Peptide TK-HR from the Skin of Chinese Folk Medicine Frog Hoplobatrachus Rugulosus Accelerates Wound Healing via the Activation of the Neurokinin-1 Receptor.

Wound healing is a complex process and remains a considerable challenge in clinical trials due to the lack of ideal therapeutic drugs. Here, a new peptide TK-HR identified from the skin of the frog Hoplobatrachus rugulosus was tested for its ability to heal cutaneous wounds in mice. Topical application of TK-HR at doses of 50-200 µg/mL significantly accelerated wound closure without causing any adverse effects in the animals. In vitro and in vivo investigations proved the regulatory role of the peptide on neutrophils, macrophages, keratinocytes, and vein endothelial cells involved in the inflammatory, proliferative, and remodeling phases of wound healing. Notably, TK-HR activated the MAPK and TGF-ß-Smad signaling pathways by acting on NK1R in RAW264.7 cells and mice. The current work has identified that TK-HR is a potent wound healing regulator that can be applied for the treatment of wounds, including diabetic foot ulcers and infected wounds, in the future.

Comprehensive analysis of cuproptosis-related genes on bladder cancer prognosis, tumor microenvironment invasion, and drug sensitivity.

Cuproptosis, a newly discovered form of programmed cell death, plays a vital role in the occurrence and development of tumors. However, the role of cuproptosis in the bladder cancer tumor microenvironment remains unclear. In this study, we developed a method for predicting the prognostic outcomes and guiding the treatment selection for patients with bladder cancer. We obtained 1001 samples and survival data points from The Cancer Genome Atlas database and Gene Expression Omnibus database. Using cuproptosis-related genes (CRGs) identified in previous studies, we analyzed CRG transcriptional changes and identified two molecular subtypes, namely high- and low-risk patients. The prognostic features of eight genes (PDGFRB, COMP, GREM1, FRRS1, SDHD, RARRES2, CRTAC1, and HMGCS2) were determined. The CRG molecular typing and risk scores were correlated with clinicopathological features, prognosis, tumor microenvironment cell infiltration characteristics, immune checkpoint activation, mutation burden, and chemotherapy drug sensitivity. Additionally, we constructed an accurate nomogram to improve the clinical applicability of the CRG_score. qRT-PCR was used to detect the expression levels of eight genes in bladder cancer tissues, and the results were consistent with the predicted results. These findings may help us to understand the role of cuproptosis in cancer and provide new directions for the design of personalized treatment and prediction of survival outcomes in patients with bladder cancer.

Single-cell analyses EMP1 as a marker of the ratio of M1/M2 macrophages is associated with EMT, immune infiltration, and prognosis in bladder cancer.

Background: Bladder cancer is among the most lethal urinary system cancers across the globe. Macrophage 1 and Macrophage 2 play an essential role in the pathogenesis of tumors. Nevertheless, prior studies failed to investigate the implication of the two cells, working in combination, in the development, growth, progression and metastasis of bladder cancer. Methods: We computed the M1/M2 ratio of the samples retrieved from The Cancer Genome Atlas (TCGA) by using the Cibersortx algorithm and calculated the ratio in 32 patients in our series by employing flow cytometry. SurvivalRandomForest was utilized to reduce the dimension of the list of the M1/M2-related genes, with an aim to obtain the most survival-predictive gene (EMP1) encoding epithelial membrane protein 1 (EMP1). The EMP1 was biologically characterized by using Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and Gene Ontology (GO). The single-cell transcriptome (sc-RNA) analysis was then applied to further look into the function of EMP1. Finally, Cellchat was employed to examine the interaction between macrophages and epithelium cells. Results: The results showed that higher M1/M2 ratio was found to be associated with a more favorable prognosis of bladder cancer. EMP1 was identified to be the key gene indicative of M1/M2 ratio and higher EMP1 expression was associated with poor prognosis. Further analyses showed that EMP1 might promote tumor invasion and metastasis via epithelial-mesenchymal transition (EMT) and focal adhesion (FA). Moreover, the expression level of EMP1 could serve as an indicator of immunotherapy efficacy. The scRNA-seq data indicated that EMP1 in cancer cells was strongly associated with tumor proliferation. Finally, the Cellchat results exhibited that EMP1 might promote the interaction between macrophages and cancer cells through the fibronectin 1-syndecan 1 (FN1-SDC1) pathway. Conclusion: Our study identified EMP1, an M1/M2-related gene, the expression of which may act as a prognostic indicator for the proliferation, metastasis, and response to immunotherapy. EMP1 might be involved in the regulation on M1/M2 ratio.

The Strong Anti-Tumor Effect of Smp24 in Lung Adenocarcinoma A549 Cells Depends on Its Induction of Mitochondrial Dysfunctions and ROS Accumulation.

Non-small cell lung cancer (NSCLC) is the leading cause of death in lung cancer due to its aggressiveness and rapid migration. The potent antitumor effect of Smp24, an antimicrobial peptide derived from Egyptian scorpion Scorpio maurus palmatus via damaging the membrane and cytoskeleton have been reported earlier. However, its effects on mitochondrial functions and ROS accumulation in human lung cancer cells remain unknown. In the current study, we discovered that Smp24 can interact with the cell membrane and be internalized into A549 cells via endocytosis, followed by targeting mitochondria and affect mitochondrial function, which significantly causes ROS overproduction, altering mitochondrial membrane potential and the expression of cell cycle distribution-related proteins, mitochondrial apoptotic pathway, MAPK, as well as PI3K/Akt/mTOR/FAK signaling pathways. In summary, the antitumor effect of Smp24 against A549 cells is related to the induction of apoptosis, autophagy plus cell cycle arrest via mitochondrial dysfunction, and ROS accumulation. Accordingly, our findings shed light on the anticancer mechanism of Smp24, which may contribute to its further development as a potential agent in the treatment of lung cancer cells.

Analysis of risk factors for early death in patients with acute promyelocytic leukaemia treated with arsenic trioxide.

To date, no specific studies have evaluated early death (ED) in patients with acute promyelocytic leukaemia (APL) homogeneously treated with arsenic trioxide induction therapy and investigated according to the white blood cell (WBC) count at onset. Such patients were retrospectively analysed in this study, including 314 patients with a WBC count ≤ 10 × 109/L (standard-risk (SR) group) and 144 with a WBC count > 10 × 109/L (high-risk (HR) group). The baseline clinical characteristics and risk factors for ED were compared between the two groups. The incidence of fibrinogen < 1.0 g/L and elevated serum uric acid, aspartate aminotransferase and creatinine levels were higher in the HR group than in the SR group (P = 0.001; P < 0.001; P < 0.001; P = 0.044, respectively). The ED rate was significantly higher in the HR group than in the SR group (29.17% vs. 10.83%, P < 0.001). The main cause of ED was bleeding, followed by infection and differentiation syndrome (DS) in the HR group, while it was bleeding, followed by DS and infection in the SR group. Male sex, age > 50 years old, and fibrinogen < 1.0 g/L were independent risk factors for ED in the SR group. Increased serum creatinine levels, decreased albumin levels, and fibrinogen < 1.0 g/L were independent risk factors for ED in the HR group. Overall, the incidence of ED was higher in the HR group, and the baseline clinical characteristics, causes, times, and predictors of ED in the HR group differed from those in the SR group.

Irisin Regulating Skeletal Response to Endurance Exercise in Ovariectomized Mice by Promoting Akt/ß-Catenin Pathway.

Purpose: Thought irisin is recognized as a pivotal modulator for bone formation, its role in regulating skeletal response to exercise training remains unknown. Therefore, we aimed to determine the change of irisin in response to 8-week exercise training and its role in regulating the effects of exercise on bone loss in ovariectomized (Ovx) mice. Methods: Forty 3-month old female C57BL/6 mic were randomly allocated into four groups: (1) Sham-operated (Sham); (2) ovariectomized; (3) Ovx plus 8-week downhill running exercise (Ex); (4) Ovx plus exercise and received twice weekly injection of cyclo RGDyk protein (a putative anti-irisin receptor agents) (ExRg). Results: Ex group showed enhanced cortical and trabecular volumetric bone mineral density (vBMD) (p < 0.05), improved bone microarchitecture, and increased intensity of alkaline phosphatase positive (ALP+) cells compared with Ovx group. However, cyclo RGDyk administration weakened the exercise-related improvement of vBMD, BV/TV, and ALP intensity in bone. Serum estradiol, irisin, and bone alkaline phosphatase were higher, whereas circulating tartrate-resistant acid phosphatase was lower in Ex group compared with Ovx group (p < 0.05). Exercise promoted mRNA expression of fibronectin type III domain-containing protein 5 (FNDC5), Akt and ß-catenin, and enhanced protein levels of FNDC5, the ratio of phosphorylated Akt (p-Akt) to Akt, and ß-catenin (p < 0.05). When irisin pathways were blocked with cyclo RGDyk, increment of Akt, p-Akt/Akt, and ß-catenin in Ex mice were attenuated. Conclusion: It is suggested that irisin plays a potential role in regulating skeletal response to exercise partly through its interaction with Akt/ß-catenin pathways.

Greater Peripouch Fat Area on CT Image Is Associated with Chronic Pouchitis and Pouch Failure in Inflammatory Bowel Diseases Patients.

BACKGROUND: The causes of chronic antibiotic refractory pouchitis (CARP) and pouch failure in inflammatory bowel disease (IBD) patients remain unknown. Our previous small study showed peripouch fat area measured by MRI was associated with pouchitis. AIMS: To explore the relationship between peripouch fat area on CT imaging and pouch outcomes. METHODS: This is a historical cohort study. Demographic, clinical, and radiographic data of IBD patients with abdominal CT scans after pouch surgery between 2002 and 2017 were collected. Peripouch fat areas and mesenteric peripouch fat areas were measured on CT images at the middle pouch level. RESULTS: A total of 435 IBD patients were included. Patients with higher peripouch fat areas had a higher prevalence of CARP. Univariate analyses demonstrated that long duration of the pouch, high weight or body mass index, the presence of primary sclerosing cholangitis or other autoimmune disorders, and greater peripouch fat area or mesenteric peripouch fat area were risk factors for CARP. Multivariable analyses demonstrated that the presence of primary sclerosing cholangitis or autoimmuned disorders, and greater peripouch fat area (odds ratio [OR] 1.031; 95% confidence interval [CI] 1.016-1.047, P < 0.001) or mesenteric peripouch fat area were independent risk factors for CARP. Of the 435 patients, 139 (32.0%) had two or more CT scans. Multivariable Cox proportional hazard analyses showed that "peripouch fat area increase ≥ 15%" (OR 3.808, 95%CI 1.703-8.517, P = 0.001) was an independent predictor of pouch failure. CONCLUSIONS: A great peripouch fat area measured on CT image is associated with a higher prevalence of CARP, and the accumulation of peripouch fat is a risk factor for pouch failure. The assessment of peripouch fat may be used to monitor the disease course of the ileal pouch.

Association of Longitudinal Patterns of Habitual Sleep Duration With Risk of Cardiovascular Events and All-Cause Mortality.

Importance: Single self-reported measures of sleep duration are associated with adverse health outcomes; however, long-term patterns of self-reported sleep duration and their association with cardiovascular events (CVEs) and all-cause mortality remain unknown. Objective: To determine whether trajectories of long-term vs single-measure sleep duration are associated with subsequent risk of CVEs and all-cause mortality. Design, Setting, and Participants: The Kailuan study is a prospective, population-based cohort study that began in 2006. The present cohort included 52 599 Chinese adults without atrial fibrillation, myocardial infarction, stroke, or cancer to 2010. Trajectories in sleep duration from January 1, 2006, to December 31, 2010, were identified to investigate the association with risk of CVEs and all-cause mortality from January 1, 2010, to December 31, 2017. Data analysis was conducted from July 1 to October 31, 2019. Exposures: Habitual self-reported nocturnal sleep durations were collected in 2006, 2008, and 2010. Trajectories in sleep duration for 4 years were identified by latent mixture modeling. Main Outcomes and Measures: All-cause mortality and first incident CVEs (atrial fibrillation, myocardial infarction, and stroke) from 2010 to 2017 were confirmed by medical records. Based on the baseline sleep duration and patterns over time, 4 trajectories were categorized (normal stable, normal decreasing, low increasing, and low stable). Results: Of the 52 599 adults included in the study (mean [SD] age at baseline, 52.5 [11.8] years), 40 087 (76.2%) were male and 12 512 (23.8%) were female. Four distinct 4-year sleep duration trajectory patterns were identified: normal stable (range, 7.4 to 7.5 hours [n = 40 262]), normal decreasing (mean decrease from 7.0 to 5.5 hours [n = 8074]), low increasing (mean increase from 4.9 to 6.9 hours [n = 3384]), and low stable (range, 4.2 to 4.9 hours [n = 879]). During a mean (SD) follow-up of 6.7 (1.1) years, 2361 individuals died and 2406 had a CVE. Compared with the normal-stable pattern and adjusting for potential confounders, a low-increasing pattern was associated with increased risk of first CVEs (hazard ratio [HR], 1.22; 95% CI, 1.04-1.43), a normal-decreasing pattern was associated with increased risk of all-cause mortality (HR, 1.34; 95% CI, 1.15-1.57), and the low-stable pattern was associated with the highest risk of CVEs (HR, 1.47; 95% CI, 1.05-2.05) and death (HR, 1.50; 95% CI, 1.07-2.10). Conclusions and Relevance: In this study, sleep duration trajectories with lower or unstable patterns were significantly associated with increased risk of subsequent first CVEs and all-cause mortality. Longitudinal sleep duration patterns may assist in more precise identification of different at-risk groups for possible intervention. People reporting consistently sleeping less than 5 hours per night should be regarded as a population at higher risk for CVE and mortality.

Depression and anxiety in relation to cancer incidence and mortality: a systematic review and meta-analysis of cohort studies.

The link between depression and anxiety status and cancer outcomes has been well-documented but remains unclear. We comprehensively quantified the association between depression and anxiety defined by symptom scales or clinical diagnosis and the risk of cancer incidence, cancer-specific mortality, and all-cause mortality in cancer patients. Pooled estimates of the relative risks (RRs) for cancer incidence and mortality were performed in a meta-analysis by random effects or fixed effects models as appropriate. Associations were tested in subgroups stratified by different study and participant characteristics. Fifty-one eligible cohort studies involving 2,611,907 participants with a mean follow-up period of 10.3 years were identified. Overall, depression and anxiety were associated with a significantly increased risk of cancer incidence (adjusted RR: 1.13, 95% CI: 1.06-1.19), cancer-specific mortality (1.21, 1.16-1.26), and all-cause mortality in cancer patients (1.24, 1.13-1.35). The estimated absolute risk increases (ARIs) associated with depression and anxiety were 34.3 events/100,000 person years (15.8-50.2) for cancer incidence and 28.2 events/100,000 person years (21.5-34.9) for cancer-specific mortality. Subgroup analyses demonstrated that clinically diagnosed depression and anxiety were related to higher cancer incidence, poorer cancer survival, and higher cancer-specific mortality. Psychological distress (symptoms of depression and anxiety) was related to higher cancer-specific mortality and poorer cancer survival but not to increased cancer incidence. Site-specific analyses indicated that overall, depression and anxiety were associated with an increased incidence risks for cancers of the lung, oral cavity, prostate and skin, a higher cancer-specific mortality risk for cancers of the lung, bladder, breast, colorectum, hematopoietic system, kidney and prostate, and an increased all-cause mortality risk in lung cancer patients. These analyses suggest that depression and anxiety may have an etiologic role and prognostic impact on cancer, although there is potential reverse causality; Furthermore, there was substantial heterogeneity among the included studies, and the results should be interpreted with caution. Early detection and effective intervention of depression and anxiety in cancer patients and the general population have public health and clinical importance.

Epidemiological Characteristics and Risk Factors of Methamphetamine-Associated Psychotic Symptoms.

Objective: To explore the epidemiological characteristics and the risk factors for methamphetamine (MA)-associated psychotic symptoms among MA users in China. Methods: A cross-sectional study was conducted between April, 2012 and October, 2015 among individuals for whom MA was the principal drug of use in a Compulsory Drug Detoxification Center in Beijing, Guangdong Province. Demographic, drug use and psychological characteristics were examined using a specifically-designed questionnaire, the Positive and Negative Syndrome Scale, Barratt Impulsive Scale, Hamilton Anxiety Scale and Beck Depression Inventory. Logistic regression was performed to explore the risk factors for MA-associated psychotic symptoms. Results: A total of 1685 participants were included. Participants were predominantly aged 30 or above, unemployed, and were unmarried Han Chinese men, with limited education. The duration of MA use was more than 3 months in 72.3%. 47.8% reported that the dose of MA use was ≥ 0.2 g per occasion of use. 11.5% had used two or more synthetic drugs. The prevalence of MA-associated psychotic symptoms was 17.0% among MA users during periods of abstinence. Multiple logistic regression analyses showed that a higher dose (≥0.2 g per time), a longer duration of MA use (>3 months) a history of heroin use and a history of tobacco use were associated with MA-associated psychotic symptoms, with adjusted odds ratios (ORs) of 1.96 (95% confidence interval [CI]: 1.40-2.76), 1.98 (95% CI: 1.33-2.96) and 2.45 (95% CI: 1.67-3.60), 1.78 (95% CI: 1.27-2.49) respectively. MA-associated psychotic symptoms were less common among married/cohabitating than unmarried (OR = 0.56; 95% CI: 0.39-0.81), and unemployed than employed (OR = 0.65; 95% CI: 0.47-0.92) individuals. MA users with anxiety and depression symptoms had significantly greater risk for MA-associated psychotic symptoms by 9.70 (6.92-13.59) and 1.90 (1.36-2.65) times respectively. Individuals with higher impulsivity were more likely to have MA-associated psychotic symptoms than those with lower (OR = 2.19; CI:1.50-3.20). Conclusion: MA-associated psychotic symptoms occurred frequently among MA users in China. The efforts that facilitate drug users' attempts to reduce MA use, abstain from poly-drug use, and control associated psychiatric symptoms and impulsivity should be supported because of their potential contribution to MA-associated psychotic symptoms in this population.

The regulation of iron metabolism by hepcidin contributes to unloading-induced bone loss.

Iron overload inhibits osteoblast function and promotes osteoclastogenesis. Hepcidin plays an important role in this process. The changes in iron content and the regulation of hepcidin under unloading-induced bone loss remain unknown. A hindlimb suspension model was adopted to simulate unloading-induced bone loss in mice. The results showed that iron deposition in both liver and bone was markedly increased in hindlimb unloaded mice, and was accompanied by the upregulation of osteoclast activity and downregulation of osteoblast activity. The iron chelator deferoxamine mesylate (DFO) reduced the iron content in bone and alleviated unloading-induced bone loss. The increased iron content in bone was mainly a result of the upregulation of transferrin receptor 1 (TfR1) and divalent metal transporter 1 with iron response element (DMT1+IRE), rather than changes in the iron transporter ferroportin 1 (FPN1). The hepcidin level in the liver was significantly higher, while the FPN1 level in the duodenum was substantially reduced. However, there were no changes in the FPN1 level in bone tissue. During hindlimb unloading, downregulation of hepcidin by siRNA increased iron uptake in bone and liver, which aggravated unloading-induced bone loss. In summary, these data show that unloading-induced bone loss was orchestrated by iron overload and coupled with the regulation of hepcidin by the liver.

Integrin αvß3 mediates the synergetic regulation of core-binding factor α1 transcriptional activity by gravity and insulin-like growth factor-1 through phosphoinositide 3-kinase signaling.

Mechanical stimulation and biological factors coordinately regulate bone development and regeneration; however, the underlying mechanisms are poorly understood. Microgravity induces bone loss, which may be partly related to the development of resistance to local cytokines, including insulin-like growth factor 1 (IGF-1). Here, we report the involvement of integrin αvß3 in microgravity-associated bone loss. An established OSE-3T3 cell model was stably transfected with a 6OSE2 (Osteoblast-Specific Element 2)-luciferase reporter and cultured under simulated microgravity (SMG) and hypergravity (HG) conditions in the presence or absence of IGF-1, the disintegrin echistatin, the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, or combinations of these agents. Activity of core-binding factor α1 (Cbfa1), an essential transcription factor for osteoblastic differentiation and osteogenesis, was reflected by luciferase activity. Different gravity conditions affected the induction of IGF-1 and subsequent effects on Cbfa1 transcription activity. SMG and HG influenced the expression and activity of integrin αvß3 and phosphorylation level of p85. LY294002 inhibited the effects of HG or IGF-1 on Cbfa1 activity, indicating that HG and IGF-1 could increase Cbfa1 activity via PI3K signaling. Inhibition of integrin αvß3 by echistatin attenuated the induction of IGF-1 and thus its effect on Cbfa1 activity under normal and HG conditions. Co-immunoprecipitation demonstrated that integrin ß3 interacted with insulin receptor substrate 1, and that this interaction was decreased under SMG and increased under HG conditions. These results suggest that integrin αvß3 mediates the synergetic regulation of Cbfa1 transcription activity by gravity and IGF-1 via PI3K signaling.