ObjectivePolygoni Multiflori Radix is a commonly used tonic traditional Chinese medicine （TCM） in clinical practice， but liver injury has often been reported in recent years. Some related preparations containing Polygoni Multiflori Radix have been reported by the National Medical Products Administration many times for the risk of liver injury. This has caused extensive discussion on the potential toxicity of TCM in China and abroad， which has limited the clinical use of Polygoni Multiflori Radix to some extent. To understand the adverse reactions of Polygoni Multiflori Radix， the safe and rational use of Polygoni Multiflori Radix in clinical practice was discussed. MethodsThe pharmacovigilance thought of modern Chinese medicine and the TCM pharmacovigilance system framework of ''identification of poison， use of poison， anti-poison， and detoxification'' were employed to mine the relevant toxicity records， usage and dosage， processing compatibility， and contraindication of taking Polygoni Multiflori Radix in ancient books. The drug safety information of Polygoni Multiflori Radix was summarized by comparing with modern reports. ResultsA total of 74 ancient books related to Polygoni Multiflori Radix were included， suggesting that the toxicity of Polygoni Multiflori Radix was recognized in ancient times. The main chemical components of Polygoni Multiflori Radix had both efficacy and toxicity， and the adverse reactions may be related to long-term use， excessive use， and individual differences. The results showed that the toxic components of Polygoni Multiflori Radix could be reduced by peeling， steaming with black beans， and processing without iron tools. The toxic effects of Polygoni Multiflori Radix could be reduced by the compatibility of Polygoni Multiflori Radix with Poria， Psoraleae Fructus， and Cistanches Herba. ConclusionReasonable dosage， standard processing， correct compatibility， and syndrome differentiation are the key points to standardize the use of Polygoni Multiflori Radix and reduce the incidence of adverse reactions. Clinically， the toxicity classification of TCM should be strengthened， and the susceptible population should be prioritized. The detection indicators and early warning mechanisms should be improved， and precise drug dosage and course of treatment should be guaranteed. These measures can ensure the safe use of Polygoni Multiflori Radix.

ObjectivePolygoni Multiflori Radix is a commonly used tonic traditional Chinese medicine （TCM） in clinical practice， but liver injury has often been reported in recent years. Some related preparations containing Polygoni Multiflori Radix have been reported by the National Medical Products Administration many times for the risk of liver injury. This has caused extensive discussion on the potential toxicity of TCM in China and abroad， which has limited the clinical use of Polygoni Multiflori Radix to some extent. To understand the adverse reactions of Polygoni Multiflori Radix， the safe and rational use of Polygoni Multiflori Radix in clinical practice was discussed. MethodsThe pharmacovigilance thought of modern Chinese medicine and the TCM pharmacovigilance system framework of ''identification of poison， use of poison， anti-poison， and detoxification'' were employed to mine the relevant toxicity records， usage and dosage， processing compatibility， and contraindication of taking Polygoni Multiflori Radix in ancient books. The drug safety information of Polygoni Multiflori Radix was summarized by comparing with modern reports. ResultsA total of 74 ancient books related to Polygoni Multiflori Radix were included， suggesting that the toxicity of Polygoni Multiflori Radix was recognized in ancient times. The main chemical components of Polygoni Multiflori Radix had both efficacy and toxicity， and the adverse reactions may be related to long-term use， excessive use， and individual differences. The results showed that the toxic components of Polygoni Multiflori Radix could be reduced by peeling， steaming with black beans， and processing without iron tools. The toxic effects of Polygoni Multiflori Radix could be reduced by the compatibility of Polygoni Multiflori Radix with Poria， Psoraleae Fructus， and Cistanches Herba. ConclusionReasonable dosage， standard processing， correct compatibility， and syndrome differentiation are the key points to standardize the use of Polygoni Multiflori Radix and reduce the incidence of adverse reactions. Clinically， the toxicity classification of TCM should be strengthened， and the susceptible population should be prioritized. The detection indicators and early warning mechanisms should be improved， and precise drug dosage and course of treatment should be guaranteed. These measures can ensure the safe use of Polygoni Multiflori Radix.

ObjectiveTo explore the effects of different dosage forms of Kaixinsan （KXS） on the morphology and function of mitochondria in rat models of Alzheimer's disease （AD） and potential mechanisms of action. MethodsMale SD rats were randomly assigned to a sham group， model group， treatment groups receiving KXS decoction， powders， and granules （3.08 g·kg^-1）， as well as donepezil group （0.51×10^-3 g·kg^-1）， with 10 rats in each group. AD model was created using intracerebroventricular injection of streptozocin （STZ）. After 30 days of administration， behavioral assessments were conducted， and mitochondrial morphology was observed using transmission electron microscopy. Mitochondrial respiratory chain complex content was measured via enzyme-linked immunosorbent assay （ELISA）. Changes in mitochondrial membrane potential were measured via JC-1 staining， and superoxide dismutase （SOD） activity and reactive oxygen species （ROS） levels were measured via biochemical assays. The mRNA expression of adenosine 5'-monophosphate-activated protein kinase （AMPK）， peroxisome proliferator-activated receptor gamma coactivator-1α （PGC-1α）， and silent information regulator 3 （SIRT3） was detected by real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）， and Western blot was used to examine the protein expression levels of optic atrophy protein1 （OPA1）， mitochondrial fission protein 1 （FIS1）， AMPK， p-AMPK， PGC-1α， and SIRT3. ResultsCompared with the sham group， rats in the model group had significantly lower recognition index， spontaneous alternation rate， escape latency， number of platform crossings， time spent in the target quadrant， and percentage of distance traveled in the target quadrant distance （P<0.05， P<0.01）. Significant mitochondrial damage was observed in the hippocampal tissue， with a marked decrease in mitochondrial respiratory chain complex content （P<0.01） and reduced mitochondrial membrane potential （P<0.05）. Additionally， the SOD activity was reduced， while ROS levels were elevated （P<0.01）. The mRNA expression of PGC-1α and SIRT3 was significantly downregulated （P<0.01）， along with decreased protein expression levels of OPA1， p-AMPK/AMPK， PGC-1α， and SIRT3， whereas FIS1 protein expression was significantly upregulated （P<0.05， P<0.01）. Compared with the model group， rats in KXS-treated groups （various dosage forms） showed significant improvement in behavioral indexes （P<0.05， P<0.01）， reduced hippocampal mitochondrial damage， and more organized mitochondrial cristae. Mitochondrial respiratory chain complex content was significantly increased （P<0.05， P<0.01）， and mitochondrial membrane potentials were elevated （P<0.05）. SOD activity was elevated， and ROS levels were significantly reduced （P<0.05， P<0.01）. Furthermore， the mRNA expression of PGC-1α and SIRT3 was upregulated， with increased protein levels of OPA1， p-AMPK/AMPK， PGC-1α， and SIRT3， while FIS1 protein expression levels were significantly reduced （P<0.05， P<0.01）. Across the KXS-treated groups， the granule group showed a higher spontaneous alternation rate than the decoction and powder groups （P<0.05）. ConclusionKXS decoction， powders， and granules can improve the learning and memory ability of rats， with granules being the most effective. The mechanism of action may involve activation of the AMPK/PGC-1α/SIRT3 signaling pathway， improvement of the mitochondrial function， and subsequent amelioration of the brain energy metabolism disorders.

ObjectiveTo explore the effects of different dosage forms of Kaixinsan （KXS） on the morphology and function of mitochondria in rat models of Alzheimer's disease （AD） and potential mechanisms of action. MethodsMale SD rats were randomly assigned to a sham group， model group， treatment groups receiving KXS decoction， powders， and granules （3.08 g·kg^-1）， as well as donepezil group （0.51×10^-3 g·kg^-1）， with 10 rats in each group. AD model was created using intracerebroventricular injection of streptozocin （STZ）. After 30 days of administration， behavioral assessments were conducted， and mitochondrial morphology was observed using transmission electron microscopy. Mitochondrial respiratory chain complex content was measured via enzyme-linked immunosorbent assay （ELISA）. Changes in mitochondrial membrane potential were measured via JC-1 staining， and superoxide dismutase （SOD） activity and reactive oxygen species （ROS） levels were measured via biochemical assays. The mRNA expression of adenosine 5'-monophosphate-activated protein kinase （AMPK）， peroxisome proliferator-activated receptor gamma coactivator-1α （PGC-1α）， and silent information regulator 3 （SIRT3） was detected by real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）， and Western blot was used to examine the protein expression levels of optic atrophy protein1 （OPA1）， mitochondrial fission protein 1 （FIS1）， AMPK， p-AMPK， PGC-1α， and SIRT3. ResultsCompared with the sham group， rats in the model group had significantly lower recognition index， spontaneous alternation rate， escape latency， number of platform crossings， time spent in the target quadrant， and percentage of distance traveled in the target quadrant distance （P<0.05， P<0.01）. Significant mitochondrial damage was observed in the hippocampal tissue， with a marked decrease in mitochondrial respiratory chain complex content （P<0.01） and reduced mitochondrial membrane potential （P<0.05）. Additionally， the SOD activity was reduced， while ROS levels were elevated （P<0.01）. The mRNA expression of PGC-1α and SIRT3 was significantly downregulated （P<0.01）， along with decreased protein expression levels of OPA1， p-AMPK/AMPK， PGC-1α， and SIRT3， whereas FIS1 protein expression was significantly upregulated （P<0.05， P<0.01）. Compared with the model group， rats in KXS-treated groups （various dosage forms） showed significant improvement in behavioral indexes （P<0.05， P<0.01）， reduced hippocampal mitochondrial damage， and more organized mitochondrial cristae. Mitochondrial respiratory chain complex content was significantly increased （P<0.05， P<0.01）， and mitochondrial membrane potentials were elevated （P<0.05）. SOD activity was elevated， and ROS levels were significantly reduced （P<0.05， P<0.01）. Furthermore， the mRNA expression of PGC-1α and SIRT3 was upregulated， with increased protein levels of OPA1， p-AMPK/AMPK， PGC-1α， and SIRT3， while FIS1 protein expression levels were significantly reduced （P<0.05， P<0.01）. Across the KXS-treated groups， the granule group showed a higher spontaneous alternation rate than the decoction and powder groups （P<0.05）. ConclusionKXS decoction， powders， and granules can improve the learning and memory ability of rats， with granules being the most effective. The mechanism of action may involve activation of the AMPK/PGC-1α/SIRT3 signaling pathway， improvement of the mitochondrial function， and subsequent amelioration of the brain energy metabolism disorders.

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

OBJECTIVE: To evaluate the effectiveness of suture anchors combined with headless compression screw fixation in treating inferior pole patellar fractures. METHODS: A retrospective analysis was conducted on 36 patients with inferior pole patellar fractures, who were admitted between January 2018 and October 2024 and met the selective criteria. There were 15 males and 21 females with a mean age of 52.3 years (range, 23-81 years). The fracture were reduced and fixed using suture anchors combined with headless compression screws. The operation time, intraoperative blood loss, and the length of hospital stay were recorded. Functional recovery was assessed using knee range of motion (ROM), Hospital for Special Surgery (HSS) knee score, and Böstman patellar fracture efficacy score. RESULTS: The operation time ranged from 10 to 100 minutes, with an average of 57.6 minutes. The intraoperative blood loss was 10 to 120 mL, with an average of 73.3 mL. The length of hospital stay was 5 to 10 days, with an average of 6.3 days. All incisions healed by first intention. All 36 patients were followed up 18-24 months (mean, 20.6 months). Postoperative X-ray films indicated that the fractures had healed; no screw breakage, anchor loosening, or implant foreign body rejection reactions occurred during follow-up. At last follow-up, the ROM of the affected knee joint was (136.0±2.3)°, and there was no significant difference when compared with the healthy side (136.6±2.3)° ( t=-1.944, P=0.060). The HSS score of the affected knee joint was 96-100 (mean, 99.1), and all cases were rated as excellent. The Böstman patellar fracture efficacy score was 27-30 (mean, 29.1), and 35 cases were rated as excellent and 1 as good. CONCLUSION The suture anchors combined with headless compression screws technique provides reliable fixation for inferior pole patellar fractures. This method combines surgical simplicity with excellent functional outcomes.
Humans ; Male ; Female ; Middle Aged ; Bone Screws ; Aged ; Retrospective Studies ; Patella/surgery* ; Fracture Fixation, Internal/instrumentation* ; Adult ; Aged, 80 and over ; Suture Anchors ; Fractures, Bone/surgery* ; Range of Motion, Articular ; Treatment Outcome ; Young Adult ; Operative Time ; Length of Stay

Primary ciliary dyskinesia (PCD) is a clinically rare, genetically and phenotypically heterogeneous condition characterized by chronic respiratory tract infections, male infertility, tympanitis, and laterality abnormalities. PCD is typically resulted from variants in genes encoding assembly or structural proteins that are indispensable for the movement of motile cilia. Here, we identified a novel nonsense mutation, c.466G>T, in cilia- and flagella-associated protein 300 ( CFAP300 ) resulting in a stop codon (p.Glu156*) through whole-exome sequencing (WES). The proband had a PCD phenotype with laterality defects and immotile sperm flagella displaying a combined loss of the inner dynein arm (IDA) and outer dynein arm (ODA). Bioinformatic programs predicted that the mutation is deleterious. Successful pregnancy was achieved through intracytoplasmic sperm injection (ICSI). Our results expand the spectrum of CFAP300 variants in PCD and provide reproductive guidance for infertile couples suffering from PCD caused by them.
Adult ; Female ; Humans ; Male ; Pregnancy ; China ; Ciliary Motility Disorders/genetics* ; Codon, Nonsense ; East Asian People/genetics* ; Exome Sequencing ; Homozygote ; Infertility, Male/genetics* ; Kartagener Syndrome/genetics* ; Pedigree ; Sperm Injections, Intracytoplasmic ; Cytoskeletal Proteins/genetics*

OBJECTIVE: The aim of this study is to analyze the clinical features and genetic etiology of a patient with multiple morphological abnormalities of the sperm flagella (MMAF) retrospectively. METHODS: A severely oligospermic patient from the Reproductive Center of the First Affiliated Hospital of Ningbo University was selected as the study subject. Clinical data and examination results were collected. High-throughput sequencing and bioinformatics were used to analyze the genetic etiology. And Sanger sequencing was employed to validate findings in the family. Transmission electron microscopy (TEM) was used to observe the sperm ultrastructure, and immunofluorescence analysis was performed to examine the localization of FSIP2 protein in the sperm. RESULTS: The patient presented with severe oligospermia, and sperm morphology displayed MMAF. TEM revealed fibrous sheath and 9+2 microtubule structural disruptions in the sperm. Sequencing identified compound heterozygous variants in the FSIP2 gene (c.17798C > T, c.5927T > G), inherited from the father and mother, respectively. According to the guidelines of the American College of Medical Genetics and Genomics, the variants were classified as pathogenic. The patient's spouse underwent intracytoplasmic single sperm injection, resulting in one embryo, but no clinical pregnancy occurred after embryo transfer. CONCLUSION This study reported the mutation of FSIP2 gene c.17798C > T, c.5927T > G in a patient with MMAF. These findings expand the mutational spectrum of the FSIP2 gene and provide insights for genetic and assisted reproductive counseling for patients with MMAF.
Humans ; Male ; Sperm Tail/pathology* ; Heterozygote ; Oligospermia/genetics* ; Spermatozoa ; Mutation ; Infertility, Male/genetics* ; Adult ; Pedigree ; Retrospective Studies ; Sperm Injections, Intracytoplasmic

HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.