BACKGROUND: Enzalutamide, a second-generation androgen receptor (AR) pathway inhibitor, is widely used in the treatment of castration-resistant prostate cancer. However, after a period of enzalutamide treatment, patients inevitably develop drug resistance. In this study, we characterized leucine-rich repeated G-protein-coupled receptor 5 (LGR5) and explored its potential therapeutic value in prostate cancer. METHODS: A total of 142 pairs of tumor and adjacent formalin-fixed paraf-fin-embedded tissue samples from patients with prostate cancer were collected from the Pathology Department at Sun Yat-sen Memorial Hos-pital. LGR5 was screened by sequencing data of enzalutamide-resistant cell lines combined with sequencing data of lesions with different Gleason scores from the same patients. The biological function of LGR5 and its effect on enzalutamide resistance were investigated in vitro and in vivo . Glutathione-S-transferase (GST) pull-down, coimmunoprecipitation, Western blotting, and immunofluorescence assays were used to explore the specific binding mechanism of LGR5 and related pathway changes. RESULTS: LGR5 was significantly upregulated in prostate cancer and negatively correlated with poor patient prognosis. Overexpression of LGR5 promoted the malignant progression of prostate cancer and reduced sensitivity to enzalutamide in vitro and in vivo . LGR5 promoted the phosphorylation of glycogen synthase kinase-3β (GSK-3β) by binding heat shock protein 90,000 alpha B1 (HSP90AB1) and mediated the activation of the Wingless/integrated (WNT)/β-catenin signaling pathway. The increased β-catenin in the cytoplasm entered the nucleus and bound to the nuclear AR, promoting the transcription level of AR, which led to the enhanced tolerance of prostate cancer to enzalutamide. Reducing HSP90AB1 binding to LGR5 significantly enhanced sensitivity to enzalutamide. CONCLUSIONS LGR5 directly binds to HSP90AB1 and mediates GSK-3β phosphorylation, promoting AR expression by regulating the WNT/β-catenin signaling pathway, thereby conferring resistance to enzalutamide treatment in prostate cancer.
Male ; Humans ; Phenylthiohydantoin/pharmacology* ; Benzamides ; Receptors, G-Protein-Coupled/genetics* ; Nitriles ; Cell Line, Tumor ; HSP90 Heat-Shock Proteins/metabolism* ; Drug Resistance, Neoplasm/genetics* ; Prostatic Neoplasms/drug therapy* ; beta Catenin/metabolism* ; Receptors, Androgen/genetics* ; Animals ; Mice ; Wnt Signaling Pathway/physiology*

Heat acclimation provides cardiovascular protection in high-temperature environments through multilevel mechanisms; however, the complete molecular basis of its effects remains unclear. In this paper, we systematically review the effects of heat acclimation on blood volume, vascular function, cardiac structure, energy metabolism, and anti-stress regulation, revealing their potential mechanisms in cardiovascular adaptive protection. We also summarizes the multilevel responses induced by heat stress and heat acclimation, including the modulatory effects of heat acclimation on heat shock proteins (HSPs), hypoxia inducible factor 1 (HIF-1), and apoptotic pathways. Additionally, we highlights the comprehensive protective effects of heat acclimation across various stressors (e.g., hypoxia, heat stress). This review provides a significant physiological basis for cardiovascular disease management and sports medicine, emphasizing the potential application of heat acclimation in response to multiple stressors and supporting its role as an effective tool in cardiovascular health management and stress protection interventions.
Humans ; Acclimatization/physiology* ; Hot Temperature ; Heat-Shock Proteins/metabolism* ; Animals ; Heat-Shock Response/physiology* ; Hypoxia-Inducible Factor 1/metabolism* ; Apoptosis/physiology*

Colorectal cancer(CRC) is one of the most common malignant tumors worldwide, primarily originating from recurrent inflammatory bowel disease(IBD). Therefore, blocking the inflammation-cancer transformation in the colon has become a focus in the early prevention and treatment of CRC. The inflammation-cancer transformation in the colon involves multiple types of cells and complex pathological processes, including inflammatory responses and tumorigenesis. In this complex pathological process, immune cells(including non-specific and specific immune cells) and non-immune cells(such as tumor cells and fibroblasts) interact with each other, collectively promoting the progression of the disease. In traditional Chinese medicine(TCM), inflammation-cancer transformation in the colon belongs to the categories of dysentery and diarrhea, with the main pathogenesis being cold and heat in complexity. This paper first elaborates on the complex molecular mechanisms involved in the inflammation-cancer transformation process in the colon from the perspectives of inflammation, cancer, and their mutual influences. Subsequently, by comparing the pathogenic characteristics and clinical manifestations between inflammation-cancer transformation and the TCM pathogenesis of cold and heat in complexity, this paper explores the intrinsic connections between the two. Furthermore, based on the correlation between inflammation-cancer transformation in the colon and the TCM pathogenesis, this paper delves into the importance of the interaction between inflammation and cancer. Finally, it summarizes and discusses the clinical and basic research progress in the TCM intervention in the inflammation-cancer transformation process, providing a theoretical basis and treatment strategy for the treatment of CRC with integrated traditional Chinese and Western medicine.
Humans ; Colon/pathology* ; Integrative Medicine ; Animals ; Cold Temperature ; Cell Transformation, Neoplastic/drug effects* ; Medicine, Chinese Traditional ; Hot Temperature ; Inflammation ; Drugs, Chinese Herbal/therapeutic use* ; Colonic Neoplasms/drug therapy*

Heat shock protein 70 (HSP70), an evolutionarily conserved molecular chaperone, serves as a central regulator within tumor immune networks. This review summarizes the multiple immune regulatory mechanisms mediated by HSP70 through its specific domains: promoting antigen presentation and cross-presentation processes; prolonging immune response duration; regulating innate and adaptive immune responses; and interacting with immune checkpoint molecules like programmed death-1 ligand 1 (PD-L1). In translation of clinical research, HSP70 can serve as a vaccine adjuvant to enhance immunogenicity, while its inhibitors can overcome resistance to immunotherapy. Additionally, membrane-bound HSP70 represents a potential immunotherapeutic target, and its targeting strategies show significant synergistic effects when combined with immune checkpoint inhibitors. However, due to the functional redundancy of the molecular chaperone network, the clinical efficacy of single-agent HSP70 inhibition is limited. In-depth elucidation of HSP70's synergistic regulatory mechanisms within the chaperone interaction network has important implications for developing novel tumor immunotherapy strategies.
HSP70 Heat-Shock Proteins/metabolism* ; Humans ; Immunotherapy/methods* ; Neoplasms/immunology* ; Animals ; B7-H1 Antigen/metabolism*

BACKGROUND: High temperatures are known to be associated with an increased risk of self-harm, but the influence of demographic changes and country-level indicators on the burden of heat-related self-harm remains unclear. This study examined the key factors driving changes in self-harm mortality linked to high temperatures and explored their impact at the country level. METHODS: This is an ecological study that analyzes data from the 2021 Global Burden of Disease (GBD) study, the World Bank, and the Climate Research Unit (CRU) were analyzed. Decomposition analyses were used to identify key factors driving changes in high temperature-related self-harm mortality between 1990 and 2021. A panel data model assessed the impact of national indicators on heat-related self-harm mortality. RESULTS: In 2021, 14,885 deaths globally were attributed to heat-related self-harm, a 41.94% increase from 1990, with low-middle SDI regions accounting for 47.84% of these deaths. While the global death rate from heat-related self-harm declined slightly over this period, South Asia and low-middle SDI regions contributed most to the decline. However, population aging exacerbated mortality rates. Demographic and meteorological factors were also linked to heat-related self-harm. CONCLUSION The global decline in heat-related self-harm mortality is largely driven by reductions in females, low-middle SDI regions, and South Asia. However, population aging and growth in these regions have added to the mortality burden, slowing the overall decline. Factors such as population density are also associated with heat-related self-harm. Targeted measures are needed to mitigate heat-induced self-harm more effectively in future.
Humans ; Self-Injurious Behavior/etiology* ; Hot Temperature/adverse effects* ; Global Health/statistics & numerical data* ; Female ; Male ; Adult ; Middle Aged ; Aged ; Young Adult ; Adolescent

BACKGROUND: Neck cooling is a practical method for preventing heat-related illness, however, its effectiveness in general workers is not well established. This study aimed to assess the effects of neck cooling on core body temperature and other physiological markers during exercise in a hot environment. METHODS: This randomized crossover trial was conducted from November 2023 to April 2024 at the Shared-Use Research Center at UOEH. Fourteen healthy adult males participated in the study under two conditions: with neck cooling (COOL) and without neck cooling (CON). All participants completed both conditions, and the order of condition assignment was determined by a random draw. Participants first rested for 10 minutes in a 28.0 °C, 50% relative humidity environment, followed by a rest in a 35.0 °C, 50% relative humidity environment for another 10 minutes. In the COOL condition, participants wore a neck cooler containing 1,200 g of ice while exercising at 50% Heart Rate Reserve on a bicycle ergometer for 20 minutes. Afterward, they rested for 15 minutes in the hot environment while still wearing the cooler. MAIN OUTCOME MEASURES: Core body temperature (rectal and esophageal), forehead skin temperature, and heart rate were continuously monitored and compared using a mixed model. Estimated sweat volume was calculated based on changes in body weight before and after the experiment. RESULTS: At the end of the rest period, no significant differences were observed between the COOL and CON conditions in rectal temperature (37.76 ± 0.18 °C versus 37.75 ± 0.24 °C, p = 0.9493), esophageal temperature (37.75 ± 0.30 °C versus 37.76 ± 0.23 °C, p = 0.7325), forehead skin temperature (36.87 ± 0.29 °C versus 36.88 ± 0.27 °C, p = 0.2160), or heart rate (104.18 ± 7.56 bpm versus 107.52 ± 7.40 bpm, p = 0.1035). Estimated sweat loss was similar between conditions (578 ± 175 g for CON versus 572 ± 242 g for COOL, p = 0.5066). While more participants felt cooler in the COOL condition, RPE showed no significant difference. CONCLUSION Neck cooling did not significantly affect core temperature or perceived exertion. Maintaining close contact with the skin at sufficiently low temperatures or utilizing cooling methods that prevent excessive negative feedback may be necessary to enhance the effectiveness of neck cooling.
Humans ; Male ; Cross-Over Studies ; Exercise/physiology* ; Adult ; Neck/physiology* ; Hot Temperature/adverse effects* ; Young Adult ; Body Temperature ; Heart Rate ; Skin Temperature ; Body Temperature Regulation ; Cold Temperature

BACKGROUND: Although smoking rates have been declining worldwide, new types of tobacco products have been gradually spreading in recent years, especially in Japan, where heated tobacco products (HTPs) users are rapidly increasing. Oxidative stress caused by reactive oxygen species (ROS) is one of the causes of smoking-induced carcinogenesis, respiratory diseases, and cardiovascular diseases. However, information on the amount of ROS contained in mainstream smoke from HTPs is limited. In this study, we measured the amount of ROS generated from HTPs to evaluate the oxidative stress-related toxicity of HTPs. METHODS: IQOS ILUMA, glo hyper+, and Ploom X ADVANCED were used as the HTP devices. Mainstream smoke was collected from each HTP according to Health Canada Intense regime (smoke volume, 55 mL; smoke duration, 2 s). The collected ROS were reacted with 2,7'-dichlorodihydrofluorescein reagents, and the amount of ROS was calculated as H₂O₂ equivalent from the fluorescence intensity obtained. RESULTS: The ROS in the mainstream smoke from IQOS ILUMA, glo hyper+ (high-temperature mode), and Ploom X ADVANCED was found to be 48.8 ± 8.6, 86.6 ± 12.6, and 40.8 ± 5.7 nmol H₂O₂/stick, respectively (n = 6, mean ± standard deviation), with the highest being from glo hyper+ (high-temperature mode). The amount of ROS was significantly higher in the high-temperature mode of glo hyper+ than in the standard mode of glo hyper+. Additionally, the estimated amount of ROS from smoking 20 heated sticks per day (674-2160 nmol H₂O₂/day) was equivalent to 2.2-96 times the amount of daily exposure to ROS in the urban atmosphere (approximately 22-300 nmol H₂O₂/day). CONCLUSIONS We found that ROS is generated from HTPs of different devices. This study suggests that HTPs users may be exposed to much more ROS than they are exposed to in normal life.
Reactive Oxygen Species/analysis* ; Tobacco Products/analysis* ; Smoke/analysis* ; Hot Temperature ; Japan ; Oxidative Stress

BACKGROUND: Heated tobacco products (HTPs) are widely used in Japan, following cigarettes, but their health effects remain unclear. HTPs are often considered a less harmful alternative to cigarettes and are commonly used by adults with asthma, even though smoking is one of the most obvious and treatable factors in asthma. We aimed to elucidate the association between HTP use and asthma symptoms in adults with asthma. METHODS: A total of 3,787 individuals with asthma were extracted from the data in the Japan COVID-19 and Society Internet Survey 2023, an ongoing longitudinal internet-based cohort study conducted by a nationwide internet research company in Japan. They were categorized into three groups (never, past, and current smokers) based on cigarette use. The association between HTP use and worsening of asthma symptoms within the previous 2 months in each group was analyzed using univariate and multivariate logistic regression analyses. Both exposure and outcomes were assessed by self-reporting. RESULTS: Among the participants, 2,470 (65.2%) were never smokers, 845 (22.3%) were past smokers, and 472 (12.5%) were current smokers. Overall, the proportion of HTP users was 429 (11.3%), and worsened asthma symptoms were observed in 400 (10.6%) individuals. The total proportion of HTP users and worsened asthma symptoms was 70 (2.8%) and 259 (10.5%) among never smokers, 180 (21.3%) and 72 (8.5%) among past smokers, and 179 (37.9%) and 69 (14.6%) among current smokers. After adjusting for confounders, the odds ratio (OR) was 3.25 (95% confidence interval [CI] 1.86-5.68, p < 0.001), 1.47 (95% CI 0.93-2.34, p = 0.1), and 2.23 (95% CI 1.46-3.43, p < 0.001) for never, past, and current cigarette smokers with HTP use, respectively, where never smokers without HTP use were set as the standard. CONCLUSION The use of HTPs, not only cigarette smoking, was associated with worsening of asthma symptoms in adults with asthma. Therefore, people need to understand the harmful effects of HTPs on asthma symptoms.
Humans ; Japan/epidemiology* ; Asthma/etiology* ; Male ; Female ; Middle Aged ; Adult ; Aged ; Tobacco Products/adverse effects* ; Internet ; Surveys and Questionnaires ; Young Adult ; Hot Temperature ; Longitudinal Studies

OBJECTIVE: To compare the cyclic fatigue resistance of nickel-titanium files made by 3 new heat treatment in simulated S-shaped root canals at different temperatures. METHODS: Gold heat-treated nickel-titanium files TruNatomy (25 mm, tip size 26#/0.04) and ProTaper Gold (25 mm, tip size 25#/0.08) were selected as the experimental group, M wire technique nickel-titanium file ProTaper Next (25 mm, tip size 25#/0.06) was selected as the control group. It was speculated that the Gold technique used in TruNatomy nickel-titanium file was R phase separation technique, which included a complete intermediate R-phase, increasing its flexibility. ProTaper Gold was a CM wire nickel-titanium file and the increased phase transformation temperature by heat treatment introduced martensite at room temperature, while it underwent gold heat treatment on the surface, generating an intermediate R phase during phase transformation, providing hyperelastic. ProTaper Next used M wire technique, M wire included austenite at room temperature, where heat mechanical processing introduced hardened martensite, which was incapable of participating phase transformation. Because of the lower elastic modulus of hardened martensite than austenite, the flexibility of the file was increased. Twenty instruments of each nickel-titanium file were submitted to the cyclic fatigue test by using a simulated canal with double curvatures at room tem-perature (24 ℃) and 65 ℃, 10 instruments of each nickel-titanium file were selected at each temperature (n=10). At the same temperature, the number of cyclic fatigue (NCF) and fragment length were analyzed by using One-Way analysis of variance at a significance level of P < 0.05. NCF and fragment length of the same nickel-titanium file at room temperature and 65 ℃ were compared by paired sample t test and the significance level was α=0.05. Fractured surfaces were analyzed by using scanning electron microscope. RESULTS: In double-curved canals, all the failure of the files due to cyclic fatigue was first seen in the apical curvature before the coronal curvature. At room temperature, in the apical curvature, NCF of TruNatomy was 344.4±96.6, ProTaper Gold was 175.0±56.1, ProTaper Next was 133.3±39.7, NCF of Tru Natomy was the highest (P < 0.05). In the coronal curvature, NCF of TruNatomy was 618.3± 75.3, ProTaper Gold was 327.5±111.8, ProTaper Next was 376.6±67.9, NCF of TruNatomy was also the highest (P < 0.05). There was no significant difference among the apical and coronal fragment length of the 3 nickel-titanium files (P>0.05). At 65 ℃, in the apical curvature, NCF of TruNatomy was 289.6±65.8, ProTaper Gold was 187.5±75.4, ProTaper Next was 103.0±38.5, NCF of TruNatomy was the highest (P < 0.05). In the coronal curvature, NCF of TruNatomy was 454.2±45.4, ProTaper Gold was 268.3±31.4, ProTaper Next was 283.8±31.7, NCF of TruNatomy was also the highest (P < 0.05). The apical fragment length of ProTaper Next was the highest (P < 0.05), and there was no significant difference among coronal fragment length of the 3 nickel-titanium files (P>0.05). Compared with room temperature, at 65 ℃, in the coronal curvature, NCF of TruNatomy decreased significantly (P < 0.05). The fractured surfaces of the three nickel-titanium files demonstrated typical cyclic fatigue. CONCLUSION Gold heat-treated nickel-titanium file had better cyclic fatigue resistance than M wire nickel-titanium file in S-shaped root canals.
Nickel/chemistry* ; Titanium/chemistry* ; Hot Temperature ; Root Canal Preparation/methods* ; Humans ; Materials Testing ; Gold/chemistry* ; Dental Alloys/chemistry* ; Stress, Mechanical

OBJECTIVES: To detect prfA and hly toxin genes of Listeria monocytogenes using polymerase chain reaction (PCR) and colloidal gold technology. METHODS: L. monocytogenes DNA was extracted by boiling method. With prfA and hly of L. monocytogenes as the target genes, the 5' ends of upstream and downstream primers of prfA gene were labeled with 6-FAM and biotin, and the 5' ends of upstream and downstream primers of hly gene were labeled with digoxin and biotin, respectively, to establish the toxin gene detection method. Using cloning transformation, sequencing analysis, cloning of positive control products, the detection kid was developed and its specificity, sensitivity, reproducibility and stability were tested, followed by verification with sample testing. RESULTS: The concentration of L. monocytogenes DNA extracted by boiling method was 148.81±0.97 ng/μL, and the A₂₆₀/A₂₈₀ ratio ranged from 1.8 to 2.0. The PCR products showed a 100% homology with the gene sequences in GenBank database after cloning, transformation and sequencing. The colloidal gold strip yielded positive results only for L. monocytogenes samples without cross-reactions with Staphylococcus aureus, Escherichia coli or Bacillus cereus, and its minimum detection limit was 10^-2 ng/μL, demonstrating a 10-fold greater sensitivity of the test than agarose gel electrophoresis. The test also showed good reproducibility of the results when performed by different operators with good stability of the test strips after storage for 6 to 12 months. The test results showed that this kit could accurately and quickly detect L.monocytogenes in the test samples. CONCLUSIONS The detection kit developed in this study can simultaneously detect prfA and hly toxin genes of L. monocytogenes with good specificity, sensitivity, reproducibility and stability for use in food safety inspection.
Listeria monocytogenes/isolation & purification* ; Gold Colloid ; Bacterial Toxins/genetics* ; Polymerase Chain Reaction/methods* ; Hemolysin Proteins/genetics* ; Bacterial Proteins/genetics* ; DNA, Bacterial/genetics* ; Food Microbiology ; Heat-Shock Proteins