CLG promotes mTOR/ULK1 pathway-mediated autophagy to inhibit OS development by inhibiting TRAF6-mediated FLT3 ubiquitination.

Corilagin (CLG) has antitumor activities in certain human malignant cancers. Herein, the effects and mechanisms of CLG on osteosarcoma (OS) were investigated. OS cell viability and proliferation were detected by MTT and colony formation assay. Cell cycle and apoptosis were examined using flow cytometry. The interaction between TRAF6 and FLT3 was investigated using a co-immunoprecipitation assay. Results demonstrated that CLG treatment inhibited OS cell viability and proliferation but promoted OS cell autophagy and apoptosis in a concentration-dependent manner. Mechanically, CLG inhibited TRAF6-mediated FLT3 ubiquitination degradation. TRAF6 overexpression abolished the effects of CLG on OS cell proliferation, autophagy, and apoptosis. Finally, CLG administration inhibited OS tumor growth in mice by inducing autophagy-dependent apoptosis. Taken together, CLG inhibited OS progression by facilitating mTOR/ULK1 pathway-mediated autophagy through inhibiting TRAF6-mediated FLT3 ubiquitination, which indicated that CLG was a promising candidate for the treatment of OS.

Enhancing diabetic wound healing through anti-bacterial and promoting angiogenesis using dual-functional slow-release microspheres-loaded dermal scaffolds.

Bacterial infections and the degeneration of the capillary network comprise the primary factors that contribute to the delayed healing of diabetic wounds. However, treatment modalities that cater to effective diabetic wounds healing in clinical settings are severely lacking. Herein, a dual-functional microsphere carrier was designed, which encapsulates polyhexamethylene biguanide (PHMB) or recombinant human vascular endothelial growth factor (rhVEGF) together. The in vitro release experiments demonstrated that the use of the microspheres ensured the sustained release of the drugs (PHMB or rhVEGF) over a period of 12 days. Additionally, the integration of these controlled-release microspheres into a dermal scaffold (DS-PLGA@PHMB/rhVEGF) imbued both antibacterial and angiogenic functions to the resulting material. Accordingly, the DS-PLGA@PHMB/rhVEGF scaffold exhibited potent antibacterial properties, effectively suppressing bacterial growth and providing a conducive environment for wound healing, thereby addressing the drawbacks associated with the susceptibility of rhVEGF to deactivation in inflammatory conditions. Additionally, the histological analysis revealed that the use of the DS-PLGA@PHMB/rhVEGF scaffold accelerated the process of wound healing by inhibiting inflammatory reactions, stimulating the production of collagen formation, and enhancing angiogenesis. This provides a novel solution for enhancing the antibacterial and vascularization capabilities of artificial dermal scaffolds, providing a beacon of hope for improving diabetic wound healing.

Casticin induces ferroptosis in human osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4.

Osteosarcoma is a primary solid bone malignancy, and surgery + chemotherapy is the most commonly used treatment. However, chemotherapeutic drugs can cause a range of side effects. Casticin, a polymethoxyflavonoid, has anti-tumor therapeutic effects. This study is aim to investigate the anti-osteosarcoma activity of casticin and explore the mechanism. Crystal violet staining, MTT assay, colony formation assay, wound healing assay, transwell assay, hoechst 33,258 staining, and flow cytometry analysis were used to investigate the effects of casticin on proliferation, migration, invasion, and apoptosis of osteosarcoma cells in vitro. The intracellular Fe2+, ROS, MDA, GSH/GSSG content changes were detected using the corresponding assay kits. The mRNA sequencing + bioinformatics analysis and western blot were used to detect the possible mechanism. We found that casticin caused G2/M phase cell cycle arrest in human osteosarcoma cells, inhibited the migration and invasion, and induced cell apoptosis and ferroptosis. Mechanistic studies showed the ferroptosis pathway was enriched stronger than apoptosis. Casticin up-regulated the expression of HMOX1, LC3 and NCOA4, meanwhile it activated MAPK signaling pathways. Animal experiments proved that casticin also inhibited the growth and metastasis of osteosarcoma cell xenograft tumor in vivo. In conclusion, casticin can induce ferroptosis in osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4. This provides a new strategy for osteosarcoma treatment.

Associations of ethylene oxide exposure and "Life's Essential 8".

Ethylene oxide (EtO) is a widely used industrial chemical with recognized health risks. While its carcinogenic properties have been extensively studied, emerging evidence suggests potential associations with cardiovascular diseases. Using the recently introduced Life's Essential 8 (LE8) score as a comprehensive cardiovascular health (CVH) measure, this study aimed to elucidate the relationship between EtO exposure and CVH. Data from the National Health and Nutrition Examination Survey (NHANES) encompassing 3748 adults was analyzed. CVH was assessed using the LE8 score, which incorporates diet, physical activity, tobacco/nicotine exposure, sleep duration, BMI, non-HDL cholesterol, blood glucose, and blood pressure. The association between EtO exposure, gauged by Hemoglobin adduct (HbEtO) levels, and CVH was examined using linear regression and Cox regression models. An inverse relationship between EtO exposure and the overall CVH score was identified. Specifically, for every 1-unit increase in ln-transformed HbEtO, a 3.69-point decrease in the total CVH score was observed. An inverted J-shaped association between ln-transformed HbEtO and CVH score emerged, with an inflection point at 3.15 pmol/g Hb. Elevated EtO exposure was not significantly linked to all-cause mortality but was robustly associated with increased cardiovascular mortality. Elevated EtO exposure is negatively associated with CVH, as outlined by the LE8 metrics. Beyond a certain threshold, this association underscores the cardiovascular risks of EtO exposure and highlights the importance of further research to determine underlying mechanisms and recommend preventive strategies.

Threshold effects and inflection points of flavonoid intake in dietary anti-inflammatory effects: Evidence from the NHANES.

Flavonoids have been shown to be beneficial in a variety of inflammatory and metabolic diseases because of their anti-inflammatory and antioxidant properties. However, previous epidemiological studies have only demonstrated a negative correlation between flavonoid intake on inflammatory markers, and the optimal intake of dietary flavonoids and subclasses in terms of dietary anti-inflammatory efficacy remains undetermined. This study was based on 3 cycles (2007-2010, 2017-2018) of the National Health and Nutrition Examination Survey and the corresponding expanded flavonoid database. Weighted multiple linear regression was used to assess linear relationships between flavonoid intake and Dietary inflammation index (DII). Smoothed curve fit and a generalized additive model were used to investigate the nonlinear relationships and threshold effects, the 2-tailed linear regression model was used to find potential inflection points. A total of 12,724 adults were included in the study. After adjusting for potential confounders, flavonoid intake was significantly associated with DII, with the strongest negative association effect for flavonols (-0.40 [-0.45, -0.35]). In subgroup analyses stratified by sex, race, age, body mass index, education levels, and diabetes, flavonol intake maintained a significant negative linear correlation with DII. In addition, we found significant nonlinear relationships (L-shaped relationships) and threshold effects between total flavonoids, flavan-3-ols, and flavanols and DII, with inflection points of 437.65 mg/days, 157.79 mg/days, and 46.36 mg/days, respectively. Our results suggest a threshold for the dietary anti-inflammatory capacity of flavonoid intake in U.S. adults.

Long non-coding HOXA-AS3 contributes to osteosarcoma progression through the miR-1286/TEAD1 axis.

Long non-coding RNA (lncRNA) HOXA cluster antisense RNA 3 (HOXA-AS3) regulates the progression of several types of human malignancy. However, the role and potential mechanism of HOXA-AS3 in osteosarcoma (OS) remain unknown. In this study, upregulation of HOXA-AS3 was observed in OS tissues and cell lines and associated with poor clinical outcomes. Silencing of HOXA-AS3 significantly inhibited the proliferation, migration and invasion of OS cells in vitro and suppressed the tumorigenesis of OS cells in vivo. Furthermore, knockdown of HOXA-AS3 inhibited the proliferation and migration of human umbilical vein endothelial cells (HUVECs) and epithelial-to-mesenchymal transition (EMT) in OS. Further investigation of this mechanism revealed that HOXA-AS3 could directly upregulate the expression of TEAD1 via its competing endogenous RNA (ceRNA) activity on miR-1286. This study clarified the oncogenic roles of the HOXA-AS3/miR-1286/TEAD1 axis in OS progression, suggesting a novel therapeutic target for OS.

Genipin Inhibits the Development of Osteosarcoma through PI3K/AKT Signaling Pathway.

BACKGROUND: Osteosarcoma is a highly invasive and early metastatic tumor. At present, the toxic and side effects of chemotherapy affect the quality of life of cancer patients to varying degrees. Genipin is an extract of the natural medicine gardenia with various pharmacological activities. OBJECTIVE: The purpose of this study was to investigate the effect of Genipin on osteosarcoma and its potential mechanism of action. METHODS: Crystal violet staining, MTT assay and colony formation assay were used to detect the effect of genipin on the proliferation of osteosarcoma. The effects of vitexin on migration and invasion of osteosarcoma were detected by scratch healing assay and transwell assay. Hoechst staining and flow cytometry were used to detect the effect of genipin on apoptosis of osteosarcoma cells. The expression of related proteins was detected by Western blot. An orthotopic tumorigenic animal model was used to verify the effect of genipin on osteosarcoma in vivo. RESULTS: The results of crystal violet staining, MTT method and colony formation method proved that genipin significantly inhibited the proliferation of osteosarcoma cells. The results of the scratch healing assay and transwell assay showed that gen significantly inhibited the migration and invasion of osteosarcoma cells. The results of Hoechst staining and flow cytometry showed that genipin significantly promoted the apoptosis of osteosarcoma cells. The results of animal experiments show that genipin has the same anti-tumor effect in vivo. Genipin may inhibit the growth of osteosarcoma through PI3K/AKT signaling. CONCLUSION: Genipin can inhibit the growth of human osteosarcoma cells, and its mechanism may be related to the regulation of PI3K/AKT signaling pathway.

A Wireless Infrared Thermometry Device for Postoperative Flap Monitoring: Proof of Concept in Patients.

BACKGROUND/NEED: Postoperative flap perfusion assessment methods still rely on the evaluation of traditional clinical indicators, which have the disadvantage of being subjective and burdensome. METHODOLOGY: This study describes a self-designed infrared wireless thermometer for flap blood supply monitoring and evaluates its efficacy in the postoperative monitoring of 40 free flaps. DEVICE DESCRIPTION: The device consists of multiple temperature and humidity modules as well as a wireless module, which has the advantages of low cost and continuous remote monitoring. PRELIMINARY RESULTS: The alarm time of the wireless infrared thermometer was 30.5 ± 3.1 hours, and the clinical observation reported 41.7 ± 13.6 hours. CURRENT STATUS: In future studies, the device will be tested on different types of flaps in a porcine model.

Superficial Circumflex Iliac Artery Perforator Flap with Bilobed Design for the Donor Defect after Wrap-Around Flap Transfer Reconstruction.

OBJECTIVE: The repair of great toe donor site defect after wrap-around flap transfer is still controversial. The bilobed superficial circumflex iliac artery perforator (SCIP) flap can improve the aesthetics of the great toe while maintaining its function. Thus, this study aimed to report our experience in the reconstruction of big toe donor site defects with the bilobed SCIP flap and describe the clinical outcomes. METHODS: This study was a retrospective trial. From May 2017 to May 2020, 13 patients with the great toe donor site defect after wrap-around flap transfer were included in this study. The average age of the patients was 44 years (range, 23-60 years). All patients received free bilobed SCIP flaps to reconstruct the donor site defect of the great toe. Relevant clinical features were recorded preoperatively. The thickness and design of the SCIP flap and the harvesting layer of the flap were measured during the operation. The survival rate of flaps and skin grafts and the incidence of infection were recorded after operation. At follow-up, donor site complications and postoperative outcomes were evaluated. RESULTS: In all cases, the SCIP flap covering the donor site of the great toe survived. All patients were followed up for 24-40 months (mean, 30.5 months). The average thickness of the SCIP flap was 0.38cm. All SCIP flaps were harvested from the superficial fascial layer except for three obese patients. The thin SCIP flap had a bilobed design with no further defatting procedures. Postoperatively, the great toe-nail flap donor site regained its original appearance without bloating or flap necrosis. There was a hidden linear scar in the groin donor site, which did not affect hip joint movement. All patients were satisfied with the aesthetics of the surgical site. CONCLUSION: The SCIP flap with bilobed design for repairing the donor defect of the great toe after wrap-around flap transfer is a kind of surgical method with excellent contour, meeting the requirements of function and aesthetics.

A wireless infrared thermometry device for postoperative flap monitoring: Proof of concept in a porcine flap model.

The application of flap surgery is becoming more and more widespread with the development of microsurgical techniques. Currently, postoperative blood flow monitoring of flaps is still mainly assessed by medical staff for traditional clinical parameters, which has the disadvantage of being subjective and unable to monitor in real-time. This study describes a self-contained infrared wireless infrared thermometry device for flap blood supply monitoring and evaluates its effectiveness on eight porcine flap models. A scapular muscle flap model was established using eight small pigs, and the vessels were ligated at irregular intervals using a lumir ligature to simulate arterial crisis and venous crisis. Laser Doppler flowmetry (LDF), the wireless infrared thermometry device, and traditional clinical observation methods were applied to monitor the blood supply of the flap and evaluate the effect. The time to the determination of blood supply disturbance by wireless infrared thermography (IRT) was 28.75 ± 3.30 min and 96.5 ± 27.09 min for the arterial and venous groups, respectively; by LDF was 6.00 ± 1.41 min and 52.75 ± 15.76 min; by clinical observation was 42.00 ± 8.60 min and 156.50 ± 40.91 min, respectively. Paired t-tests were performed between the wireless IRT device and clinical observations, and the statistical results were significantly different in the arterial group and not significantly different in the venous group. Paired t-testing of the wireless infrared thermometry device with the LDF also showed significant differences in the arterial group and non-significant differences in the venous group. This wireless infrared thermometry device outperforms traditional clinical observation methods in monitoring blood supply in a porcine skin flap model. Because of its low cost, real-time monitoring, simple operation, and non-invasive features, it has the potential to be used in clinical practice as a routine means of postoperative blood supply monitoring in flap surgery.

A Novel Bifunctional Nanoplatform with Aggregation-Induced Emission Property for Efficient Photodynamic Killing of Bacteria and Wound Healing.

Background: Photodynamic antimicrobial therapy (PDAT) has been extensively studied because of its potential applications such as precise controllability, high spatiotemporal accuracy, and non-invasiveness. More importantly, it is difficult for bacteria to develop resistance to the aforementioned PDATs. However, the selectivity of traditional PDAT methods to bacteria is generally poor, so it has been proposed to introduce positively charged components such as quaternary ammonium salts to enhance the targeting of bacteria; however, they always possess high toxicity to normal cells. As a result, measures should be taken to enhance the targeting of bacteria and avoid side effects on normal cells. Methods and Results: In our work, we creatively design a nanoplatform with high anti-bacterial efficiency, low side effects and its size is approximately 121 nm. BSA, as a nanocarrier, encapsulates the photosensitizer (E)-4-(4-(diphenylamino)styryl)-1-methylpyridin-1-ium with AIE properties named as BSA-Tpy, which increases its circulation time in vivo and improves the biocompatibility. Under acidic conditions (pH = 5.0), the surface positive charge of the BSA-Tpy is increased to +18.8 mV due to protonation of amine residues to achieve the targeting effect on bacteria. Besides, under the irradiation of white light, the BSA-Tpy will produce ROS to kill bacteria efficiently about 99.99% for both Gram-positive and Gram-negative bacteria, which shows the potential application value for the treatment of infected wounds. Conclusion: We have developed a feasible method for photodynamic antibacterial therapy, possessing excellent biocompatibility and high antibacterial efficiency with good fluorescence imaging property.

Association between SII and hepatic steatosis and liver fibrosis: A population-based study.

Background: The systemic immune-inflammation index (SII) is a novel marker of inflammation, and hepatic steatosis and fibrosis are associated with inflammation. This study aimed to investigate the possible relationship between SII and hepatic steatosis and fibrosis. Methods: The datasets from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 were used in a cross-sectional investigation. Multivariate linear regression models were used to examine the linear connection between SII and controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Fitted smoothing curves and threshold effect analysis were used to describe the nonlinear relationship. Results: This population-based study included a total of 6,792 adults aged 18-80 years. In a multivariate linear regression analysis, a significant positive association between SII and CAP was shown [0.006 (0.001, 0.010)]. This positive association in a subgroup analysis was maintained in men [0.011 (0.004, 0.018)] but not in women. Furthermore, the association between SII and CAP was nonlinear; using a two-segment linear regression model, we found an inverted U-shaped relationship between SII and CAP with an inflection point of 687.059 (1,000 cells/µl). The results of the multiple regression analysis showed that the relationship between SII and LSM was not significant (P = 0.263). Conclusions: Our findings imply that increased SII levels are linked to hepatic steatosis, but SII is not linked to liver fibrosis. To confirm our findings, more large-scale prospective investigations are needed.

Relationship between nonalcoholic fatty liver disease and bone mineral density in adolescents.

Liver metabolism is strongly linked to bone metabolism, and a significant correlation between nonalcoholic fatty liver disease (NAFLD) and bone mineral density (BMD) in adults has been demonstrated. However, the current relationship between NAFLD and BMD in the adolescent population remains controversial. The purpose of this study was to investigate the specific relationship between NAFLD and BMD in adolescents aged 12 to 19 years in the United States. The quantitative relationship between NAFLD and total BMD was investigated using multivariate logistic regression and smoothed fitted curve curves based on multiperspective data from the National Health and Nutrition Examination Survey (NHANES). A total of 740 adolescents were included in this study after excluding unusable samples. The results showed that NAFLD was positively associated with total BMD in adolescents. The results of the subgroup analysis showed that this positive association was mainly found in boys, whites and blacks. The association was not significant in girls, Mexican Americans and other racial groups. Among US adolescents, there was a significant positive association between NAFLD and total BMD, and this relationship varied by gender and race.

Saturation Effect of Body Mass Index on Bone Mineral Density in Adolescents of Different Ages: A Population-Based Study.

Background: Adolescence is a critical period for bone development, and peak bone mass may be reached in late adolescence. Boosting bone accumulation at this time can help preserve adult bone health and avoid osteoporosis later in life. Body mass index (BMI) has been found to have a favorable impact on bone mineral density (BMD) in previous research. However, excessive obesity is harmful to health and may lead to various systemic diseases. Therefore, finding an appropriate BMI to maintain a balance between obesity and BMD is critical for adolescents. Methods: The datasets from the National Health and Nutrition Examination Survey (NHANES) 2011-2020 were used in a cross-sectional investigation. Multivariate linear regression models were used to examine the linear connection between BMI and BMD. Fitted smoothing curves and threshold effect analysis were used to describe the nonlinear relationship. Subgroup analyses were then conducted based on gender and age. Results: This population-based study included a total of 6,143 adolescents aged 8-19 years. In a multivariate linear regression analysis, a good association between BMI and total BMD was shown [0.014 (0.013, 0.014)]. This positive association was maintained in all subgroup analyses grouped by sex and age. Furthermore, the association between BMI and BMD was nonlinear with a saturation point present, as evidenced by smoothed curve fitting. According to the threshold effect study, with an age group of two years, adolescents of different ages had different BMI saturation values with respect to BMD. Conclusions: Our study showed a significant positive and saturated association between BMI and BMD in adolescents aged 8-19 years. Maintaining BMI at saturation values may reduce other adverse effects while achieving optimal BMD.

High Low-Density Lipoprotein Cholesterol Levels are Associated with Osteoporosis Among Adults 20-59 Years of Age.

BACKGROUND: Serum lipids are highly inheritable and play a major role in bone health. However, the relationship between low-density lipoprotein cholesterol (LDL-C) and bone mineral density (BMD) remains uncertain. The goal of this study was to see if there was a link between LDL-C levels and BMD in persons aged 20 to 59. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018, multivariate logistic regression models were utilized to investigate the association between LDL-C and lumbar BMD. Fitted smoothing curves and generalized additive models were also used. RESULTS: The analysis included a total of 4909 adults. After controlling for various variables, we discovered that LDL-C was negatively linked with lumbar BMD. The favorable connection of LDL-C with lumbar BMD was maintained in subgroup analyses stratified by gender and race in both males and females, Whites and Mexican Americans, but not in Blacks and other races. The relationship between LDL-C and lumbar BMD in other races was an inverted U-shaped curve with the inflection point: 2.327 (mmol/L). CONCLUSION: In people aged 20 to 59, our research discovered a negative relationship among LDL-C and lumbar BMD. Among races other than Whites, Blacks, Mexican Americans, this relationship followed an inverted U-shaped curve (inflection point: 2.327mmol/L). LDL-C measurement might be used as a responsive biomarker for detecting osteoporosis early and guiding therapy.

Positive association between high-density lipoprotein cholesterol and bone mineral density in U.S. adults: the NHANES 2011-2018.

BACKGROUND: Serum lipids are highly inheritable and play a major role in bone health. However, the relationship between high-density lipoprotein cholesterol (HDL-C) and bone mineral density (BMD) remains uncertain. The goal of this study was to see if there was a link between HDL-C levels and BMD in persons aged 20-59. METHODS: Multivariate logistic regression models were used to determine the link between HDL-C and lumbar BMD using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018. Generalized additive models and fitted smoothing curves were also used. RESULTS: The analysis included a total of 10,635 adults. After controlling for various variables, we discovered that HDL-C was positively linked with lumbar BMD. The favorable connection of HDL-C with lumbar BMD was maintained in subgroup analyses stratified by sex and race in women, but not in men, and in blacks, but not in whites. The relationship between HDL-C and lumbar BMD in men and whites was a U-shaped curve with the same inflection point: 0.98 mmol/L. CONCLUSIONS: In people aged 20 to 59, our research discovered a positive relationship among HDL-C and lumbar BMD. Among males and whites, this relationship followed a U-shaped curve (inflection point: 0.98 mmol/L). HDL-C measurement might be used as a responsive biomarker for detecting osteoporosis early and guiding therapy.

Electrical stimulation by semi-implantable electrodes decreases the levels of proteins associated with sciatic nerve injury-induced muscle atrophy.

Muscle atrophy is a disease that is usually caused by denervation. The aim of the present study was to determine whether electrical stimulation by semi-implantable electrodes is capable of decreasing the levels of specific proteins associated with sciatic nerve injury-induced muscle atrophy. Male Sprague Dawley (SD) rats with damaged sciatic nerves were maintained on a 12­h light/dark cycle. Thirty-two SD rats were randomly allocated into 4 groups (each group, n=8). The rats in group C received no electrical stimulation; the rats in groups D, N and DN received electrical stimulation by semi-implantable electrodes during the daytime alone, nighttime alone and both the daytime and nighttime, respectively. Immunoblot assays were performed to detect the expression of cellular proteins associated with muscle atrophy. The number of muscle satellite cells was determined using a microscope, indicating that electrical stimulation increased the number of muscle satellite cells. Immunoblot assay results showed that electrical stimulation reduced the expression levels of cathepsin L, calpain 1 and the ubiquitinated muscle ring finger­1 (MuRF-1) protein. In conclusion, electrical stimulation by semi-implantable electrodes constitutes a potential method for the treatment of sciatic nerve injury-induced muscle atrophy. The decreased expression levels of the cellular proteins cathepsin L and calpain 1, as well as the ubiquitinated protein MuRF-1, are associated with the attenuation of sciatic nerve injury-induced muscle atrophy.