 5.3. The results showed that, in terms of behavioral tests, GLP-1 RAs could improve the learning and memory abilities of AD rodents; in terms of pathology, GLP-1 RAs could reduce Aß deposition and phosphorylated tau levels in the brains of AD rodents. The therapeutic potential of GLP-1 RAs in AD involves a range of mechanisms that work synergistically to enhance the alleviation of various pathological manifestations associated with the condition. A total of five clinical trials were retrieved from ClinicalTrials.gov. More large-scale and high-quality preclinical trials should be conducted to more accurately assess the therapeutic effects of GLP-1 RAs on AD.

Triglyceride Glucose Index is Strongly Associated with a Fragility Fracture in Postmenopausal Elderly Females with Type 2 Diabetes Mellitus Combined with Osteoporosis: A 6-Year Follow-Up Study.

Purpose: The triglyceride glucose (TyG) index serves as an indicator of insulin resistance (IR), which is also associated with bone metabolism. However, research on the relationship between the TyG index and a fragility fracture in individuals with type 2 diabetes mellitus (T2DM) or osteoporosis (OP) remains sparse. This study aims to explore the association between the TyG index and fragility fracture risk in postmenopausal elderly females with T2DM combined with OP based on an ambispective cohort study. Patients and Methods: A total of 220 postmenopausal women hospitalized with T2DM combined with OP between January 2015 and December 2020 were eligible for inclusion in this study. All participants were followed up every 6 months for 6 years with a median of 42 months. According to the tertiles of the TyG index, participants were divided into three groups: low-level (≤ 8.79, n =73), moderate-level (8.80-9.32, n=73), and high-level (≥ 9.33, n=74). The association between the TyG index and fragility fracture risk was then assessed. Results: Out of 220 patients, 46 experienced fragility fracture events (20.9%). Multivariate Cox regression analysis showed that the TyG index was positively associated with a fragility fracture in postmenopausal women with T2DM combined with OP. Furthermore, compared to the low-level group, with the TyG index level increase by 1.0, the risk for fragility fracture increased 1.293-fold in the high-level group (HR=2.293, 95% CI=1.007-5.221, P < 0.05). Kaplan-Meier survival analysis indicated that fragility fractures were more likely to occur in patients with high levels of TyG index (log-rank, all P < 0.05). Conclusion: Our study showed that the TyG index was strongly associated with a fragility fracture in postmenopausal women with T2DM combined with OP. Therefore, special attention should be paid to postmenopausal elderly females with T2DM combined with OP in routine clinical practice.

Moschus exerted protective activity against H2O2-induced cell injury in PC12 cells through regulating Nrf-2/ARE signaling pathways.

The pivotal characteristics of Alzheimer's disease (AD) are irreversible memory loss and progressive cognitive decline, eventually causing death from brain failure. In the various proposed hypotheses of AD, oxidative stress is also regarded as a symbolic pathophysiologic cascade contributing to brain diseases. Using Chinese herbal medicine may be beneficial for treating and preventing AD. As a rare and valuable animal medicine, Moschus possesses antioxidant and antiapoptotic efficacy and is extensively applied for treating unconsciousness, stroke, coma, and cerebrovascular diseases. We aim to evaluate whether Moschus protects PC12 cells from hydrogen peroxide (H2O2)-induced cellular injury. The chemical constituents of Moschus are analyzed by GC-MS assay. The cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP) levels, oxidative stress-related indicators, and apoptotic proteins are determined. Through GC-MS analysis, nineteen active contents were identified. The cell viability loss, lactate dehydrogenase releases, MMP levels, ROS productions, and Malondialdehyde (MDA) activities decreased, and BAX, Caspase-3, and Kelch-like ECH-associated protein 1 expression also significantly down-regulated and heme oxygenase 1, nuclear factor erythroid-2-related factor 2 (Nrf-2), and quinine oxidoreductase 1 expression upregulated after pretreatment of Moschus. The result indicated Moschus has neuroprotective activity in relieving H2O2-induced cellular damage, and the potential mechanism might be associated with regulating the Nrf-2/ARE signaling pathway. A more in-depth and comprehensive understanding of Moschus in the pathogenesis of AD will provide a fundamental basis for in vivo AD animal model research, which may be able to provide further insights and new targets for AD therapy.

Moschus ameliorates glutamate-induced cellular damage by regulating autophagy and apoptosis pathway.

Alzheimer's disease (AD), a neurodegenerative disorder, causes short-term memory and cognition declines. It is estimated that one in three elderly people die from AD or other dementias. Chinese herbal medicine as a potential drug for treating AD has gained growing interest from many researchers. Moschus, a rare and valuable traditional Chinese animal medicine, was originally documented in Shennong Ben Cao Jing and recognized for its properties of reviving consciousness/resuscitation. Additionally, Moschus has the efficacy of "regulation of menstruation with blood activation, relief of swelling and pain" and is used for treating unconsciousness, stroke, coma, and cerebrovascular diseases. However, it is uncertain whether Moschus has any protective effect on AD patients. We explored whether Moschus could protect glutamate (Glu)-induced PC12 cells from cellular injury and preliminarily explored their related action mechanisms. The chemical compounds of Moschus were analyzed and identified by GC-MS. The Glu-induced differentiated PC12 cell model was thought to be the common AD cellular model. The study aims to preliminarily investigate the intervention effect of Moschus on Glu-induced PC12 cell damage as well as their related action mechanisms. Cell viability, lactate dehydrogenase (LDH), mitochondrial reactive oxygen species, mitochondrial membrane potential (MMP), cell apoptosis, autophagic vacuoles, autolysosomes or autophagosomes, proteins related to apoptosis, and the proteins related to autophagy were examined and analyzed. Seventeen active compounds of the Moschus sample were identified based on GC-MS analysis. In comparison to the control group, Glu stimulation increased cell viability loss, LDH release, mitochondrial damage, loss of MMP, apoptosis rate, and the number of cells containing autophagic vacuoles, and autolysosomes or autophagosomes, while these results were decreased after the pretreatment with Moschus and 3-methyladenine (3-MA). Furthermore, Glu stimulation significantly increased cleaved caspase-3, Beclin1, and LC3II protein expression, and reduced B-cell lymphoma 2/BAX ratio and p62 protein expression, but these results were reversed after pretreatment of Moschus and 3-MA. Moschus has protective activity in Glu-induced PC12 cell injury, and the potential mechanism might involve the regulation of autophagy and apoptosis. Our study may promote research on Moschus in the field of neurodegenerative diseases, and Moschus may be considered as a potential therapeutic agent for AD.

A Novel Wound Therapy Modality: Autologous Wound Edge Dotted Full-Thickness Skin Grafting Improving Diabetic Foot Ulcer Healing.

Aim: To explore the therapeutic efficacy of autologous wound edge-dotted full-thickness skin grafting in improving diabetic foot ulcer healing. Methods: Sixty-three patients were divided into three groups: conventional wound therapy (CWT) (n = 23), platelet-rich plasma (PRP) (n = 20), and graft (n = 20). All participants were followed up for 12 weeks. The therapeutic efficacy of the three different wound treatment modalities was analyzed. Results: After follow-up, 37 (58.7%) patients showed complete wound re-epithelialization, of which 10 (43.5%) occurred in the CWT group, 14 (70.0%) in the PRP group, and 13 (65.0%) in the graft group. Multivariate Cox analysis showed that the independent predictive factors for ulcer healing were different treatment modalities (graft: HR = 3.214, 95% CI=1.300-7.945, P < 0.05; platelet-rich plasma: HR = 3.075, 95% CI=1.320-7.161, P < 0.01), ABI (HR = 9.917, 95% CI=2.675-36.760, P < 0.01), and TcPO2 (HR = 1.040; 95% CI=1.005-1.076; P < 0.05). Stratified analysis showed that higher ABI in graft group or PRP group had higher wound healing rate (graft group: HR = 3.748, 95% CI=1.210-11.607, P < 0.05; PRP group: HR = 5.029, 95% CI=1.743-14.509, P < 0.05); higher TcPO2 in the graft group had higher wound healing rate (HR = 15.805, 95% CI=4.414-56.594, P < 0.01). Additionally, the wound healing time (P < 0.0167) and cumulative healing rate (P < 0.05) in both the PRP group and graft group were more advantageous. The graft group promotes wound re-epithelialization earlier and faster than in the CWT group and PRP group (P < 0.05). Meanwhile, the graft group had lower medical costs (P < 0.0167). Conclusion: Autologous wound edge dotted full-thickness skin grafting has a higher cost-performance ratio than traditional diabetic foot ulcer wound care and is worthy of further clinical application.

The Ratio of Serum Uric Acid to Glycosylated Haemoglobin as a Predictor of All-Mortality in Elderly Patients with Diabetic Foot Ulcers: A Longitudinal Cohort Study.

Aim: To clarify the relationship between serum uric acid (UA) and glycosylated hemoglobin (UA/HbA1c) ratio and all-cause mortality in patients with diabetic foot ulcers (DFUs). Methods: A total of 172 inpatients with DFUs (PEDIS grades 2-4) were eligible for inclusion in this study from 2018 to 2023. This was a retrospective, longitudinal cohort study. All subjects were followed up every 6 months for a median of 60 months. According to the cutoff value of the UA/HbA1c ratio of 39.07 obtained from ROC analysis, the participants were divided into two groups: low-level (≤ 39.07, n = 107) and high-level (> 39.07, n = 65) groups. The correlation between UA/HbA1c ratio and all-cause mortality was also evaluated by Cox regression analysis TheKaplan-Meier survival curve analysis and Log rank tests were used to assess the incidence rates of all-cause mortality. The contribution rate of risk factors was estimated by the population-attributable risk percentage (PAR%) analysis. Results: ROC analysis showed that the optimal cutoff values for UA and the UA/HbA1c ratio were 372 µmol/L and 39.07, respectively. Multivariate Cox regression analysis indicated that a high UA/HbA1c ratio (HR =4.63; 95% CI = 2.004-10.7, P < 0.001) was independently associated with a high risk of all-cause mortality in patients with DFUs. Stratified analysis indicated that subjects aged ≥ 60 years had a greater risk of all-cause mortality associated with a high UA/HbA1c ratio (HR = 4.450; 95% CI = 1.711-11.574, P = 0.002). Kaplan-Meier survival analysis showed that all-cause mortality had a significant positive association with a high UA/HbA1c ratio (log-rank, P < 0.001) and a significant negative correlation with the lowered HbA1c level (< 6.5%) after a follow-up of 32 months (log-rank, P < 0.001). The population attributable risk percentage (PAR%) analysis suggested that the contribution rate of the high-level UA/HbA1c ratio to all-cause mortality was 33.7%, which was much greater than the 19.69% of UA. Conclusion: In brief, our study showed that for every 1.0% increase in the UA/HbA1c ratio, the all-cause mortality rate in elderly patients with DFUs aged ≥ 60 years increased by 3.45-fold. For elderly patients with DFUs, a safe and effective strategy to reduce all-cause mortality is to strictly control serum UA levels to < 372 µmol/L and appropriately loosen the control goal of HbA1c to ≥ 6.5%.

The cellular model for Alzheimer's disease research: PC12 cells.

Alzheimer's disease (AD) is a common age-related neurodegenerative disease characterized by progressive cognitive decline and irreversible memory impairment. Currently, several studies have failed to fully elucidate AD's cellular and molecular mechanisms. For this purpose, research on related cellular models may propose potential predictive models for the drug development of AD. Therefore, many cells characterized by neuronal properties are widely used to mimic the pathological process of AD, such as PC12, SH-SY5Y, and N2a, especially the PC12 pheochromocytoma cell line. Thus, this review covers the most systematic essay that used PC12 cells to study AD. We depict the cellular source, culture condition, differentiation methods, transfection methods, drugs inducing AD, general approaches (evaluation methods and metrics), and in vitro cellular models used in parallel with PC12 cells.

Effect and Mechanism of Exogenous Melatonin on Cognitive Deficits in Animal Models of Alzheimer's Disease: A Systematic Review and Meta-analysis.

Melatonin (MT) has been reported to control and prevent Alzheimer's disease (AD) in the clinic; however, the effect and mechanism of MT on AD have not been specifically described. Therefore, the main purpose of this meta-analysis was to explore the effect and mechanism of MT on AD models by studying behavioural indicators and pathological features. Seven databases were searched and 583 articles were retrieved. Finally, nine studies (13 analyses, 294 animals) were included according to pre-set criteria. Three authors independently judged the selected literature and the methodological quality. Meta-analysis showed that MT markedly ameliorated the learning ability by reducing the escape latency, and the memory deficit was significantly corrected by increasing the dwell time in the target quadrant and crossings over the platform location in the Morris Water Maze (MWM). Among the pathological features, subgroup analysis found that MT may ease the symptoms of AD mainly by reducing the deposition of Aß40 and Aß42 in the cortex. In addition, MT exerted a superior effect on ameliorating the learning ability of senescence-related and metabolic AD models, and corrected the memory deficit of the toxin-induced AD model. The study was registered at PROSPERO (CRD42021226594).