The circadian clock plays a critical role in regulating various physiological processes, including gene expression, metabolic regulation, immune response, and the sleep-wake cycle in living organisms. Post-translational modifications (PTMs) are crucial regulatory mechanisms to maintain the precise oscillation of the circadian clock. By modulating the stability, activity, cell localization and protein-protein interactions of core clock proteins, PTMs enable these proteins to respond dynamically to environmental and intracellular changes, thereby sustaining the periodic oscillations of the circadian clock. Different types of PTMs exert their effects through distincting molecular mechanisms, collectively ensuring the proper function of the circadian system. This review systematically summarized several major types of PTMs, including phosphorylation, acetylation, ubiquitination, SUMOylation and oxidative modification, and overviewed their roles in regulating the core clock proteins and the associated pathways, with the goals of providing a theoretical foundation for the deeper understanding of clock mechanisms and the treatment of diseases associated with circadian disruption.
Protein Processing, Post-Translational/physiology* ; Circadian Rhythm/physiology* ; Humans ; Animals ; CLOCK Proteins/physiology* ; Circadian Clocks/physiology* ; Phosphorylation ; Acetylation ; Ubiquitination ; Sumoylation

The aim of this study was to investigate the contribution of lung zinc ions to pathogenesis of lung ischemia/reperfusion (I/R) injury in rats. Male Sprague Dawley (SD) rats were randomly divided into control group, lung I/R group (I/R group), lung I/R + low-dose zinc chloride group (LZnCl₂+I/R group), lung I/R + high-dose ZnCl₂ group (HZnCl₂+I/R group), lung I/R + medium-dose ZnCl₂ group (MZnCl₂+I/R group) and TPEN+MZnCl₂+I/R group (n = 8 in each group). Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the concentration of zinc ions in lung tissue. The degree of lung tissue injury was analyzed by observing HE staining, alveolar damage index, lung wet/dry weight ratio and lung tissue gross changes. TUNEL staining was used to detect cellular apoptosis in lung tissue. Western blot and RT-qPCR were used to determine the protein expression levels of caspase-3 and ZIP8, as well as the mRNA expression levels of zinc transporters (ZIP, ZNT) in lung tissue. The mitochondrial membrane potential (MMP) of lung tissue was detected by JC-1 MMP detection kit. The results showed that, compared with the control group, the lung tissue damage, lung wet/dry weight ratio and alveolar damage index were significantly increased in the I/R group. And in the lung tissue, the concentration of Zn²⁺ was markedly decreased, while the cleaved caspase-3/caspase-3 ratio and apoptotic levels were significantly increased. The expression levels of ZIP8 mRNA and protein were down-regulated significantly, while the mRNA expression of other zinc transporters remained unchanged. There was also a significant decrease in MMP. Compared with the I/R group, both MZnCl₂+I/R group and HZnCl₂+I/R group exhibited significantly reduced lung tissue injury, lung wet/dry weight ratio and alveolar damage index, increased Zn²⁺ concentration, decreased ratio of cleaved caspase-3/caspase-3 and apoptosis, and up-regulated expression levels of ZIP8 mRNA and protein. In addition, the MMP was significantly increased in the lung tissue. Zn²⁺ chelating agent TPEN reversed the above-mentioned protective effects of medium-dose ZnCl₂ on the lung tissue in the I/R group. The aforementioned results suggest that exogenous administration of ZnCl₂ can improve lung I/R injury in rats.
Animals ; Reperfusion Injury/pathology* ; Male ; Rats, Sprague-Dawley ; Rats ; Chlorides/administration & dosage* ; Lung/pathology* ; Zinc Compounds/administration & dosage* ; Apoptosis/drug effects* ; Caspase 3/metabolism* ; Cation Transport Proteins/metabolism*

Qing court records show that Arecae Semen was extensively applied. The royal medical records of the Qing Dynasty document nine types of Arecae Semen, with the Palace Museum preserving seven kinds, totaling twelve cultural relics. Historical documents and physical artifacts corroborate each other, providing evidence for the study of the supply channels and court processing of Arecae Semen in the Qing court. According to relevant Qing court archival records, the sources of Arecae Semen used in the imperial court were diverse, including tributes from foreign countries such as Vietnam and Gurkha, annual tributes from local governments in Guangdong, gifts from close aides, and commodities purchased by the Imperial Household Department from civilian shops. The imperial physicians of the Qing court placed great emphasis on the specifications of Arecae Semen slices and were extremely meticulous about their processing. The variety of Arecae Semen slices used in the Qing palace exceeded those recorded in the botanical texts of the era. Compared with the commonly used processing methods for Arecae Semen in the Qing Dynasty, the imperial physicians adjusted the properties and efficacy of the herbs through different processing techniques, based on the patient's condition, constitution, and other factors, in order to meet the clinical treatment needs of the court. The slicing of Arecae Semen in the Qing court required strict control of thickness, with an average thickness of 0.44 mm, which is significantly thinner than the Arecae Semen slices found in today's markets. The texture was softer, making them easier to chew and absorb. Both the Qing court Arecae Semen slices and the Muxiang Binglang Pills focused on the use of authentic medicinal materials, ensuring the quality of the medicine and enhancing the efficacy of Arecae Semen through meticulous selection and preparation.
China ; Drugs, Chinese Herbal/history* ; Humans ; Medicine, Chinese Traditional/history* ; History, 19th Century ; History, Ancient ; History, 17th Century ; History, 18th Century

OBJECTIVES: To investigate the effects of methylenetetrahydrofolate reductase (MTHFR) rs1801133 and γ-glutamyl hydrolase (GGH) rs11545078 gene polymorphisms on plasma concentrations and toxicity following high-dose methotrexate (MTX) therapy in children with acute lymphoblastic leukemia (ALL). METHODS: Children with ALL treated at the Xuzhou Children's Hospital of Xuzhou Medical University from January 2021 to April 2024 were selected for this study. Genotypes of MTHFR rs1801133 and GGH rs11545078 were determined using multiplex polymerase chain reaction. MTX plasma concentrations were measured by enzyme-multiplied immunoassay technique, and toxicity was graded according to the Common Terminology Criteria for Adverse Events version 5.0. The relationships between MTHFR rs1801133 and GGH rs11545078 genotypes and both MTX plasma concentrations and associated toxicities were analyzed. RESULTS: In the low-risk ALL group, the MTHFR rs1801133 genotype was associated with increased MTX plasma concentrations at 72 hours (P<0.05). In the intermediate- to high-risk group, the MTHFR rs1801133 genotype was associated with increased MTX plasma concentrations at 48 hours (P<0.05), and the GGH rs11545078 genotype was associated with increased MTX plasma concentrations at 48 hours (P<0.05). In the intermediate- to high-risk group, the MTHFR rs1801133 genotype was associated with the occurrence of reduced hemoglobin (P<0.05), and the GGH rs11545078 genotype was associated with the occurrence of thrombocytopenia (P<0.05). CONCLUSIONS Detection of MTHFR rs1801133 and GGH rs11545078 genotypes can be used to predict increased MTX plasma concentrations and the occurrence of toxic reactions in high-dose MTX treatment of ALL, enabling timely interventions to enhance safety.
Humans ; Methotrexate/toxicity* ; Methylenetetrahydrofolate Reductase (NADPH2)/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood* ; Male ; Female ; Child ; Child, Preschool ; gamma-Glutamyl Hydrolase/genetics* ; Antimetabolites, Antineoplastic/adverse effects* ; Infant ; Polymorphism, Genetic ; Adolescent ; Genotype ; Polymorphism, Single Nucleotide

OBJECTIVE: By analyzing the hormone secretion of the adenohypophysis, thyroid glands, gonads, and adrenal cortex in patients with hematological diseases before and after hematopoietic stem cell transplantation (HSCT), this study aims to preliminarily explore the effect of HSCT on patients' hormone secretion and glandular damage. METHODS: The baseline data of 209 hematological disease patients who underwent HSCT in our hospital from January 2019 to December 2023, as well as the data on the levels of hormones secreted by the adenohypophysis, thyroid glands, gonads and adrenal cortex before and after HSCT were collected, and the changes in hormone levels before and after transplantation were analyzed. RESULTS: After allogeneic HSCT, the levels of thyroid-stimulating hormone (TSH), triiodothyronine (T3), free triiodothyronine (FT3) and estradiol (E2) decreased, while the levels of luteinizing hormone (LH) and follicle- stimulating hormone (FSH) increased. The T3 level of patients with decreased TSH after transplantation was lower than that of those with increased TSH after transplantation. In female patients, the levels of prolactin (PRL), progesterone (Prog), and testosterone (Testo) decreased after HSCT. Testo and PRL decreased when there was a donor-recipient sex mismatch, and the levels of adrenocorticotropic hormone (ACTH) and cortisol (COR) decreased when the HLA matching was haploidentical. The levels of T3, FT3, and PRL decreased after autologous HSCT. In allogeneic HSCT patients, the levels of TSH, T4, T3, FT3, and ACTH in the group with graft-versus-host disease (GVHD) were significantly lower than those in the group without GVHD. Logistic regression analysis showed the changes in hormone levels after transplantation were not correlated with factors such as the patient's sex, age, or whether the blood types of the donor and the recipient are the same. CONCLUSION HSCT can affect the endocrine function of patients with hematological diseases, mainly affecting target glandular organs such as the thyroid, gonads, and adrenal glands, while the secretory function of the adenohypophysis is less affected.
Humans ; Hematopoietic Stem Cell Transplantation ; Female ; Male ; Hematologic Diseases/blood* ; Follicle Stimulating Hormone/blood* ; Triiodothyronine/blood* ; Luteinizing Hormone/blood* ; Thyroid Gland/metabolism* ; Estradiol/blood* ; Thyrotropin/blood* ; Gonads/metabolism* ; Adult ; Middle Aged ; Adrenocorticotropic Hormone/blood* ; Hormones/metabolism* ; Adrenal Cortex/metabolism* ; Prolactin

OBJECTIVE: To investigate the effect and mechanism of Shuangshi Tonglin Capsules (SSTL) in the treatment of prostate fibrosis (PF). METHODS: Human prostate stromal cells (WPMY-1) were used for in vitro experiments to establish PF cell models induced with estradiol (E₂). The cell proliferation, migration and clonogenic capacity were determined by cell counting kit-8, scratch assay, and crystal violet staining, respectively. Sprague-Dawley rats were used for in vivo experiments. The changes in histomorphology and organ index of rat prostate by SSTL were determined. Pathologic changes and collagen deposition changes in rat prostate were observed by haematoxylin and eosin (HE) and Masson staining. Enzyme-linked immunosorbent assay kits were used to determine changes in rat PF markers fibroblast growth factor-23 (FGF-23), E₂ and prostate specific antigen (PSA). Mechanistically, changes in oxidative stress indicators by SSTL were determined in WPMY-1 cells and PF rats. Then the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and transforming growth factor-β1 (TGF-β1)/Smad pathway-related proteins as well as Nrf2 and TGF-β1 mRNA were further detected by Western blot or quantitative real-time polymerase chain reaction both in vivo and in vitro. RESULTS: In the efficacy study, SSTL significantly reduced the proliferation, migration, and clonogenic ability of cells, improved the morphology of the glandular tissue, significantly reduced the prostate index, reduced glandular fibrous tissue and collagen deposition, and resulted in a significant decrease in the levels of FGF-23, E₂ and PSA (P<0.01 or P<0.05). In the mechanistic study, SSTL ameliorated oxidative stress by significantly increasing superoxide dismutase and glutathione peroxidase levels and decreasing malondialdehyde level in WPMY-1 cells and rats (P<0.01 or P<0.05). SSTL significantly elevated the expressions of Nrf2, HO-1, NAD(P)H quinone oxidoreductase 1 (NQO-1), and Smad7 proteins in both cells and rats, and significantly decreased the expressions of TGF-β1, collagen I, α-smooth muscle actin and Smad4 proteins (P<0.01 or P<0.05). SSTL also elevated the content of Nrf2 mRNA and decreased the content of TGF-β1 mRNA in cells and rats (P<0.01 or P<0.05). The Nrf2 inhibitor ML385 was added in in vitro experiments to further validate the pathway relevance. CONCLUSION SSTL was effective in improving PF in vivo and in vitro, and its mechanism of action may function through the Nrf2/TGF-β1 signaling pathway.
Male ; NF-E2-Related Factor 2/metabolism* ; Animals ; Drugs, Chinese Herbal/therapeutic use* ; Signal Transduction/drug effects* ; Transforming Growth Factor beta1/metabolism* ; Rats, Sprague-Dawley ; Humans ; Fibrosis ; Prostate/drug effects* ; Cell Proliferation/drug effects* ; Capsules ; Cell Movement/drug effects* ; Oxidative Stress/drug effects* ; Rats

Objective: There is controversy among different guidelines regarding the use of thermal ablation to treat clinical T1a renal cell carcinomas with tumor sizes ranging from 3.1–4 cm. Therefore, we compared oncological outcomes between heat-based thermal ablation (hTA) and cryoablation (CA) in patients with solid T1a renal cell carcinomas, including those with a tumor size ≤3 cm and a tumor size of 3.1–4 cm. Materials and Methods: Within the Surveillance, Epidemiology, and End Results database (2000–2019), we identified patients with clinical T1a renal cell carcinomas that were histologically confirmed and treated with hTA or CA. After propensity score matching using a 1:1 ratio, the overall survival (OS) and cancer-specific survival (CSS) were estimated and compared between the two methods. Cancer-specific mortality (CSM) was also analyzed, considering other-cause mortality as a competing risk. Results: Of the 3513 assessable patients, 1426 (40.6%) and 2087 (59.4%) were treated with hTA and CA, respectively. After propensity score matching, the hTA and CA groups included 1393 and 1393 patients, respectively. hTA was associated with shorter OS than CA with a hazard ratio of 1.17 (95% confidence interval, 1.04–1.32; P = 0.010). The hTA and CA groups did not reveal statistically significant differences in CSS with a hazard ratio of 1.07 (95% confidence interval, 0.76–1.50; P = 0.706). The hTA and CA groups did not show statistically significant differences in CSM (P = 0.849). However, the hTA group showed a significantly higher other-cause mortality (P = 0.011). Conclusion In patients with clinical stage T1a renal cell carcinomas, hTA was comparable to CA in terms of CSS and CSM.However, hTA resulted in a slightly shorter OS than CA. Large-scale randomized clinical trials are required to obtain more robust evidence.

Objective:Xanthohumol is a kind of isoamyl olefinic flavonoid natural compounds,which have antitumor activity and impact on a variety of cell signaling pathways,The objective of this study was to explore the effects of xanthohumol on proliferation and apoptosis of thyroid cancer cells B-CPAP through the Notch signaling pathway.Methods:B-CPAP cells were cultivated in vitro,Xanthohumol was divided into control group(0 μ mol/L),low dose group(10 μ mol/L),middle dose group(20 μ mol/L),high dose group(40 μ mol/L)according to the different concentrations,The logarithmic growth cells were cultivated with different concentrations of xanthohumol intervention,application of MTT colorimetry in the detection of proliferation inhibition rates of B-CPAP cells.B-CPAP cells morphological changes were observed by using fluorescence microscope after appli-cation of Hoechst 33258 dyeing.B-CPAP cells apoptosis were detected by Annexin V-FITC/PI flow cytometry.Notch signaling pathway related proteins were determined?by?Western blotting.Re-sults:MTT showed that low dose group,middle dose group and high dose group,respectively pro-cessing after 24h,48h,72h,proliferation inhibition rates of the three groups were statistical?signifi-cance(F=189.34,131.73,124.51,P＜0.05);Respectively treated after 24h,48h,72h,proliferation in-hibition rates of xanthohumol increased over time in the same group,The differences were statisti-cally significant(F=204.51,169.64,183.15,P＜0.05).B-CPAP cells of high dose group appeared ob-viously apoptosis morphological changes compared with the control group through Hoechst33258 dying.Flow cytometry showed apoptosis rates of concrol group,low dose group and high dose group compared were statistical?significance(F=1235.54,P＜0.05).Apoptosis rate was higher in the high-dose group.Western blotting showed that Notch1,Treatment was performed for 72h,Hes1,Bcl-2 expression were significantly decreased in low dose group,middle dose group and high dose group compared with the control group(F=203.22,161.52,224.78),while cleaved caspase-3 ex-pression significantly increased(F=463.27),the differences were statistically significant(P＜0.05).Conclusions:Xanthohumol inhibits B-CPAP cells proliferation and induces cells apoptosis maybe through the Notch signaling pathway.

Afferent baroreflex failure(ABF)is a rare disease.It refers to the clinical syndrome caused by the impairment of the afferent limb of the baroreflex or its central connections at the level of the medul-la.The recognized causes include trauma,surgery in related areas(radical neck tumor surgery,carotid endarterectomy),neck radiotherapy,brain stem stroke,tumor growth paraganglioma and hereditary diseases,among which the most common cause is extensive neck surgery or radiotherapy for neck cancer.The main manifestations are fluctuating hypertension,orthostatic hypotension,paroxysmal tachycardia and bradycardia.This case is a young man,whose main feature is blood pressure fluctuation,accom-panied by neurogenic orthostatic hypotension(nOH).After examination,the common causes of hyper-tension and nOH were ruled out.Combined with the previous neck radiotherapy and neck lymph node dissection,it was considered that the blood pressure regulation was abnormal due to the damage of carotid sinus baroreceptor after radiotherapy for nasopharyngeal carcinoma and neck lymph node dissection,which was called ABF.At the same time,the patient was complicated with chronic hyponatremia.Com-bined with clinical and laboratory examination,the final consideration was caused by syndrome of in-appropriate antidiuretic hormone(SIADH).Baroreceptors controlled the secretion of heart rate,blood pres-sure and antidiuretic hormone through the mandatory"inhibition"signal.We speculate that the carotid sinus baroreceptor was damaged after neck radiotherapy and surgery,which leads to abnormal blood pres-sure regulation and nOH,while the function of inhibiting ADH secretion was weakened,resulting in higher ADH than normal level and mild hyponatremia.The goal of treating ABF patients was to reduce the frequency and amplitude of sudden changes in blood pressure and heart rate,and to alleviate the on-set of symptomatic hypotension.At present,drug treatment is still controversial,and non-drug treatment may alleviate some patients'symptoms,but long-term effective treatment still needs further study.The incidence of ABF is not high,but it may lead to serious cardiovascular and cerebrovascular events,and the mechanism involved is extremely complicated,and there are few related studies.The reports of rele-vant medical records warn that patients undergoing neck radiotherapy or surgery should minimize the da-mage to the baroreceptor in the carotid sinus in order to reduce the adverse prognosis caused by complica-tions.