Multi-target analgesics with minimal side effects and high efficacy are a key research focus in addressing the global pain crisis. Using a molecular networking approach, five pairs of potent analgesic alkaloid enantiomers were isolated from the roots of Anacyclus pyrethrum (A. pyrethrum). Their structures were elucidated by comprehensive spectroscopic data analysis, including LR-HSQMBC and ¹H-¹⁵N HMBC, quantum ¹³C NMR DP4+ and ECD calculations, and single-crystal X-ray diffraction analysis. Anacyphrethines A (1) and B (2) are highly conjugated and polymethylated 6/6/6/6/5/7/5/5-fused octacyclic tetraazabic alkaloids possessing an unprecedented 8,14,18,24-tetraaza-octacyclo[16.8.2.1^1,23.0^4,28.0^5,17.0^9,16.0^11,15.0^21,27] nonacosane motif. Their biosynthetic pathways are proposed involving key aldol, hydroamination, and Schiff base reactions. All isolates showed potent analgesic effects in vivo. Even at a lower dose of 0.2 mg/kg, (±)-1 and (+)-1 still exhibited more potent analgesic activities than morphine. Interestingly, the racemic mixture (±)-1 showed stronger analgesic effect than either pure enantiomer alone at higher doses of 5 and 1 mg/kg; while, (±)-1 showed significant analgesic activities comparable to (+)-1 at lower doses of 0.2 and 0.04 mg/kg. (+)-1 had stronger analgesic effect than (-)-1 at five tested does. Further tests on 44 analgesic-related targets demonstrated that (+)-1 showed significant inhibitory effects against many ion channels such as TRPM8, Kv1.2, Kv1.3, and Ca_v2.1 with IC₅₀ values of 1.10 ± 0.26, 4.20 ± 0.07, 2.20 ± 0.24, and 10.40 ± 0.69 μmol/L, respectively, while (-)-1 primarily inhibited TRPC6, Kv1.2, and Kv1.3 ion channels with IC₅₀ values of 0.81 ± 0.05, 0.91 ± 0.04, and 1.50 ± 0.13 μmol/L, respectively, without affecting the opioid receptors, suggesting their non-opioid analgesic potentials. The molecular dockings provided structural guidance to develop potent non-opioid analgesics.

Gallbladder carcinoma,a relatively rare malignancy within the biliary tract,presents a grave prognosis primarily due to asymptomatic early stages leading to advanced stage diagnosis and the absence of efficacious treatment options.Research has identified chronic inflammation,predom-inantly caused by gallstones,as a critical etiological factor.While surgical intervention offers potential curative outcomes in early stages,the majority of cases are identified too late for optimal surgical outcomes.Chemotherapy and targeted therapy,despite offering new therapeutic avenues,have not significantly improved overall survival rates.Thus,understanding the pathogenesis of gallbladder cancer,especially its association with key genetic and molecular pathways,is imperative for devising novel therapeutic strategies.This review delineates the epidemiology,pathogenesis,current treat-ment modalities,and research advancements in gallbladder cancer,aiming to provide innovative in-sights for clinical management and guide future research endeavors.

Osteoporotic proximal humeral fracture (OPHF) is one of the common osteoporotic fractures in the aged, with an incidence only lower than vertebral compression fracture, hip fracture, and distal radius fracture. OPHF, secondary to osteoporosis and characterized by poor bone quality, comminuted fracture pattern, slow healing, and severely impaired shoulder joint function, poses a big challenge to the current clinical diagnosis and treatment. In the field of diagnosis, treatment, and rehabilitation of OPHF, traditional Chinese and Western medicine have accumulated rich experience and evidence from evidence-based medicine and achieved favorable outcomes. However, there is still a lack of guidance from a relevant consensus as to how to integrate the advantages of the two medical systems and achieve the integrated diagnosis and treatment. To promote the diagnosis and treatment of OPHF with integrated traditional Chinese and Western medicine, relevant experts from Orthopedic Expert Committee of Geriatric Branch of Chinese Association of Gerontology and Geriatrics, Youth Osteoporosis Group of Orthopedic Branch of Chinese Medical Association, Osteoporosis Group of Orthopedic Surgeon Branch of Chinese Medical Doctor Association, and Osteoporosis Committee of Shanghai Association of Integrated Traditional Chinese and Western Medicine have been organized to formulate Expert consensus on the diagnosis and treatment of osteoporotic proximal humeral fracture with integrated traditional Chinese and Western medicine ( version 2024) by searching related literatures and based on the evidences from evidence-based medicine. This consensus consists of 13 recommendations about the diagnosis, treatment and rehabilitation of OPHF with integrated traditional Chinese medicine and Western medicine, aimed at standardizing, systematizing, and personalizing the diagnosis and treatment of OPHF with integrated traditional Chinse and Western medicine to improve the patients ′ function.

Lower extremity deep vein thrombosis (DVT) is one of the main complications in patients with traumatic fractures, and for severe patients, the DVT can even affect arterial blood supply, resulting in insufficient limb blood supply. If the thrombus breaks off, pulmonary embolism may occur, with a high mortality. The treatment and rehabilitation strategies of thrombosis in patients with lower extremity fractures have its particularity. DVT in traumatic fractures patients has attracted extensive attention and been largely studied, and the measures for prevention and treatment of DVT are constantly developing. In recent years, a series of thrombosis prevention and treatment guidelines have been updated at home and abroad, but there are still many doubts about the prevention and treatment of DVT in patients with different traumatic fractures. Accordingly, on the basis of summarizing the latest evidence-based medical evidence at home and abroad and the clinical experience of the majority of experts, the authors summarize the clinical treatment and prevention protocols for DVT in patients with traumatic fractures, and make this consensus on the examination and assessment, treatment, prevention and preventive measures for DVT in patients with different fractures so as to provide a practicable approach suitable for China ′s national conditions and improve the prognosis and the life quality of patients.

Diabetic wound healing disorder，one of the common chronic complications of diabetes，seriously influences the quality of life of patients and even causes disability and death，bringing a heavy burden to the society. Chinese medicine，a unique and precious resource in China，is safe with definite effect. Oxidative stress plays an important role in the occurrence and development of diabetic wound and the disturbance of antioxidant defense mechanism is among the causes of the lingering diabetic wound. As a vital transcription factor for intracellular redox homeostasis，nuclear factor erythroid 2-related factor 2 （Nrf2） regulates oxidative/heterogenous stress and reduces inflammatory responses. Although it is unnecessary for common wound healing，it is of great importance for diabetic wound healing. Many Chinese medicinals and the active ingredients have been found to enhance diabetic wound healing by mechanisms related to activation of the Nrf2 signaling pathway. Targeted activation of Nrf2 by Chinese medicine can alleviate oxidative stress，inflammatory response，and apoptosis in diabetic wound，thereby delaying further exacerbation of symptoms. Therefore，Nrf2 is regarded as a potential target for drugs to boost diabetic wound healing. This study summarizes the relationship between the Nrf2 signaling pathway and diabetic wound and analyzes the mode of action and possible mechanisms of Chinese medicine and its active ingredients in promoting diabetic wound healing through modulating the Nrf2 pathway，which is expected to serve as a reference for developing drugs for diabetic wound based on this pathway.

Objective: To investigate the current situation of cell phone use and sleep quality among college students, establish a sleep quality trajectory model and explore the influence of cell phone use on the sleep quality trajectory. Methods: Based on data from the College Student Behavior and Health Cohort Study 2019-2020, a latent class growth modeling was used to establish a sleep quality trajectory model among college students. The baseline influencing factors of sleep quality trajectories among college students were analyzed by χ² test, and the effects of cell phone use on sleep quality trajectories were analyzed by binary logistic regression. Results: A total of 1 092 college students were included in the analysis. The detection rates of cell phone use and poor sleep quality were 24.5% and 13.3%. Latent class growth model identified two groups of sleep quality trend trajactories: an improved sleep quality group (86.0%) and a decreased sleep quality group (14.0%). The result of binary logistic regression showed that the cell phone use was a risk factor of sleep quality trajectories. Conclusion: The cell phone use during college period could increase the risk of poor sleep quality. Targeted intervention measures about cell phone use should be adopted to improve the sleep quality among college students.
Humans ; Sleep Quality ; Cohort Studies ; Cell Phone Use ; Surveys and Questionnaires ; Students ; Sleep Initiation and Maintenance Disorders ; Cell Phone ; Sleep

Diabetic wounds are slow to heal， which poses a challenge to the medical field. Being vulnerable to infection， they are a major cause of amputation and even death and thus are costly. Chronic inflammation is an important culprit of the lingering diabetic wounds. NOD-like receptor protein 3 （NLRP3）， apoptosis associated speck-like protein （ASC）， and aspartate-specific proteasezymogen procaspase-1 （pro-Caspase-1）， constitute an intracellular protein complex called the NLRP3 inflammasome. Activated NLRP3 inflammasome can induce the release of pro-inflammatory factors interleukin（IL）-1β and IL-18 and participate in a variety of inflammatory responses. The activation of the NLRP3 inflammasome is associated with several inflammatory diseases. It has been concluded that many factors such as microcirculation disorder of diabetic wounds， accumulation of advanced glycation end products， oxidative stress injury， and long-term infiltration of macrophages can influence NLRP3 inflammasome， which induce persistent inflammation of the wounds. Therefore， solutions to the diabetic wound， such as targeting the NLRP3 inflammasome， reducing its hyperactivation， and inhibiting its overexpression， have emerged. Based on the correlation between the pathological changes of diabetic wounds and NLRP3 inflammasome， this article summarized the research on the methods of reducing NLRP3 inflammasome expression to promote the healing of diabetic wounds， such as regulating diabetic wound oxidative stress， balancing neutrophil extracellular traps （NETs） / NLRP3 inflammasome axis， inducing macrophage M2 polarization， reducing the production of advanced glycation end products， and enhancing autophagy. Moreover， the mechanisms of active constituents of Chinese medicine and compound Chinese medicine prescriptions against NLRP3 inflammasome activation were analyzed. Thereby， this paper is expected to provide new targets for diabetic wound healing and a reference for research the mechanism of Chinese medicine in anti-inflammation and promoting healing.

OBJECTIVES: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. METHODS: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. RESULTS: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). CONCLUSIONS Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).
Administration, Inhalation ; Adult ; China ; Coronavirus Infections ; diagnosis ; drug therapy ; mortality ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Follow-Up Studies ; Humans ; Integrative Medicine ; Interferon-alpha ; administration & dosage ; Lopinavir ; administration & dosage ; Male ; Middle Aged ; Pandemics ; Pneumonia, Viral ; diagnosis ; drug therapy ; mortality ; Risk Assessment ; Severe Acute Respiratory Syndrome ; diagnosis ; drug therapy ; mortality ; Severity of Illness Index ; Survival Rate

OBJECTIVE: To assess the associations of different monitoring metrics for short-term exposure to ambient ozone (O₃) with pulmonary function and airway inflammation in healthy young adults. METHODS: A total of 97 healthy young college students were recruited and followed in a panel study conducted from December 2017 to June 2018. Each participant underwent 3 follow-up visits, and lung function and fractional exhaled nitric oxide (FeNO) were measured at each visit. Ambient air pollutant concentrations were obtained from the environment monitoring station of Beijing closest to the participant residences, and meteorological data were collected from China Meteorological Data Service Center. Linear mixed-effect models were applied to assess the associations between different monitoring metrics for ambient O₃ short-term exposure with pulmonary function or airway inflammation in the healthy young adults. RESULTS: During the study period, the P₅₀ (P₂₅, P₇₅) values for ambient O₃ concentration expressed as daily 1-hour maximum (O₃-1 h max), daily maximum 8-hour average (O₃-8 h max) and 24-hour average (O₃-24 h avg) were 102.5 (76.8, 163.0) μg/m³, 91.1 (68.3, 154.3) μg/m³ and 61.6 (36.9, 81.7) μg/m³, respectively. The different monitoring metrics for short-term exposure to ambient O₃ were significantly associated with reduced forced expiratory volume in the first second (FEV₁) and increased FeNO. An interquartile range (IQR) increase in 6-d moving average of O₃-1 h max (IQR=71.5 μg/m³) was associated with a 6.2% (95%CI: －11.8%, －0.5%) decrease in FEV₁ and a 63.3% (95%CI: 13.8%, 134.3%) increase in FeNO. An IQR increase in 7-d moving average of O₃-8 h max (IQR=62.0 μg/m³) was associated with a 6.2% (95%CI: －11.6%, －0.7%) decrease in FEV₁and a 75.5% (95%CI: 19.3%, 158.0%) increase in FeNO. An IQR increase in 5-d moving average of O₃-24 h avg (IQR=32.9 μg/m³) was associated with a 3.7% (95%CI: －7.1%, －0.2%) decrease in FEV₁and a 25.3% (95%CI: 3.6%, 51.6%) increase in FeNO. There was no significant association between the three monitoring metrics for O₃ exposure and peak expiratory flow (PEF). CONCLUSION Short-term exposure to ambient O₃ was associated with decreased lung function and increased airway inflammation among the healthy young adults, and daily 1-hour maximum was more sensitively to the respiratory effects of O₃.
Air Pollutants ; Air Pollution ; Benchmarking ; China ; Environmental Exposure ; Humans ; Inflammation ; Ozone ; Particulate Matter ; Young Adult

OBJECTIVE: To analyze the subcellular localization of GTPase of immunity-associated protein 2 (GIMAP2) for the further functional study. METHODS: In the study, we first obtained the protein sequences of GTPase of immunity-associated protein 2 (GIMAP2) from National Center for Biotechnology Information (NCBI) database, and then performed a prediction analysis of its transmembrane structure, nuclear localization signal (NLS), nuclear export signal (NES) and subcellular localization through bioinformatics online tools. GIMAP2 gene amplified by PCR was inserted into the expression vector pQCXIP-mCherry-N1 and positive clones were selected by ampicillin resistance. After using methods to extract and purify, the sequenced recombinant plasmid pQCXIP-GIMAP2-mCherry, together with the retroviral packaging plasmids VSVG and Gag/pol, was transferred into HEK293FT cells by liposomes for virus packaging. The virus supernatant was collected 48 h after transfection and directly infected the human breast cancer cell line MDA-MB-436. Immunofluorescence staining was constructed to detect the localization of endogenous and exogenous GIMAP2 in MDA-MB-436 cells. Meanwhile, green fluorescent chemical dyes were used to label mitochondria, endoplasmic reticulum, and lipid droplets in living MDA-MB-436 cells stably expressing the GIMAP2-mCherry fusion protein. Images for the three dye-labeled organelles and GIMAP2-mCherry fusion protein were captured by super-resolution microscope N-SIM. RESULTS: Bioinformatics analysis data showed that GIMAP2 protein composed of 337 amino acids might contain two transmembrane helix (TM) structures at the carboxyl terminus, of which TMs were estimated to contain 40-41 expected amino acids, followed by the residual protein structures toward the cytoplasmic side. NES was located at the 279-281 amino acids of the carboxyl terminus whereas NLS was not found. GIMAP2 might locate in the lumen of the endoplasmic reticulum. Sequencing results indicated that the expression vector pQCXIP-GIMAP2-mCherry was successfully constructed. Fluorescent staining confirmed that GIMAP2-mCherry fusion protein, co-localized well with endogenous GIMAP2, expressed successfully in the endoplasmic reticulum and on the surface of lipid droplets in MDA-MB-436 cells. CONCLUSION GIMAP2 localizes in the endoplasmic reticulum and on the surface of LDs, suggesting potential involvement of GIMAP2 in lipid metabolism.
Amino Acid Sequence ; Cytoplasm ; GTP Phosphohydrolases ; Humans ; Membrane Proteins ; Nuclear Export Signals ; Nuclear Localization Signals ; Recombinant Fusion Proteins ; Transfection