P-glycoprotein(P-gp)is an ATP-dependent efflux transporter that is distributed in many tissues and organs.P-gp can selectively pump endogenous substrates and exogenous chemicals from the cell to the outside of the cell to maintain a stable endo-environment.However,it meanwhile restricts the entry of therapeutic drug into tissues and organs,and in particular,mediates the multidrug resistance of tumor cells to chemotherapeutic drugs.Therefore,understanding the localization of P-gp in different tissues and organs may be an important breakthrough point for disease treatment.In this paper,we mainly review the molecular structure,transport mechanism,localization,and regulation of P-gp in different tissues and organs,providing reference for the subsequent treatment of diseases.
Humans ; ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry* ; Animals ; Drug Resistance, Multiple

Objective To assess the blood pressure control and its influencing factors among hypertensive patients in communities in different time periods by 24 h ambulatory blood pressure monitoring(24 h ABPM)and provide reference for optimizing the health management services for hypertension in communities. Methods A total of 765 hypertensive patients registered in the hypertension management project of national essential public health services in Sanxiang Town,Zhongshan City from October 2022 to September 2023 were identified as target subjects.The 24 h ABPM devices were distributed for blood pressure monitoring and a questionnaire survey was conducted to analyze the influencing factors of blood pressure control. Results Of all the participants,16.5% did not monitor blood pressure regularly,and 59.2% monitored blood pressure 1-2 times per week.The patients who were not on night shifts/staying up late had higher mean rates of achieving the target blood pressure and the circadian rhythm of blood pressure during 24 h,nighttime,and early morning than those who were on night shifts/staying up late(all P<0.05).The patients who never drank alcohol had higher rate of achieving the target blood pressure in early morning than those who drank alcohol(P=0.012).The average blood pressure during daytime,nighttime,and 24 h were different by sex(all P<0.05).The average blood pressure during nighttime was different by age and job types(all P<0.05).The average blood pressure during daytime,nighttime,and 24 h were different in patients with different body weight types(all P<0.05).The results of the multivariate logistic regression analysis showed that uncontrolled blood pressure during daytime was more likely to occur in male patients(OR=1.394,95%CI=1.045-1.858,P=0.024),and that during nighttime was more likely to be associated with male patients(OR=1.573,95%CI=1.088-2.275,P=0.016)and night shifts(OR=2.467,95%CI=1.198-5.077,P=0.014).It was difficult to achieve blood pressure control in early morning for the patients who drank alcohol for more than three times per week(OR=4.567,95%CI=1.629-12.807,P=0.004),woke up at night(OR=1.800,95%CI=1.125-2.878,P=0.014),and had night shifts(OR=1.579,95%CI=1.102-2.465,P=0.044).The patients on night shifts were more likely to have abnormal circadian rhythm of blood pressure(OR=1.753,95%CI:1.018-3.018,P=0.043). Conclusions The personal characteristics and lifestyle of hypertensive patients significantly affect the blood pressure control in different time periods(daytime,nighttime,and early morning)and the circadian rhythm of blood pressure.The family doctor team of community healthcare institutions can implement targeted and precise intervention measures for hypertensive patients according to the influencing factors of blood pressure control in different time periods,so as to achieve better management effects.
Humans ; Blood Pressure Monitoring, Ambulatory ; Hypertension/physiopathology* ; Male ; Female ; Middle Aged ; Circadian Rhythm ; Blood Pressure ; Surveys and Questionnaires ; Adult ; Aged ; Time Factors

The circadian clock is an important internal time regulatory system for a range of physiological and behavioral rhythms within living organisms. Testosterone, as one of the most critical sex hormones, is essential for the development of the reproductive system, maintenance of reproductive function, and the overall health of males. The secretion of testosterone in mammals is characterized by distinct circadian rhythms and is closely associated with the regulation of circadian clock genes. Here we review the central and peripheral regulatory mechanisms underlying the influence of circadian clock genes upon testosterone synthesis. We also examined the specific effects of these genes on the occurrence, development, and treatment of common male diseases, including late-onset hypogonadism, erectile dysfunction, male infertility, and prostate cancer.
Testosterone/metabolism* ; Humans ; Male ; Circadian Clocks/genetics* ; Circadian Rhythm Signaling Peptides and Proteins/metabolism* ; Circadian Rhythm/physiology* ; Hypogonadism/metabolism* ; Erectile Dysfunction/metabolism* ; Infertility, Male/metabolism* ; Prostatic Neoplasms/metabolism* ; Men's Health

OBJECTIVE: To explore the construction method of a resistant multiple myeloma (MM) patient-derived xenotransplantation (PDX) model. METHODS: 1.0×10⁷ MM patient-derived mononuclear cells (MNCs), 2.0×10⁶ MM.1S cells and 2.0×10⁶ NCI-H929 cells were respectively subcutaneously inoculated into NOD.CB17-Prkdc^scid Il2rg^tm1/Bcgen (B-NDG) mice with a volume of 100 μl per mouse to establish mouse model. The morphologic, phenotypic, proliferative and genetic characteristics of PDX tumor were studied by hematoxylin-eosin staining, immunohistochemical staining (IHC), cell cycle analysis, flow cytometry and fluorescence in situ hybridization (FISH). The sensitivity of PDX tumor to bortezomib and anlotinib monotherapy or in combination was investigated through cell proliferation, apoptosis and in vitro and in vivo experiments. The effects of anlotinib therapy on tumor blood vessel and cell apoptosis were analyzed by IHC, TUNEL staining and confocal fluorescence microscope. RESULTS: MM PDX model was successfully established by subcutaneously inoculating primary MNCs. The morphologic features of tumor cells from MM PDX model were similar to those of mature plasma cells. MM PDX tumor cells positively expressed CD138 and CD38, which presented 1q21 amplification, deletion of Rb1 and IgH rearrangement, and had a lower proliferative activity than MM cell lines. in vitro, PDX, MM.1S and NCI-H929 cells were treated by bortezomib and anlotinib for 24 hours, respectively. Cell viability assay showed that the IC₅₀ value of bortezomib were 5 716.486, 1.025 and 2.775 nmol/L, and IC₅₀ value of anlotinib were 5 5107.337, 0.706 and 5.13 μmol/L, respectively. Anlotinib treatment increased the apoptosis of MM.1S cells (P < 0.01), but did not affect PDX tumor cells (P >0.05). in vivo, there was no significant difference in PDX tumor growth between bortezomib monotherapy group and control group (P >0.05), while both anlotinib monotherapy and anlotinib combined with bortezomib effectively inhibited PDX tumor growth (both P < 0.05). The vascular perfusion and vascular density of PDX tumor were decreased in anlotinib treatment group (both P < 0.01). The apoptotic cells in anlotinib treatment group were increased compared with those in control group (P < 0.05). CONCLUSION Bortezomib-resistant MM PDX model can be successfully established by subcutaneous inoculation of MNCs from MM patients in B-NDG mice. This PDX model, which retains the basic biological characteristics of MM cells, can be used to study the novel therapies.
Animals ; Bortezomib ; Humans ; Multiple Myeloma/pathology* ; Mice ; Apoptosis ; Drug Resistance, Neoplasm ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Mice, Inbred NOD ; Disease Models, Animal ; Cell Proliferation ; Transplantation, Heterologous

OBJECTIVE

To determine the prevalence of rectal colonization with carbapenem-resistant organisms (CRO) among PGH neonatal intensive care unit (NICU) patients.

A prospective single-center observational study conducted over a 1-month period included all NICU 3 and cohort area patients admitted on April 24, 2024. Rectal swabs were collected for multidrug-resistant organism (MDRO) screening and repeated weekly for 1 month while admitted. Swabs were inoculated on chromogenic media, and isolates were identified and tested for antimicrobial sensitivity by disk diffusion. Clinical characteristics and outcomes were collected for 30 days from initial MDRO screening. Descriptive statistics were used to summarize the data.

The point prevalence of CRO colonization was 37% (14 of 38) at initial screening. There were 14 incident colonizations, hence the 4-week period prevalence of CRO colonization was 72.5% (29 of 40). The patients were mostly very preterm, very low birth weight neonates, majority were tested within the first 2 weeks of life, and half were exposed to meropenem at initial screening. Nosocomial infection developed in 29% and 64%, and 30-day mortality rate was 8% and 21% among initially non-CRO-colonized and CRO-colonized patients respectively. Despite high CRO colonization, no culture-proven CRO infection was observed. Surveillance screening documented persistent CRO colonization in 37%, but no decolonization. Escherichia coli, Klebsiella spp. and Serratia spp. were the most common colonizers.

The high prevalence of rectal CRO colonization in the NICU emphasizes the burden of antimicrobial resistance, but despite the high CRO colonization, no CRO infection was documented from the limited sample and study period.

BACKGROUND AND OBJECTIVE

Antimicrobial resistance (AMR) is a leading global public health concern as it resulted in more difficult-to-treat infections and fatalities. In the Philippines, drug-resistant E. coli, including multidrug-resistant (MDR), extended-spectrum beta-lactamase (ESBL)-producing, carbapenemase-producing carbapenem-resistant (CP-CR) E. coli, have been isolated from common food animals, increasing the risk of cross-contamination between humans, animals, and the environment. However, there is a lack of data on the distribution of E. coli in chicken meat in public wet markets. This study aims to describe the AMR profile of E. coli in raw chicken meat from retail stalls in a selected wet market in Manila City.

This quantitative descriptive study characterized the AMR profile of E. coli isolated from 25 raw chicken meat samples from a wet market in Manila City. Antimicrobial susceptibility was determined through disk diffusion method against 23 antimicrobial agents in 16 antimicrobial classes. MDR E. coli were identified based on the resistance patterns. ESBL- and carbapenemase-producing capacities of the bacteria were tested through double disk synergy test and modified carbapenem inactivation method, respectively.

Twenty-four out of 25 (96%) chicken samples contained E. coli isolates. Of these, 23 (96%) were classified as MDR. High resistance rates were observed against ampicillin (92%), tetracycline (88%), trimethoprim-sulfamethoxazole (83%), chloramphenicol (79%), ampicillin-sulbactam (75%), amoxicillin-clavulanic acid (67%), fosfomycin (67%), and streptomycin (54%). The majority of the E. coli isolates were still susceptible to a wide range of selected antimicrobial agents, including carbapenems (100%), ceftriaxone (100%), cefepime (100%), cefuroxime (96%), cefotaxime (96%), ceftazidime (96%), piperacillin-tazobactam (96%), aztreonam (96%), cefoxitin (92%), and nitrofurantoin (83%), among others. Meanwhile, none of the 24 isolated E. coli samples were classified as ESBL- and CP-CR E. coli.

Among the 25 chicken samples, 24 E. coli colonies were isolated that exhibited 0% to 92% resistance rates against selected antimicrobial agents. Most isolates were classified as MDR, but none were considered ESBLand CP-CR E. coli. This study suggests that chickens in wet markets can potentially serve as reservoir hosts for drugresistance genes, which could transfer to other bacteria and contaminate humans, animals, and the environment within the food production and supply chain. These findings emphasize the need for AMR surveillance and strategies to combat AMR in the Philippines through the One Health approach.

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

Circadian rhythms are core regulatory mechanisms that evolved to align biological functions with the Earth's rotation. These rhythms are conserved across organisms from unicellular life to multicellular species and play essential roles in metabolism, immune responses, and sleep-wake cycle. Circadian disruptions are strongly associated with various diseases. Over the past decades, genetic studies in Drosophila and mice have identified key conserved clock genes and uncovered transcription-translation feedback loops governing circadian regulation. Additionally, rhythmic neurons in the brain integrate complex neural circuits to precisely regulate physiological and behavioral rhythms. This review highlights recent advances in understanding the neuronal circuit mechanisms of rhythmic neurons in the Drosophila brain and discusses future directions for translating circadian rhythm research into chronomedicine and precision therapies.
Animals ; Circadian Rhythm/genetics* ; Neurons/physiology* ; Drosophila/physiology* ; Brain/physiology* ; Nerve Net/physiology*

The circadian rhythm regulates the 24-hour physiological and behavioral cycles through endogenous molecular clocks governed by core clock genes via the transcription-translation feedback loop (TTFL). In mammals, the suprachiasmatic nucleus (SCN) serves as the central pacemaker, coordinating the timing of physiological processes throughout the body by regulating clock genes such as CLOCK, BMAL1, PER, and CRY. The molecular clocks of peripheral tissues and cells are synchronized by the SCN through TTFLs to regulate metabolism, immunity, and energy homeostasis. Numerous studies indicate that circadian rhythm disruption is closely related to obesity, type 2 diabetes, metabolic syndrome and other diseases, and the mechanism involves the dysregulation of glucose and lipid metabolism, abnormal insulin signaling and low-grade inflammation. In recent years, small-molecule compounds targeting the core clock components such as CRY, REV-ERB, and ROR have been identified and shown potential to modulate metabolic diseases by stabilizing or inhibiting the activity of key clock proteins. This review summarizes the mechanisms and advances in these compounds, and explores the challenges and future directions for their clinical translation, providing insights for chronotherapy-based metabolic disease interventions.
Humans ; Metabolic Diseases/physiopathology* ; Animals ; Circadian Rhythm/physiology* ; Biological Clocks/drug effects* ; CLOCK Proteins/physiology* ; Circadian Clocks/physiology* ; Suprachiasmatic Nucleus/physiology*

The circadian clock is an endogenous time-keeping system that maintains physiological homeostasis by integrating environmental and genetic interactions. Heart failure is a complex clinical syndrome characterized by structural abnormalities and/or functional impairment of the heart. Growing evidence suggests that core circadian components, such as BMAL1 and REV-ERBα, play important roles in modulating myocardial energy metabolism, inflammatory responses, and oxidative stress, contributing to myocardial structural and metabolic remodeling during heart failure progression. Notably, circadian disruption is closely associated with heart failure, with aberrant blood pressure rhythms and disturbances in the sleep-wake cycle in patients. The time-dependent efficacy of heart failure medications further supports the potential of chronotherapy-based strategies to improve clinical outcomes. Here, we summarize the multifaceted regulatory roles of the circadian clock, particularly core clock genes, in heart failure pathogenesis, providing a theoretical framework for developing personalized chronotherapeutic strategies for heart failure management.
Humans ; Heart Failure/physiopathology* ; Circadian Rhythm/physiology* ; Circadian Clocks/physiology* ; ARNTL Transcription Factors/physiology* ; Nuclear Receptor Subfamily 1, Group D, Member 1/physiology* ; Oxidative Stress ; Energy Metabolism ; Animals