Association of conventional cigarette smoking, heated tobacco product use and dual use with hypertension.

BACKGROUND: Heated tobacco products (HTPs) have emerged as alternatives to conventional cigarettes. However, their health effects remain largely unknown. This study aimed to prospectively explore the association between the use of cigarettes and HTPs and the risk of hypertension. METHODS: This cohort study analysed data from 30 152 workers (82.0% men, mean age 42.9 ± 11.0 years) who were initially free of hypertension, participating in the Japan Epidemiology Collaboration on Occupational Health Study. Participants were categorized into five groups based on their self-reported tobacco product use: never smokers, past smokers, exclusive cigarette smokers, exclusive HTP users and dual users of cigarettes and HTPs. Hypertension cases were identified using three data points from annual health checkup data collected between 2019 and 2021. Cox proportional hazards regression models were used to investigate the association between tobacco product use and hypertension. RESULTS: During a mean follow-up of 2.6 years (range: 0.1-4.0 years), 3656 new cases of hypertension were identified. Compared with never smokers, the risk of hypertension was higher among exclusive cigarette smokers [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.13-1.41] and exclusive HTP users (HR 1.19, 95% CI 1.06-1.34). There was also a suggestion of increased risk of hypertension among dual users (HR 1.16, 95% CI 0.98-1.38). Furthermore, the risk of hypertension increased with the intensity of cigarette/HTP use in all tobacco product users. CONCLUSIONS: Similarly, both cigarette smoking and HTP use elevate the risk of hypertension. HTPs should not be regarded as less harmful alternatives to traditional cigarettes for preventing hypertension.

Association of conventional cigarette smoking, heated tobacco product use, and dual use with hearing loss: A working population-based study.

INTRODUCTION: Although conventional cigarette smoking has been linked to an increased risk of hearing loss, the association between heated tobacco products (HTPs) and hearing loss is unknown. The objective of this study was to investigate the association between cigarette and HTP use and hearing loss. METHODS: This cross-sectional study examined the data of 7769 employees from five companies (Study I) and 34404 employees from a large company (Study II), all participants in the Japan Epidemiology Collaboration on Occupational Health Study. The participants were categorized into five groups based on their self-reported tobacco use: never smokers, former smokers, exclusive cigarette smokers, exclusive users of HTPs, and those who used both cigarettes and HTPs. Hearing levels were measured using pure-tone audiometry at 1 and 4 kHz frequencies. Separate analyses were carried out for each study, and the results were then combined using fixed-effect models to pool the estimates. RESULTS: The analysis included 42173 participants, with a prevalence of 12.9% for exclusive cigarette smoking, 9.8% for exclusive HTP use, and 5.5% for dual use. The pooled adjusted odds ratios with 95% confidence intervals for unilateral hearing loss at 4 kHz were 1.21 (95% CI: 1.10-1.33) for former smokers, 1.83 (95% CI: 1.64-2.05) for exclusive cigarette smokers,1.46 (95% CI: 1.28-1.67) for exclusive HTP users, and 1.66 (95% CI: 1.41-1.96) for dual users, compared to never smokers. Additionally, the adjusted odds ratios for hearing loss at 4 kHz among exclusive cigarette smokers, exclusive HTP users, and dual users increased with the intensity of cigarette/HTP consumption (all p for trend <0.001). No significant associations were found between exclusive HTP use, dual use, and hearing loss at 1 kHz, apart from exclusive cigarette smoking. CONCLUSIONS: In this cross-sectional study, associations were found between exclusive cigarette smoking, exclusive HTP use, dual use, and hearing loss, particularly at 4 kHz. Further research is needed to confirm these findings.

Application of Natural Medicinal Plants Active Ingredients in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignant cancer of the head and neck, with high morbidity and mortality, ranking as the sixth most common cancer in the world. The treatment of OSCC is mainly radiotherapy, chemotherapy and surgery, however, the prognosis of patients is still poor and the recurrence rate is high. This paper reviews the range of effects of natural medicinal plant active ingredients (NMPAIs) on OSCC cancer, including the types of NMPAIs, anti-cancer mechanisms, involved signaling pathways, and clinical trials. The NMPAIs include terpenoids, phenols, flavonoids, glycosides, alkaloids, coumarins, and volatile oils. These active ingredients inhibit proliferation, induce apoptosis and autophagy, inhibit migration and invasion of OSCC cells, and regulate cancer immunity to exert anti-cancer effects. The mechanism involves signaling pathways such as mitogen-activated protein kinase, phosphatidylinositol 3 kinase/protein kinase B, nuclear factor kappa B, miR-22/WNT1/ß-catenin and Nrf2/Keap1. Clinically, NMPAIs can inhibit the growth of OSCC, and the combined drug is more effective. Natural medicinal plants are promising candidates for the treatment of OSCC.

Worm-Based Diagnosis Combining Microfluidics toward Early Cancer Screening.

Early cancer diagnosis increases therapy efficiency and saves huge medical costs. Traditional blood-based cancer markers and endoscopy procedures demonstrate limited capability in the diagnosis. Reliable, non-invasive, and cost-effective methods are in high demand across the world. Worm-based diagnosis, utilizing the chemosensory neuronal system of C. elegans, emerges as a non-invasive approach for early cancer diagnosis with high sensitivity. It facilitates effectiveness in large-scale cancer screening for the foreseeable future. Here, we review the progress of a unique route of early cancer diagnosis based on the chemosensory neuronal system of C. elegans. We first introduce the basic procedures of the chemotaxis assay of C. elegans: synchronization, behavior assay, immobilization, and counting. Then, we review the progress of each procedure and the various cancer types for which this method has achieved early diagnosis. For each procedure, we list examples of microfluidics technologies that have improved the automation, throughput, and efficiency of each step or module. Finally, we envision that microfluidics technologies combined with the chemotaxis assay of C. elegans can lead to an automated, cost-effective, non-invasive early cancer screening technology, with the development of more mature microfluidic modules as well as systematic integration of functional modules.

Should insulin resistance (HOMA-IR), insulin secretion (HOMA-ß), and visceral fat area be considered for improving the performance of diabetes risk prediction models.

INTRODUCTION: Insulin resistance and defects in pancreatic beta cells are the two major pathophysiologic abnormalities that underlie type 2 diabetes. In addition, visceral fat area (VFA) is reported to be a stronger predictor for diabetes than body mass index (BMI). Here, we tested whether the performance of diabetes prediction models could be improved by adding HOMA-IR and HOMA-ß and replacing BMI with VFA. RESEARCH DESIGN AND METHODS: We developed five prediction models using data from a cohort study (5578 individuals, of whom 94.7% were male, and 943 had incident diabetes). We conducted a baseline model (model 1) including age, sex, BMI, smoking, dyslipidemia, hypertension, and HbA1c. Subsequently, we developed another four models: model 2, predictors in model 1 plus fasting plasma glucose (FPG); model 3, predictors in model 1 plus HOMA-IR and HOMA-ß; model 4, predictors in model 1 plus FPG, HOMA-IR, and HOMA-ß; model 5, replaced BMI with VFA in model 2. We assessed model discrimination and calibration for the first 10 years of follow-up. RESULTS: The addition of FPG to model 1 obviously increased the value of the area under the receiver operating characteristic curve from 0.79 (95% CI 0.78, 0.81) to 0.84 (0.83, 0.85). Compared with model 1, model 2 also significantly improved the risk reclassification and discrimination, with a continuous net reclassification improvement index of 0.61 (0.56, 0.70) and an integrated discrimination improvement index of 0.09 (0.08, 0.10). Adding HOMA-IR and HOMA-ß (models 3 and 4) or replacing BMI with VFA (model 5) did not further materially improve the performance. CONCLUSIONS: This cohort study, primarily composed of male workers, suggests that a model with BMI, FPG, and HbA1c effectively identifies those at high diabetes risk. However, adding HOMA-IR, HOMA-ß, or replacing BMI with VFA does not significantly improve the model. Further studies are needed to confirm our findings.

Integrated microbiome and metabolomics revealed the protective effect of baicalin on alveolar bone inflammatory resorption in aging.

BACKGROUND: With the growing aging population and longer life expectancy, periodontitis and tooth loss have become major health concerns. The gut microbiota, as a key regulator in bone homeostasis, has gathered immense interest. Baicalin, a flavonoid compound extracted from Scutellaria baicalensis Georgi, has shown antioxidant and anti-inflammatory activities. PURPOSE: This study investigated, for the first time, the protective mechanism of baicalin against alveolar bone inflammatory resorption in aging mice by regulating intestinal flora and metabolites, as well as intestinal barrier function. METHODS: A ligature-induced periodontitis model was established in d-galactose (D-gal)-induced aging mice, and baicalin was administered at different dosages for 13 weeks. Body weight was measured weekly. The antioxidant and anti-inflammatory activity of baicalin were evaluated using serum superoxide dismutase (SOD), malonaldehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels. The immune capability was assessed by thymus and spleen indices. Histopathological changes were observed in the heart, liver, ileum, and periodontal tissues. Alveolar bone absorption of maxillary second molars was examined, and osteoclasts were counted by tartrate-resistant acid phosphatase (TRAP) staining. Furthermore, fecal samples were analyzed using 16S rRNA sequencing and non-targeted metabolomics to identify differences in intestinal bacterial composition and metabolites. RESULTS: Baicalin exhibited anti-aging properties, as evidenced by increased SOD activity and decreased levels of MDA, IL-6, and TNF-α in serum compared to the control group. Baicalin also ameliorated alveolar bone loss in the d-gal-induced aging-periodontitis group (p < 0.05). Furthermore, baicalin restored ileal permeability by up-regulating the expression of ZO-1 and occludin in aging-periodontitis groups (p < 0.05). Alpha diversity analysis indicated that baicalin-treated mice harbored a higher diversity of gut microbe. PCoA and ANOSIM results revealed significant dissimilarity between groups. The Firmicutes/Bacteroidetes (F/B) ratio, which decreased in periodontitis mice, was restored by baicalin treatment. Additionally, medium-dosage baicalin promoted the production of beneficial flavonoids, and enriched short-chain fatty acids (SCFAs)-producing bacteria. CONCLUSION: Intestinal homeostasis is a potential avenue for treating age-related alveolar bone loss. Baicalin exerts anti-inflammatory, antioxidant, and osteo-protective properties by regulating the gut microbiota and metabolites.

Boosting the Cycle Performance of Iron Trifluoride Based Solid State Batteries at Elevated Temperatures by Engineering the Cathode Solid Electrolyte Interface.

Iron trifluoride (FeF3) is attracting tremendous interest due to its lower cost and the possibility to enable higher energy density in lithium-ion batteries. However, its cycle performance deteriorates rapidly in less than 50 cycles at elevated temperatures due to cracking of the unstable cathode solid electrolyte interface (CEI) followed by active materials dissolution in liquid electrolyte. Herein, by engineering the salt composition, the Fe3O4-type CEI with the doping of boron (B) atoms in a polymer electrolyte at 60 °C is successfully stabilized. The cycle life of the well-designed FeF3-based composite cathode exceeds an unprecedented 1000 cycles and utilizes up to 70% of its theoretical capacities. Advanced electron microscopy combined with density functional theory (DFT) calculations reveal that the B in lithium salt migrates into the cathode and promotes the formation of an elastic and mechanic robust boron-contained CEI (BOR-CEI) during cycling, by which the durability of the CEI to frequent cyclic large volume changes is significantly enhanced. To this end, the notorious active materials dissolution is largely prohibited, resulting in a superior cycle life. The results suggest that engineering the CEI such as tuning its composition is a viable approach to achieving FeF3 cathode-based batteries with enhanced performance.

The mechanism of high mobility group box-1 protein and its bidirectional regulation in tumors.

High mobility group protein box-1 (HMGB1) is a nonhistone chromatin-related protein widely found in eukaryotic cells. It is involved in the transcription, replication and repair of DNA to maintain nuclear homeostasis. It participates in cell growth, differentiation and signal transduction. Recent studies showed that HMGB1 has a bidirectional regulatory effect on tumors by regulating TLR4/MYD88/NF-κB and RAGE/AMPK/mTOR signaling pathways. On one hand, it is highly expressed in a variety of tumors, promoting tumor proliferation and invasion, whilst on the other hand, it induces autophagy and apoptosis of tumor cells and stimulates tumor-infiltrating lymphocytes to produce anti-tumor immune response. At present, HMGB1 could be used as a target to regulate the drug-resistance and prognostication in cancer. Clinical applications of HMGB1 in cancer need further in-depth studies.

A case report and literature review of immune checkpoint inhibitor-associated pneumonia caused by penpulimab.

Objective: From the perspective of intensive care physicians, this paper reviews the diagnosis and treatment of CIP patients, analyzes and refines relevant literature on CIP. To summarize the characteristics of diagnosis and treatment of severe CIP provides the basis and reference for early identification, diagnosis and treatment. Methods: A case of severe CIP caused by piamprilizumab and ICI was reviewed and the literature was reviewed. Results: This was a patient with lung squamous cell carcinoma with lymphoma who had been treated with multiple chemoradiotherapy and immunotherapy with piamprizumab. The patient was admitted to the ICU with respiratory failure. The intensive care physician performs anti-infective, fluid management, hormonal anti-inflammatory, respiratory and nutritional support treatment, and relies on mNGS to exclude severe infection and CIP treatment, thus successfully saving the patient's life and improving discharge. Conclusions: The incidence of CIP is very low, and its diagnosis should be combined with clinical manifestations and previous drug use. mNGS can provide certain value in the exclusion of severe infections, so as to provide basis and reference for the early identification, diagnosis and treatment of severe CIP.

Tumor necrosis factor-α stimulation endothelial-to-mesenchymal transition during cardiac fibrosis via endothelin-1 signaling.

Cardiac fibrosis is an important pathological change after myocardial infarction (MI). High concentration of tumor necrosis factor-α (TNF-α) contributes to cardiac fibrosis, and TNF-α has been demonstrated to be involved in transforming growth factor-ß1-induced endothelial-to-mesenchymal transition (EndMT). However, the role and molecular mechanisms of TNF-α during cardiac fibrosis remain largely unexplored. In this study, we demonstrated that TNF-α and endothelin-1 (ET-1) were upregulated in cardiac fibrosis after MI, and genes associated with EndMT were also upregulated. An in vitro model of EndMT demonstrated that TNF-α promoted EndMT by upregulation of vimentin and α-smooth muscle actin, and which strongly increased ET-1 expression. ET-1 promoted TNF-α-induced expression of gene program through phosphorylation levels of SMAD family member 2, while subsequent inhibition of ET-1 almost abolished the effect of TNF-α during the process of EndMT. In summary, these findings demonstrated that ET-1 is involved in the EndMT induced by TNF-α during cardiac fibrosis.

Blood selenium level can alleviate the nephrotoxicity of lead and cadmium in the general population of the United States: a retrospective cross section analysis of population-based nationally representative data.

The current understanding of the interplay between blood selenium, cadmium and lead levels, and chronic kidney disease (CKD) is limited. Our objective was to investigate whether elevated blood selenium levels can mitigate the nephrotoxic effects of lead and cadmium. The exposure variables examined in this study include blood selenium, cadmium, and lead levels measured by ICP-MS. The outcome of interest was CKD, defined as an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2. In total, 10630 participants (mean (SD) age:48.9 ± 18.4; 48.3% male) were included in this analysis. The median (IQR) of blood selenium, cadmium, and lead levels was 191 (177-207) µg/L, 0.300 (0.180-0.540) µg/L, and 0.940 (0.570-1.510) µg/dL, respectively. We observed a significant positive association between cadmium and lead levels and CKD (OR; 1.86; 95%CI: 1.31- 2.64; OR:2.23; 95%CI:1.54-3.24). However, selenium had a negative association with CKD (OR:0.096; 95%CI:0.020-0.457). Based on a reference group with a selenium concentration of ≤ 191 µg/L and cadmium level of > 0.300 µg/L, a significant protective factor in the CKD was seen in subjects with high plasma selenium and lower cadmium concentrations (OR:0.685; 95%CI:0.515-0.912). Then selenium concentration of ≤ 191 µg/L and lead level of > 0.940 µg/dL were set as a reference group, and the OR for CKD decreased among the other group (OR:0.564; 95%CI;0.417- 0.762). The subgroup analysis indicated that there were no effect modifiers. Blood selenium has the potential to mitigate the nephrotoxic effects of lead and cadmium in the general population of the United States.

Structural basis of human PRPS2 filaments.

BACKGROUND: PRPP synthase (PRPS) transfers the pyrophosphate groups from ATP to ribose-5-phosphate to produce 5-phosphate ribose-1-pyrophosphate (PRPP), a key intermediate in the biosynthesis of several metabolites including nucleotides, dinucleotides and some amino acids. There are three PRPS isoforms encoded in human genome. While human PRPS1 (hPRPS1) and human PRPS2 (hPRPS2) are expressed in most tissues, human PRPS3 (hPRPS3) is exclusively expressed in testis. Although hPRPS1 and hPRPS2 share 95% sequence identity, hPRPS2 has been shown to be less sensitive to allosteric inhibition and specifically upregulated in certain cancers in the translational level. Recent studies demonstrate that PRPS can form a subcellular compartment termed the cytoophidium in multiple organisms across prokaryotes and eukaryotes. Forming filaments and cytoophidia is considered as a distinctive mechanism involving the polymerization of the protein. Previously we solved the filament structures of Escherichia coli PRPS (ecPRPS) using cryo-electron microscopy (cryo-EM) 1. RESULTS: Order to investigate the function and molecular mechanism of hPRPS2 polymerization, here we solve the polymer structure of hPRPS2 at 3.08 Å resolution. hPRPS2 hexamers stack into polymers in the conditions with the allosteric/competitive inhibitor ADP. The binding modes of ADP at the canonical allosteric site and at the catalytic active site are clearly determined. A point mutation disrupting the inter-hexamer interaction prevents hPRPS2 polymerization and results in significantly reduced catalytic activity. CONCLUSION: Findings suggest that the regulation of hPRPS2 polymer is distinct from ecPRPS polymer and provide new insights to the regulation of hPRPS2 with structural basis.

Effect of Alloying Powders on Microstructure and Mechanical Properties of Aluminum Alloy Arc Additive Manufacturing.

Cold metal transfer arc additive manufacturing technique was used to produce 5356 aluminum alloy by adding refining agents to solve the problems of coarse grains and poor performance. Metallic powders (Ti, TiH, and Ti+B4C) were used to refine the grain size and promote the mechanical properties of the alloy. The effects of refining agents on the microstructure and mechanical properties of straight wall samples (SWSs) were studied. Samples with Ti+B4C addition had a profound impact on morphology. However, the TiH added sample revealed uneven transition between sediment layers, unstable precipitation process, unstable wall height and wall width, poor morphology, and defects. All SWSs with powder addition revealed the formation of the Al3Ti phase. Moreover, the columnar grains between the layers were transformed into equiaxed grains and finer grains at the center of the layers. There was a significant effect of TiH on the grain refinement. The samples with Ti demonstrated superior mechanical properties. The tensile strength and elongation of the SWSs increased by 28 MPa and 4.6% in the parallel additive direction and by 37 MPa and 8.9% in the vertical direction. The addition of Ti also contributed to the even distribution of the mechanical properties in both directions.

Anticancer Activity of Diosgenin and Its Molecular Mechanism.

Diosgenin, a steroidal sapogenin, obtained from Trigonella foenum-graecum, Dioscorea, and Rhizoma polgonati, has shown high potential and interest in the treatment of various cancers such as oral squamous cell carcinoma, laryngeal cancer, esophageal cancer, liver cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, glioma, and leukemia. This article aims to provide an overview of the in vivo, in vitro, and clinical studies reporting the diosgenin's anticancer effects. Preclinical studies have shown promising effects of diosgenin on inhibiting tumor cell proliferation and growth, promoting apoptosis, inducing differentiation and autophagy, inhibiting tumor cell metastasis and invasion, blocking cell cycle, regulating immunity and improving gut microbiome. Clinical investigations have revealed clinical dosage and safety property of diosgenin. Furthermore, in order to improve the biological activity and bioavailability of diosgenin, this review focuses on the development of diosgenin nano drug carriers, combined drugs and the diosgenin derivatives. However, further designed trials are needed to unravel the diosgenin's deficiencies in clinical application.

Elevated expression of TNFRSF4 impacts immune cell infiltration and gene mutation in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes prognostic prediction challenging.We aimed to investigate association of TNFRSF4 expression with the immune infiltration and gene mutation in HCC. METHODS: In this study, the expression profiles and corresponding clinical data of HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database.Kaplan-Meier and Cox regression were used to evaluate the clinical value of TNFRSF4. ESTIMATE and CIBERSORT algorithms were applied to investigate the infiltration ratio of 22 immune cells. The WGCNA and LASSO COX algorithms were performed, establishing a prognostic risk model that was then validated by HCC samples from GEO. Finally, the effects on gene mutation occurring in HCC patients of TNFRSF4 expression and risk score were appraised. RESULTS: In HCC tissues, it was found the TNFRSF4 expression profile was significantly different with age, gender, tumor grade, disease stage, prominently affecting the survival outcome and prognosis of patients. Univariate and multivariate COX regression analysis suggested that TNFRSF4 was an independent prognostic marker. Samples of high/low expression of TNFRSF4 were screened for differential genes, and then the WGCNA and LASSO COX constructed a 13-gene signature, excellently dividing samples into hign/low risk groups. Compared with the low-risk group, the overall survival (OS) of high-risk group was markedly lower, with P< 0.0001. By ROC curve analysis, the predictive ability of the 13-gene signature was further confirmed. Both the high/low TNFRSF4 expression and the high/low risk score were demonstrated to exert effects on the frequency of gene mutation in HCC. CONCLUSIONS: As an independent prognostic marker of HCC, TNFRSF4 was found simultaneously to affect the immune infiltration of cells and the frequency of gene mutations.

Heated tobacco product use and abnormal glucose metabolism: a working population-based study.

AIMS: We aimed to assess the cross-sectional association of heated tobacco product (HTP) use with prediabetes and diabetes. METHODS: The present analysis included 8950 workers from 5 companies (Study I) and 31,341 workers from another large company (Study II), who participated in the Japan Epidemiology Collaboration on Occupational Health Study. The participants were divided into five groups: never smokers, past smokers, exclusive HTP users, dual users of cigarettes and HTPs, and exclusive cigarette smokers. Diabetes and prediabetes were defined according to the fasting blood glucose and HbA1c levels and self-reported diabetes treatment, using the American Diabetes Association criteria. We analyzed the data of Study I and II separately, and then pooled these estimates using the fixed-effect models, with adjustment for a wide range of covariates. RESULTS: In this study that included 40,291 participants (mean age, 46.6 years; men, 84.3%), about half of the current tobacco-related product users reported using HTPs. Exclusive HTP users had higher odds of prediabetes (pooled odds ratio 1.36; 95% CI 1.25-1.47) and diabetes (1.68; 95% CI 1.45-1.94) than never smokers. Similarly, dual users also had increased odds of prediabetes (pooled odds ratio, 1.26; 95% CI 1.13-1.39) and diabetes (1.93; 95% CI 1.63-2.29). The strength of these associations was comparable to that of cigarette smokers. We observed significantly higher HbA1c and fasting blood glucose levels among both exclusive HTP users and dual users compared to never smokers. CONCLUSION: HTP use was associated with an increased likelihood of prediabetes and diabetes. Prospective studies are warranted to confirm the cross-sectional association.

Stage-specific and location-specific cartilage calcification in osteoarthritis development.

OBJECTIVES: This study investigated the stage-specific and location-specific deposition and characteristics of minerals in human osteoarthritis (OA) cartilages via multiple nano-analytical technologies. METHODS: Normal and OA cartilages were serially sectioned for micro-CT, scanning electron microscopy with energy dispersive X-ray spectroscopy, micro-Raman spectroscopy, focused ion beam scanning electron microscopy, high-resolution electron energy loss spectrometry with transmission electron microscopy, nanoindentation and atomic force microscopy to analyse the structural, compositional and mechanical properties of cartilage in OA progression. RESULTS: We found that OA progressed by both top-down calcification at the joint surface and bottom-up calcification at the osteochondral interface. The top-down calcification process started with spherical mineral particle formation in the joint surface during early-stage OA (OA-E), followed by fibre formation and densely packed material transformation deep into the cartilage during advanced-stage OA (OA-A). The bottom-up calcification in OA-E started when an excessive layer of calcified tissue formed above the original calcified cartilage, exhibiting a calcified sandwich structure. Over time, the original and upper layers of calcified cartilage fused, which thickened the calcified cartilage region and disrupted the cartilage structure. During OA-E, the calcified cartilage was hypermineralised, containing stiffer carbonated hydroxyapatite (HAp). During OA-A, it was hypomineralised and contained softer HAp. This discrepancy may be attributed to matrix vesicle nucleation during OA-E and carbonate cores during OA-A. CONCLUSIONS: This work refines our current understanding of the mechanism underlying OA progression and provides the foothold for potential therapeutic targeting strategies once the location-specific cartilage calcification features in OA are established.

Effect of maleic anhydride grafted poly(lactic acid) on rheological behaviors and mechanical performance of poly(lactic acid)/poly(ethylene glycol) (PLA/PEG) blends.

A series of polylactic acid (PLA)/polyethylene glycol (PEG) blends was prepared by melt blending using PEG as a plasticizer to address the disadvantages of PLA brittleness. PEG can weaken the intermolecular chain interactions of PLA and improve its processing properties. PLA-grafted maleic anhydride (GPLA) was reactively blended with PLA/PEG to obtain a high tenacity PLA/PEG/GPLA blend. GPLA was prepared by melt grafting using diisopropyl peroxide as the initiator and maleic anhydride as the graft. The effects of different PEG molecular weights (1000-10 000 g mol-1) on the properties of PLA/PEG/GPLA blends were investigated. GPLA reacted with PEG1000 (M w = 1000 g mol-1) to form short PLA branched chains and reacted with PEG10000 (M w = 10 000 g mol-1) to form a small number of PLA branched chains, which was unconducive to increasing the intermolecular chain entanglement. The branched PLA formed by the reaction between PEG6000 (M w = 6000 g mol-1) and GPLA had a remarkable effect on increasing intermolecular chain entanglement. The complex viscosity, modulus, and melt strength values of PLA/PEG6000/GPLA blends were relatively large. The elongation at break of the blends reached 526.9%, and the tensile strength was 30.91 MPa. It provides an effective way to prepare PLA materials with excellent comprehensive properties.

Effects of Sophora flavescens aiton and the absorbed bioactive metabolite matrine individually and in combination with 5-fluorouracil on proliferation and apoptosis of gastric cancer cells in nude mice.

Background: Sophora flavescens aiton (SFA) and its main bioactive metabolite matrine are widely used in traditional Chinese medicine (TCM) preparations and have achieved good curative effects for the treatment of various tumors. However, the mechanisms underlying SFA and matrine individually and in combination with chemotherapeutic drugs for treatment of gastric cancer (GC) remain unclear. Aim of the study: To elucidate the mechanisms underlying the ability of SFA and matrine individually and in combination with chemotherapeutic drugs to inhibit proliferation and promote apoptosis of human GC cells. Materials and methods: Forty-eight nude mice were randomly divided into six groups that were treated with normal saline (model group), 5-fluorouracil (5-FU), SFA decoction (SFAD), matrine, SFAD+5-FU, or matrine+5-FU. A subcutaneous heterotopic tumor model was established in nude mice by implantation of human GC BGC-823 cells. All mice were treated for 28 days. Bioactive metabolites in SFA were determined by HPLC-MS/MS. The tumor volume, tumor weight, and tumor inhibition rate of mice were documented. Histopathology and ultramicroscopic pathology of tumor tissues were observed. The tumor cell cycle and apoptosis in vivo were detected. Serum levels of PCNA, BAX, Bcl-2, Caspase-9, Caspase-3 and cleaved Caspase-3 were measured. Protein levels of MS4A10, MS4A8, MS4A7, PCNA, BAX, Bcl-2, Caspase-3, and cleaved Caspase-3 were measured in tumor tissues. Results: Both SFAD and matrine inhibited the growth of transplanted GC cells, which was more effective when combined with 5-FU. The tumor inhibition rates of the 5-FU, SFAD, matrine, SFAD+5-FU, and matrine+5-FU groups were 53.85%, 33.96%, 30.44%, 59.74%, and 56.55%, respectively. The body weight of tumor-bearing nude mice was greater in the SFAD group than the normal saline and matrine groups. SFAD+5-FU and matrine+5-FU blocked BGC-823 cells in the G0-G1/S transition, promoted apoptosis, and significantly decreased the content of serum apoptosis-inhibitory proteins (PCNA and Bcl-2) as well as protein expression of MS4A8, MS4A10, Bcl-2, and PCNA in tumor tissues, while increasing serum levels of pro-apoptotic proteins (Caspase-9, Caspase-3 and cleaved-Caspase-3) and protein expression of BAX and cleaved-Caspase-3 in tumor tissues. Conclusion: SFAD and matrine both individually and in combination with 5-FU ameliorated malignancy of transplanted tumors by reducing proliferation and promoting apoptosis of BGC-823 cells. These findings confirm the anti-tumor synergistic effect of TCM and chemotherapeutic drugs.

Heated tobacco products and circulating high-density lipoprotein cholesterol concentrations.

We aimed to assess the association between heated tobacco product (HTP) use and high-density lipoprotein cholesterol (HDL-C) concentration. Our study included 12,268 workers from five companies (Study I) and 36,503 workers from another large company (Study II). Participants were categorized into five groups: never smokers, past smokers, exclusive HTP users, dual users of cigarettes and HTPs, and exclusive cigarette smokers. We analyzed the data of Studies I and II separately and then pooled these estimates using a fixed-effect model. Of the 48,771 participants, 9.3% were exclusive HTP users, and 6.0% were dual users. Exclusive HTP users had modestly but significantly lower concentrations of HDL-C than never smokers, with the pooled mean difference being - 1.1 (95% CI - 1.5 to - 0.6) mg/dL. Dual users showed a further reduction (mean difference - 3.7 (- 4.2 to - 3.2) mg/dL), which was comparable to that of exclusive cigarette smokers versus never smokers (mean difference - 4.3 (- 4.7 to - 3.9) mg/dL). The pooled odds ratios (95% CIs) of having low HDL-C (< 40 mg/dL for men and 50 mg/dL for women) were 1, 0.99 (0.90-1.11), 1.25 (1.09-1.43), 2.02 (1.76-2.32), and 2.09 (1.88-2.32) for never smokers, past smokers, exclusive HTP users, dual users, and exclusive cigarette smokers, respectively. In conclusion, exclusive HTP users had lower HDL-C concentrations than never smokers, although higher than exclusive cigarette smokers. Moreover, dual users had HDL-C concentrations similar to those in exclusive cigarette smokers.