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.

With the widespread use of antibiotics, drug-resistant bacterial infections have become a significant threat to human health. Finding new antibacterial strategies that can effectively control drug-resistant bacterial infections has become an urgent task. Unlike small molecule drugs that target bacterial proteins, antisense oligonucleotide (ASO) can target genes related to bacterial resistance, pathogenesis, growth, reproduction and biofilm formation. By regulating the expression of these genes, ASO can inhibit or kill bacteria, providing a novel approach for the development of antibacterial drugs. To overcome the challenge of delivering antisense oligonucleotide into bacterial cells, various drug delivery systems have been applied in this field, including cell-penetrating peptides, lipid nanoparticles and inorganic nanoparticles, which have injected new momentum into the development of antisense oligonucleotide in the antibacterial realm. This review summarizes the current development of small nucleic acid drugs, the antibacterial mechanisms, targets, sequences and delivery vectors of antisense oligonucleotide, providing a reference for the research and development of antisense oligonucleotide in the treatment of bacterial infections.

The auxin/indole-3-acetic acid (Aux/IAA) gene family is an important regulator for plant growth hormone signaling, involved in plant growth, development, as well as response to environmental stresses. In the present study, we identified SmIAA7 which is potentially associated with Salvia miltiorrhiza leaf development through comparatively analyzed the transcriptome data from different pinnate leaves. SmIAA7 was successfully isolated from S. miltiorrhiza using the specific primers. Then subsequent bioinformatic analysis, prokaryotic expression and purification, subcellular localization, and induction expression analysis under auxin and abiotic stress were performed. The full-length of SmIAA7 contained an ORF of 684 bp encoding a protein of 227 amino acid with a molecular weight of 25.3 kD. Conserved domain analysis showed that SmIAA7 contains the conserved Aux_IAA domain (pfam02309). Sequence analysis and phylogenetic tree analysis results indicated SmIAA7 was phylogenetically close to IAA7 and IAA14 from other plants, suggesting SmIAA7 involved in plant growth and development as well as response to environmental stresses. The prokaryotic expression vector pET28a-SmIAA7 was constructed and SmIAA7 recombinant protein was successfully expressed in E. coli Rosetta (DE3) strain. Subcellular localization experiment demonstrated that SmIAA7 localized in the nucleus of plant cells. Real-time fluorescence quantitative PCR results showed that the expression level of SmIAA7 was upregulated in response to auxin. Drought, low temperature, and salt stress significantly increased the transcript level of SmIAA7 gene. This study lays a foundation for further elucidating the role of SmIAA7 in leaf development, signal transduction, and stress defense in S. miltiorrhiza.

Xanthine oxidase (XO) is an important therapeutic target for the treatment of hyperuricemia and gout. Based on the previously identified potent XO inhibitor 1, seventeen oxadiazoles and their ring-opening analogues were designed and synthesized via the bioisostere replacement strategy. Among them, compounds 2l, 2n, and 3b showed obvious XO inhibitory activity at the concentration of 10 μmol·L^-1, and compound 3b exhibited an IC₅₀ value of 1.45 μmol·L^-1.

Parkinson’s disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, manifests a variety of motor symptoms, such as bradykinesia, resting tremor, rigidity, postural balance disorder, and also presents non-motor symptoms, including cognitive decline, depression, constipation, and sleep disorders. Currently, treatment for PD primarily encompasses pharmacological interventions, with levodopa being the first-line therapy, and non-pharmacological approaches such as deep brain stimulation (DBS). However, both approaches exhibit therapeutic limitations, with potential adverse reactions emerging from long-term use. Levodopa is associated with dyskinesia, while DBS may lead to mental confusion, cognitive decline, and depression. Exercise, as an effective adjuvant strategy for drug treatment of PD, can significantly improve PD motor disorders. Recently, studies have found that the mechanisms of exercise improving PD motor symptoms are associated with exerkines. Exerkine refers to signalling moieties secreted in response to acute and/or chronic exercise. This review mainly summarizes the improvement of PD motor disorders by various exerkines and the underlying mechanisms. Firstly, exercise can trigger the secretion of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in the substantia nigra (SN) and the striatum, potentially improving PD. Recent evidence has suggested that both BDNF and GDNF could improve motor symptoms of PD via restoring the number of dopaminergic neurons in the SN and striatum, increasing striatal dopamine contents, and reducing α-synuclein (α-syn) accumulation in the SN. In addition, BDNF also alleviates motor symptoms of PD by enhancing long-term potentiation and increasing the spine density of spiny projection neurons in the striatum, while GDNF by inhibiting neuroinflammation in the SN via suppressing the activation of microglia, reducing interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) expressions, reducing the phosphorylation of inhibitor of nuclear factor kappa Bα (IκBα), and increasing the anti-inflammatory factors IL-10 and transforming growth factor-β (TGF-β). Secondly, exercise, a main trigger for irisin secretion from skeletal muscle, can improve PD motor symptoms by stimulating the irisin/adenosine monophosphate-activated protein kinase (AMPK)/Sirtuin-1 (SIRT1) pathway. Specifically, irisin alleviates motor symptoms in PD through multiple mechanisms, including inhibiting excessive mitochondrial fission by reducing the expressions of dynamin-related protein 1 (Drp1) and mitochondrial fission protein 1 (Fis1), alleviating the apoptosis of dopaminergic neurons by increasing B-cell lymphoma 2 (Bcl-2) expression and reducing Bcl-2-associated X protein (Bax) and caspase 3 expressions, and restoring the number of dopaminergic neurons. Thirdly, new biomarkers of PD (cathepsin B and Fetuin-A) also play roles in PD development. Cathepsin B can promote the clearance of pathogenic α-syn in PD by enhancing the function of lysosomes, including strengthening the lysosomal degradation capacity, elevating the transport rate, and increasing the activity of lysosomal glucocerebrosidase (GCase). Fetuin-A has been demonstrated to improve PD by restoring the number and the morphology of Purkinje cells, which are the only efferent neurons in the cerebellar cortex and play an important role in maintaining motor coordination. This review aims to facilitate a deep understanding of the mechanism by which exercise improves PD motor symptoms and provide a theoretical basis for promotion of exercise in PD.

Aim To investigate the synergistic sensiti-zation effect of saikosaponin D(SSD)combined with temozolomide(TMZ)on glioblastoma cells(GBM)and its molecular mechanism.Methods The sensitiv-ity of RG-2,U251 and LN-428 GBM cell lines to SSD and TMZ was analyzed by CCK-8 method combined with HE staining,and the optimal compatible concen-tration was screened.The effect of HE staining com-bined with Hoechst fluorescence staining on the prolif-eration of GBM cell line was detected by clonal forma-tion experiment.The autophagosome formation of GBM cells was observed by monodansylcadaverine(MDC)staining.The expression and distribution of endoplas-mic reticulum stress-related factors and apoptosis and autophagy proteins were detected by Western blot and ICC.Results The sensitivity order of GBM cells to TMZ was RG-2＞U251＞LN-428.The results of com-bined administration showed the synergistic inhibitory effect of SSD combined with TMZ on proliferation of GBM cell lines,which was confirmed by cell cloning formation experiment.Compared with the TMZ group,Hoechst fluorescence staining showed a significant in-crease in the number of nuclear bright staining in the combined administration group.MDC fluorescence staining showed that there were more dense green parti-cles in the cytoplasm of SSD/TMZ plus group than that of TMZ group.Western blot results showed that com-pared with TMZ group,the expression of ER stress markers GRP78,CHOP,p-PERK and ATF6 signifi-cantly increased in SSD/TMZ group(P＜0.05).The expressions of apoptosis proteins caspase-12,caspase-9,caspase-3,cleaved caspase-3,Bax and autophagy proteins LC3 and Beclin-1 significantly increased(P＜0.05),which were verified by ICC test.Conclusions SSD can cooperate with TMZ to inhibit the prolifera-tion of GBM cells and induce apoptosis and autophagy,and enhance the sensitivity of GBM cells to TMZ by ac-tivating endoplasmic reticulum stress pathway.

Aim To establish limited sampling strategy to esti-mate area under the drug concentration versus time curve(AUC0-t)of lymphoma patients treated with autologous stem cell transplantation(ASCT)who had busulfan intravenous infu-sion.Methods Twelve lymphoma patients treated with ASCT received a conditioning regimen containing busulfan 105 mg·m-2,Ⅳ infusion for 3 h.Blood samples were obtained 1 h after the start of the first dose of the busulfan infusion,at 5 min,1 h,2 h,4 h,6 h and 18 h after the end of the drug administration.LC-MS/MS was used to determine the busulfan serum concentra-tion.After obtaining the clinical pharmacokinetic parameters of busulfan by traditional pharmacokinetic method,multiple linear stepwise regression analysis was used to establish the AUC0-t es-timation model of busulfan based on limited sampling method.The model was further verified by Jackknife and Bootstrap meth-od.Bland-Altman plots were used to evaluate the consistency between the limited sampling method and the classical pharma-cokinetic method.Results The multiple linear regression equa-tion analysis of C60min,C180min and C300min was obtained by the limited sampling method.The regression equation was AUC0-t=295.003C60min+233.050C180min+273.163C300min-1202.713,r2=0.995,MPE=-0.87％,RMSE=2.40％.Conclusion The limited sampling model with three-point estimation can be used to estimate the AUC0-t of busulfan exposure in lymphoma patients with ASCT to provide reference for clinical application of busulfan.

Aim To investigate the effects of L-argi-nine on spontaneous contraction of rat colon and the relative mechanisms.Methods An organ bath system was use to measure the spontaneous contraction of both longitudinal smooth muscle strips(LMS)and circular muscle strips(CMS).Whole-cell voltage-clamp tech-niques were applied to observe the alterations in cur-rents of L-type voltage-dependent Ca2+channels(VD-CCs),and voltage-gated K+channel(Kv)in single smooth muscle cells(SMCs)from rat colon.Results L-Arginine(1 mmol·L-1)significantly enhanced the spontaneous contraction of both LMS and CMS.The excitatory response to L-arginine was remarkably attenuated by tetrodotoxin(1 mmol·L-1)and atro-pine(1 mmol·L-1),antagonist of muscarinic ACh receptor(mAChR).However,the inhibitor of nitric oxide(NO)synthesis L-NNA(1 mmol·L-1)failed to block the action of L-Arginine.Furthermore,whole-cell patch-clamp recordings showed that L-arginine ac-tivated VDCCs and inhibited Kv channels on SMCs.Conclusions L-Arginine exerts an excitatory effect on colonic motility in a nitric oxide(NO)-independent manner and the stimulatory action of L-arginine is part-ly mediated by mAChR.In addition,VDCCs and Kv channels are both involved in L-arginine-induced exci-tation.

Aim To investigate the regulatory mecha-nism of prostaglandin E2(PGE2)on the membrane expression of organic anion transporter 1(OAT1)in synoviocytes and the effect of paeoniflorin-6'-O-ben-zene sulfonate(CP-25).Methods Immunofluores-cence was used to detect the effects of CP-25 on the expression of OAT1 and prostaglandin E receptor 4(EP4)in PGE2 stimulated synoviocytes.EP4 agonists(TCS2510)and antagonists(GW627368X)were used to explore the role of EP4 in regulation of OAT1.CP-25 and protein kinase A(PKA)inhibitor H-89 were used to investigate the effects of CP-25 and PKA on OAT1 expression in synoviocytes.Results Membrane expression of EP4 and OAT1 was down-regulated with-in 0～10 min,and thereby up-regulated between 20～60 min in the presence of PGE2 simulation(P＜0.05).CP-25 significantly up-regulated the expres-sions of OAT1 and EP4 in PGE2 stimulated synovio-cytes(P＜0.05).TCS2510 significantly up-regulated the expression of OAT1 in cell membrane of synovio-cytes(P＜0.01).CP-25 up-regulated the expression of OAT1 in PGE2-treated cells,while the effect of CP-25 on expression of OAT1 was significantly inhibited after the together use of GW627368X and H-89.(P＜0.01).Conclusions PGE2-mediated EP4/PKA sig-naling pathway regulates the expression of OAT1 on membranes of synoviocytes.CP-25 can significantly in-crease the membrane expression of OAT1 in synovio-cytes by activating the EP4/PKA signaling pathway.

Aim To explore the mechanism and mate-rial basis of Shenkang injection(SKI)in the treatment of renal fibrosis(RF)by bioinformatics and in vitro experiments.Methods The differentially expressed genes of RF were screened by GEO database.With the help of CMAP database,based on the similarity princi-ple of gene expression profile,the drugs that regulated RF were repositioned,and then the components of SKI potential treatment RF were screened by molecular fin-gerprint similarity analysis.At the same time,the core targets and pathways of SKI regulating RF were predic-ted based on network pharmacology.Finally,it was verified by molecular docking and cell experiments.Results Based on the GEO database,two RF-related data sets were screened,and CMAP was relocated to three common RF therapeutic drugs(saracatinib,da-satinib,pp-2).Molecular fingerprint similarity analysis showed that RF therapeutic drugs had high structural similarity with five SKI components such as salvianolic acid B and hydroxysafflor yellow A.Molecular docking results showed that salvianolic acid B,hydroxysafflor yellow A and other components had good binding abili-ty with MMP1 and MMP13,which were the core targets of SKI-regulated potential treatment of RF.Network pharmacology analysis suggested that the core targets of SKI were mainly enriched in signaling pathways such as Relaxin and AGE-RAGE.Cell experiments showed that SKI could significantly reduce the mRNA expres-sion levels of AGER,NFKB1,COL1A1,SERPINE1,VEGFC in AGE-RAGE signaling pathway and MMP1 and MMP13 in Relaxin signaling pathway in RF model cells,and significantly increase the mRNA expression level of RXFP1.Conclusions SKI can play a role in the treatment of RF by regulating Relaxin and AGE-RAGE signaling pathways,and its material basis may be salvianolic acid B,hydroxysafflor yellow A and other components.