Circadian rhythm is an endogenous biological clock mechanism that enables organisms to adapt to the earth’s alternation of day and night. It plays a fundamental role in regulating physiological functions and behavioral patterns, such as sleep, feeding, hormone levels and body temperature. By aligning these processes with environmental changes, circadian rhythm plays a pivotal role in maintaining homeostasis and promoting optimal health. However, modern lifestyles, characterized by irregular work schedules and pervasive exposure to artificial light, have disrupted these rhythms for many individuals. Such disruptions have been linked to a variety of health problems, including sleep disorders, metabolic syndromes, cardiovascular diseases, and immune dysfunction, underscoring the critical role of circadian rhythm in human health. Among the numerous systems influenced by circadian rhythm, the skin—a multifunctional organ and the largest by surface area—is particularly noteworthy. As the body’s first line of defense against environmental insults such as UV radiation, pollutants, and pathogens, the skin is highly affected by changes in circadian rhythm. Circadian rhythm regulates multiple skin-related processes, including cyclic changes in cell proliferation, differentiation, and apoptosis, as well as DNA repair mechanisms and antioxidant defenses. For instance, studies have shown that keratinocyte proliferation peaks during the night, coinciding with reduced environmental stress, while DNA repair mechanisms are most active during the day to counteract UV-induced damage. This temporal coordination highlights the critical role of circadian rhythms in preserving skin integrity and function. Beyond maintaining homeostasis, circadian rhythm is also pivotal in the skin’s repair and regeneration processes following injury. Skin regeneration is a complex, multi-stage process involving hemostasis, inflammation, proliferation, and remodeling, all of which are influenced by circadian regulation. Key cellular activities, such as fibroblast migration, keratinocyte activation, and extracellular matrix remodeling, are modulated by the circadian clock, ensuring that repair processes occur with optimal efficiency. Additionally, circadian rhythm regulates the secretion of cytokines and growth factors, which are critical for coordinating cellular communication and orchestrating tissue regeneration. Disruptions to these rhythms can impair the repair process, leading to delayed wound healing, increased scarring, or chronic inflammatory conditions. The aim of this review is to synthesize recent information on the interactions between circadian rhythms and skin physiology, with a particular focus on skin tissue repair and regeneration. Molecular mechanisms of circadian regulation in skin cells, including the role of core clock genes such as Clock, Bmal1, Per and Cry. These genes control the expression of downstream effectors involved in cell cycle regulation, DNA repair, oxidative stress response and inflammatory pathways. By understanding how these mechanisms operate in healthy and diseased states, we can discover new insights into the temporal dynamics of skin regeneration. In addition, by exploring the therapeutic potential of circadian biology in enhancing skin repair and regeneration, strategies such as topical medications that can be applied in a time-limited manner, phototherapy that is synchronized with circadian rhythms, and pharmacological modulation of clock genes are expected to optimize clinical outcomes. Interventions based on the skin’s natural rhythms can provide a personalized and efficient approach to promote skin regeneration and recovery. This review not only introduces the important role of circadian rhythms in skin biology, but also provides a new idea for future innovative therapies and regenerative medicine based on circadian rhythms.

Tangye Jingfa Tu is an important content in the ancient book Fuxingjue from Dunhuang， implying the fundamental principles of formula compatibility in traditional Chinese medicine （TCM）. Our research group has delved into nearly 200 formulas （both classical and contemporary formulas） recorded in the Fangjixue under the theoretical framework of the deficiency or excess syndrome of five Zang-organs together with the reinforcing and reducing effects of Chinese medicinal materials of five flavors. We have initially elucidated the essential principles of the correspondence between formulas and syndromes， revealing the deep-level logic of medicinal material selection and compatibility， thus enriching the understanding about the core characteristics and essence of the diseases and syndromes targeted by formulas. The lunar year of 2024 is Jia Chen year. The formula recorded in Sanyin Jiyi Bingzheng Fanglun for treating the epidemic diseases characterized by excessive earth， prevalent dampness and wetness， and invasion of pathogenic factors into the kidney water in Jia Chen year is Fuzi Shanzhuyutang. Therefore， elucidating the compatibility principle of Fuzi Shanzhuyutang is of great significance for clinical prescription and medication modification in Jia Chen year. According to the Tangye Jingfa Tu theory on the deficiency or excess of syndrome of five Zang-organs and the reinforcing and reducing effects of Chinese medicinal materials of five flavors， this article dissects Fuzi Shanzhuyutang regarding the etiology and pathogenesis of the main indications， as well as the five-element properties and efficacy characteristics of Chinese medicinal materials constituting this formula. It explains the compatibility principles of Fuzi Shanzhuyutang and puts forward suggestions for modifying the formula to address different indications， providing a reference for guiding clinical syndrome differentiation and treatment.

Tangye Jingfa Tu is an important content in the ancient book Fuxingjue from Dunhuang， implying the fundamental principles of formula compatibility in traditional Chinese medicine （TCM）. Our research group has delved into nearly 200 formulas （both classical and contemporary formulas） recorded in the Fangjixue under the theoretical framework of the deficiency or excess syndrome of five Zang-organs together with the reinforcing and reducing effects of Chinese medicinal materials of five flavors. We have initially elucidated the essential principles of the correspondence between formulas and syndromes， revealing the deep-level logic of medicinal material selection and compatibility， thus enriching the understanding about the core characteristics and essence of the diseases and syndromes targeted by formulas. The lunar year of 2024 is Jia Chen year. The formula recorded in Sanyin Jiyi Bingzheng Fanglun for treating the epidemic diseases characterized by excessive earth， prevalent dampness and wetness， and invasion of pathogenic factors into the kidney water in Jia Chen year is Fuzi Shanzhuyutang. Therefore， elucidating the compatibility principle of Fuzi Shanzhuyutang is of great significance for clinical prescription and medication modification in Jia Chen year. According to the Tangye Jingfa Tu theory on the deficiency or excess of syndrome of five Zang-organs and the reinforcing and reducing effects of Chinese medicinal materials of five flavors， this article dissects Fuzi Shanzhuyutang regarding the etiology and pathogenesis of the main indications， as well as the five-element properties and efficacy characteristics of Chinese medicinal materials constituting this formula. It explains the compatibility principles of Fuzi Shanzhuyutang and puts forward suggestions for modifying the formula to address different indications， providing a reference for guiding clinical syndrome differentiation and treatment.

ObjectiveThe nucleolar protein PES1 (Pescadillo homolog 1) plays critical roles in ribosome biogenesis and cell cycle regulation, yet its involvement in cellular senescence remains poorly understood. This study aimed to comprehensively investigate the functional consequences of PES1 suppression in cellular senescence and elucidate the molecular mechanisms underlying its regulatory role. MethodsInitially, we assessed PES1 expression patterns in two distinct senescence models: replicative senescent mouse embryonic fibroblasts (MEFs) and doxorubicin-induced senescent human hepatocellular carcinoma HepG2 cells. Subsequently, PES1 expression was specifically downregulated using siRNA-mediated knockdown in these cell lines as well as additional relevant cell types. Cellular proliferation and senescence were assessed by EdU incorporation and SA-β-gal staining assays, respectively. The expression of senescence-associated proteins (p53, p21, and Rb) and SASP factors (IL-6, IL-1β, and IL-8) were analyzed by Western blot or qPCR. Furthermore, Northern blot and immunofluorescence were employed to evaluate pre-rRNA processing and nucleolar morphology. ResultsPES1 expression was significantly downregulated in senescent MEFs and HepG2 cells. PES1 knockdown resulted in decreased EdU-positive cells and increased SA‑β‑gal-positive cells, indicating proliferation inhibition and senescence induction. Mechanistically, PES1 suppression activated the p53-p21 pathway without affecting Rb expression, while upregulating IL-6, IL-1β, and IL-8 production. Notably, PES1 depletion impaired pre-rRNA maturation and induced nucleolar stress, as evidenced by aberrant nucleolar morphology. ConclusionOur findings demonstrate that PES1 deficiency triggers nucleolar stress and promotes p53-dependent (but Rb-independent) cellular senescence, highlighting its crucial role in maintaining nucleolar homeostasis and regulating senescence-associated pathways.

Platycodonis Radix is the dry root of Platycodon grandiflorum of Campanulaceae, which has a variety of pharmacological effects and is a commonly used bulk Chinese medicine. In this study, the chloroplast genome sequences of six P. grandiflorum from different producing areas has been sequenced with Illumina HiSeq X Ten platform. The specific DNA barcodes were screened, and the germplasm resources and genetic diversity were analyzed according to the specific barcodes. The total length of the chloroplast genome of 6 P. grandiflorum samples was 172 260-172 275 bp, and all chloroplast genomes showed a typical circular tetrad structure and encoded 141 genes. The comparative genomics analysis and results of amplification efficiency demonstrated that trnG-UCC and ndhG_ndhF were the potential specific DNA barcodes for identification the germplasm resources of P. grandiflorum. A total of 305 P. grandiflorum samples were collected from 15 production areas in 9 provinces, for which the fragments of trnG-UCC and ndhG_ndhF were amplificated and the sequences were analyzed. The results showed that trnG-UCC and ndhG_ndhF have 5 and 11 mutation sites, respectively, and 5 and 7 haplotypes were identified, respectively. The combined analysis of the two sequences formed 13 haplotypes (named Hap1-Hap13), and Hap4 is the main genotype, followed by Hap1. The unique haplotypes possessed by the three producing areas can be used as DNA molecular tags in this area to distinguish from the germplasm resources of P. grandiflorum from other areas. The haplotype diversity, nucleotide diversity and genetic distance were 0.94, 4.79×10^-3 and 0.000 0-0.020 3, respectively, suggesting that the genetic diversity was abundant and intraspecific kinship was relatively close. This study laid a foundation for the identification of P. grandiflorum, the protection and utilization of germplasm resources, and molecular breeding.

Objective To evaluate the efficacy and safety of brexpiprazole in treating acute schizophrenia.Methods Patients with schizophrenia were randomly divided into treatment group and control group.The treatment group was given brexpiprozole 2-4 mg·d-1 orally and the control group was given aripiprazole 10-20 mg·d-1orally,both were treated for 6 weeks.Clinical efficacy of the two groups,the response rate at endpoint,the changes from baseline to endpoint of Positive and Negative Syndrome Scale(PANSS),Clinical Global Impression-Improvement(CGI-S),Personal and Social Performance scale(PSP),PANSS Positive syndrome subscale,PANSS negative syndrome subscale were compared.The incidence of treatment-related adverse events in two groups were compared.Results There were 184 patients in treatment group and 186 patients in control group.After treatment,the response rates of treatment group and control group were 79.50％(140 cases/184 cases)and 82.40％(150 cases/186 cases),the scores of CGI-I of treatment group and control group were(2.00±1.20)and(1.90±1.01),with no significant difference(all P＞0.05).From baseline to Week 6,the mean change of PANSS total score wese(-30.70±16.96)points in treatment group and(-32.20±17.00)points in control group,with no significant difference(P＞0.05).The changes of CGI-S scores in treatment group and control group were(-2.00±1.27)and(-1.90±1.22)points,PSP scores were(18.80±14.77)and(19.20±14.55)points,PANSS positive syndrome scores were(-10.30±5.93)and(-10.80±5.81)points,PANSS negative syndrome scores were(-6.80±5.98)and(-7.30±5.15)points,with no significant difference(P＞0.05).There was no significant difference in the incidence of treatment-related adverse events between the two group(69.00％vs.64.50％,P＞0.05).Conclusion The non-inferiority of Brexpiprazole to aripiprazole was established,with comparable efficacy and acceptability.

Objective To study the pharmacokinetic characteristics of the test formulation of compound lidocaine cream and reference formulation of lidocaine and prilocaine cream in Chinese healthy subjects and to evaluate whether there is bioequivalence between the two formulations.Methods A single-center,single-dose,randomized,open-label,two-period,two-sequence,crossover design was used.This study included 40 healthy subjects,and in each period,test formulation or reference formulation 60 g was applied to the skin in front of both thighs(200 cm2 each side,a total of 400 cm2)under fasting conditions,and the drug was left on for at least 5 h after application.The concentrations of lidocaine and prilocaine in plasma were determined using liquid chromatography-tandem mass spectrometry(LC-MS/MS)method.Pharmacokinetic parameters were calculated using WinNonlin 8.0 software to evaluate the bioequivalence of the two formulations.Results After the application of the test formulation compound lidocaine cream and the reference formulation lidocaine and prilocaine cream on both thighs of the subjects,the pharmacokinetic parameters of lidocaine in plasma were as follows:Cmax were(167.27±91.33)and(156.13±66.86)ng·mL-1,AUC0-t were(1 651.78±685.09)and(1 636.69±617.23)ng·mL-1·h,AUC0-∞ were(1 669.85±684.65)and(1 654.37±618.30)ng·mL-1·h,the adjusted geometric mean ratios were 104.49％,101.88％and 101.89％,respectively,with 90％confidence intervals of 98.18％-111.20％,97.80％-106.13％and 97.87％-106.07％,all within the range of 80.00％-125.00％.The pharmacokinetic parameters of prilocaine in plasma were as follows:Cmax were(95.66±48.84)and(87.52±39.16)ng·mL-1,AUC0-t were(790.86±263.99)and(774.14±256.42)ng·mL-1·h,AUC0_m were(807.27±264.67)and(792.84±254.06)ng·mL-1 h,the adjusted geometric mean ratios were 107.34％,103.55％and 102.98％,respectively with 90％confidence intervals of 101.69％-113.31％,99.94％-107.30％and 99.65％-106.43％,all within the range of 80.00％-125.00％.Conclusion The test formulation compound lidocaine cream and the reference formulation lidocaine and prilocaine cream are bioequivalent.

Objective To observe the inhibitory effect of Guiqi Yiyuan ointment on tumor growth in mice with Lewis lung cancer,and to explore the molecular mechanism of Guiqi Yiyuan ointment combined with cisplatin through phosphoinositide 3-kinase/protein kinase B/mammalian rapamycin target protein(PI3K/Akt/mTOR)signal pathway.Methods Sixty C57BL/6 mice were randomly divided into 6 groups with 10 mice in each group.Except for the blank group(0.9％NaCl),Lewis lung cancer-bearing mice were randomly divided into model group(0.9％NaCl),control group(0.9％NaCl,cisplatin 5 mg·kg-1)and low,medium,high dose experimental groups(Guiqi Yiyuan ointment 1.6,3.3,6.6 g·kg-1,cisplatin 5 mg·kg-1).Flow cytometry was used to detect bone marrow-derived suppressor cells(MDSCs);the expression of related proteins in tumor tissues was detected by Western blot.Results The tumor inhibition rates in control group and low,medium,high dose experimental groups were(39.87±4.45)％,(45.74±14.97)％,(57.78±4.70)％and(69.82±11.05)％.The proportion of MDSCs in bone marrow of in blank group,model group,control group and low,medium,high dose experimental groups were(36.13±1.08)％,(68.63±2.94)％,(58.93±2.02)％,(58.00±1.50)％,(50.93±5.06)％and(43.07±2.41)％.The protein expressions of p-PI3K/PI3K in model group,control group and low,medium and high experimental groups were 0.97±0.03,0.77±0.02,0.72±0.01,0.68±0.03 and 0.53±0.02;PTEN were 0.21±0.07,0.65±0.07,0.74±0.06,0.99±0.13,1.11±0.13;p-Akt/Akt were 1.01±0.02,0.82±0.02,0.77±0.00,0.72±0.03 and 0.52±0.04;p-mTOR/mTOR were 1.01±0.01,0.76±0.05,0.69±0.07,0.59±0.06 and 0.47±0.06.There were significant differences between low,medium,high experimental groups and control group(all P＜0.05).Conclusion Guiqi Yiyuan ointment combined with cisplatin can significantly improve the quality of life and inhibit tumor growth in mice.The mechanism may be the inhibition of PI3K/Akt/mTOR signal pathway and the enhancement of tumor cell apoptosis and autophagy.

Objective To observe the effects of traditional Chinese medicine compound Platycodon grandiflorum Bai powder on the growth of subcutaneously implanted tumor and the expression of B-cell lymphoma-2(Bcl-2),Bcl-2 associated X protein(Bax),cysteinyl aspartate specific proteinase(caspase)-3 and caspase-9 in subcutaneously implanted tumor of Lewis lung cancer mice.Methods The model of transplanted tumor of Lewis lung cancer in mice was established.Seventy SPF male C57BL/6 mice were randomly divided into blank group,model group,low dose experimental group,medium dose experimental group,high dose experimental group,control group and combined group.Blank group and model group were given 0.9％NaCl 0.2 mL by gavage;control group was given 0.9％NaCl by gavage and 25 mg·kg-1cisplatin intraperitoneally;high,medium,low dose experimental groups were given 193,96,48 mg·kg-1·d-1 Platycodon grandiflorum Bai powder 0.2 mL by gavage,respectively;combined group was given 96 mg·kg-1·d-1 Platycodon grandiflorum Bai powder 0.2 mL by gavage,and 25 mg·kg-1 cisplatin intraperitoneally,once every other day.The myelogenous suppressor cells(MDSCs)of mouse bone marrow were detected by flow cytometry,and the expressions of Bel-2,Bax,caspase-3 and caspase-9 in tumor cells were detected by immunofluorescence.Results The percentage of MDSCs in bone marrow of mice in blank group,model group,low dose experimental,medium,high dose experimental group,control group and combination group were(32.50±2.76)％,(63.13±3.14)％,(48.43±2.23)％,(42.53±1.28)％,(32.93±3.56)％,(51.30±4.25)％and(19.90±6.21)％,respectively.The fluorescence intensities of Bax in model group,low dose experimental group,medium dose experimental group,high dose experimental group,control group and combination group were 10.42±0.68,12.40±1.23,15.14±0.65,22.95±1.76,27.18±1.62 and 31.61±1.28;Bel-2 were 36.85±0.80,33.92±4.20,28.88±1.01,20.04±2.21,15.69±2.36 and 6.05±0.73;caspase-3 were 5.28±0.44,7.63±0.55,9.66±0.85,14.73±1.18,17.95±1.29 and 22.92±1.95;caspase-9 were 9.48±0.90,11.57±0.72,13.45±0.93,15.73±1.44,19.20±0.96 and 23.21±1.51.There were significant differences between medium,high dose experimental groups and model group(all P＜0.05),and there were significant differences between combined group and control group(all P＜0.05).Conclusion Platycodon grandiflorum Bai powder can up-regulating the expression of Bax,caspase-3 and caspase-9,down-regulating the expression of Bel-2,inhibiting MDSCs,promoting tumor cell apoptosis and inhibiting tumor growth.

Objective To study the bioequivalence and safety of two olmesartan medoxomil and hydrochlorothiazide tablets in Chinese healthy subjects.Methods A total of 24 healthy subjects underwent fasting and postprandial tests in a single-center,randomized,open-label,single-dose,two-formulation,two-sequence,two-period,self-cross-over controlled design.The subjects were administered a single oral dose of the test formulation and reference formulation(each containingolmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg)in a random cross-over fashion.The plasma concentrations of olmesartan and hydrochlorothiazide were determined by LC-MS/MS.The non-compartmental model analysis of olmesartan and hydrochlorothiazide was conducted using WinNonlin 7.0 software to calculate pharmacokinetic parameters and assess bioequivalence.Results In the fasting test,the pharmacokinetic parameters of olmesartan of test and reference were as follows:Cmax were(798.35±206.78)and(664.52±168.25)ng·mL-1,AUC0-t were(4 430.71±1 294.87)and(3 976.67±1 083.54)h·ng·mL-1,AUC0-∞ were(4 551.67±1 303.06)and(4 090.37±1 103.97)h·ng·mL-1.The pharmacokinetic parameters of hydrochlorothiazide of test and reference were as follows:Cmax were(92.39±35.96)and(96.15±38.76)ng·mL-1,AUC0_t were(548.69±217.11)and(564.41±208.68)h·ng·mL-1,AUC0-∞ were(603.04±228.59)and(619.26±223.27)h·ng·mL-1.In the fed test,the pharmacokinetic parameters of olmesartan of T and R were as follows:Cmax were(583.15±149.48)and(550.57±104.76)ng·mL-1,AUC0-t were(3 585.18±952.72)and(3 292.19±904.58)h·ng·mL-1,AUC0-∞ were(3 696.05±996.55)and(3 396.30±923.41)h·ng·mL-1.The pharmacokinetic parameters of hydrochlorothiazide of test and reference were as follows:Cmax were(70.30±17.88)and(74.70±21.65)ng·mL-1,AUC0-t were(476.60±119.39)and(492.91±144.81)h·ng·mL-1,AUC0-∞ were(523.37±132.67)and(535.81±151.92)h·ng·mL-1.In fasting and fed condition,the 90％confidence interval(90％CI)of Cmax,AUC0-t and AUC0-∞ of olmesartan and hydrochlorothiazide were in 80.00％-125.00％.Conclusion The two olmesartan medoxomil and hydrochlorothiazide tablets were bioequivalent under fasting and fed conditions,and good security.