Loss-of-function variants of low-density lipoprotein receptor-related protein 5 (LRP5) can lead to reduced bone formation, culminating in diminished bone mass. Our previous study reported transcription factor osterix (SP7)‍-binding sites on the LRP5 promoter and its pivotal role in upregulating LRP5 expression during implant osseointegration. However, the potential role of SP7 in ameliorating LRP5-dependent osteoporosis remained unknown. In this study, we used mice with a conditional knockout (cKO) of LRP5 in mature osteoblasts, which presented decreased osteogenesis. The in vitro experimental results showed that SP7 could promote LRP5 expression, thereby upregulating the osteogenic markers such as alkaline phosphatase (ALP), Runt-related transcription factor 2 (Runx2), and β‍-catenin (P<0.05). For the in vivo experiment, the SP7 overexpression virus was injected into a bone defect model of LRP5 cKO mice, resulting in increased bone mineral density (BMD) (P<0.001) and volumetric density (bone volume (BV)/total volume (TV)) (P<0.001), and decreased trabecular separation (Tb.‍Sp) (P<0.05). These data suggested that SP7 could ameliorate bone defect healing in LRP5 cKO mice. Our study provides new insights into potential therapeutic opportunities for ameliorating LRP5-dependent osteoporosis.
Animals ; Low Density Lipoprotein Receptor-Related Protein-5/metabolism* ; Osteoporosis/genetics* ; Mice ; Mice, Knockout ; Sp7 Transcription Factor/physiology* ; Osteogenesis ; Bone Density ; Osteoblasts/metabolism* ; Core Binding Factor Alpha 1 Subunit/metabolism* ; Mice, Inbred C57BL ; beta Catenin/metabolism*

ObjectiveTo explore the potential mechanism of action of the combination of Sanguisorbae Radix-Sophorae Flos （DH） in the treatment of ulcerative colitis （UC） using network pharmacology methods and molecular docking technology. MethodsNetwork pharmacology analysis was utilized to predict the potential targets of DH for the treatment of UC. The therapeutic effects were experimentally validated by inducing a UC model in mice with 3% dextran sulfate sodium （DSS）. The experimental groups were the normal group， the model group， the salazosulfapyridine group （100 mg·kg^-1）， and the low， medium， and high dose groups of DH （1.2， 2.4， and 4.8 g·kg^-1）. The efficacy of the treatment was assessed through the general condition of the mice， histopathological examination， and the expression levels of inflammatory markers in the colon. The effect of DH on angiogenesis was explored by messenger RNA （mRNA） detection of colonic angiogenesis-related mediators， vascular endothelial growth factor （VEGF） immunohistochemistry， microvessel density （MVD） detection， and transmission electron microscopy. The phosphatidylinositol-3-kinase （PI3K）-protein kinase B （Akt） signaling pathway proteins were quantitatively analyzed through Western blot to assess whether the suppression of pathological angiogenesis by DH is associated with this pathway. ResultsNetwork pharmacological analysis yielded 112 potential core therapeutic targets for the treatment of UC with DH， of which the core targets were tumor protein 53 （TP53）， JUN， interleukin （IL）-6， Akt1， and tumor necrosis factor （TNF）. Compared with the normal group， mice in the model group showed significant weight loss， colon shortening， and high DAI score， increased expression of inflammatory factors IL-6， IL-1β， and TNF-α， as well as increased mRNA expression levels of angiogenesis-related mediators VEGF， vascular cell adhesion molecule 1 （VCAM1）， angiotensin 1 （Ang1）， matrix metalloproteinase （MMP）-1， MMP-2， and MMP-9. The positive expression of CD31 and VEGF in colonic tissue increased， and the protein expression of the PI3K/Akt pathway was increased （P<0.05）. The endothelial cells of the colonic mucosa and the colonic vasculature were severely damaged. Compared with the model group， mice in the DH groups had significantly reduced weight loss and colon shortening， lower DAI scores， and a significant decrease in mRNA expression of inflammatory factors and angiogenesis-related mediators. In addition， there was decreased positive expression of CD31 and VEGF in colonic tissue and decreased protein expression of the PI3K/Akt pathway （P<0.05）. ConclusionNetwork pharmacology， molecular docking， and experimental validation are applied to explore the mechanism of action of DH in the treatment of UC， and it is found that DH is able to improve the symptoms of colitis and inhibit the pathological angiogenesis in UC mice. Its action might be related to affecting the PI3K/Akt pathway.

ObjectiveTo explore the potential mechanism of action of the combination of Sanguisorbae Radix-Sophorae Flos （DH） in the treatment of ulcerative colitis （UC） using network pharmacology methods and molecular docking technology. MethodsNetwork pharmacology analysis was utilized to predict the potential targets of DH for the treatment of UC. The therapeutic effects were experimentally validated by inducing a UC model in mice with 3% dextran sulfate sodium （DSS）. The experimental groups were the normal group， the model group， the salazosulfapyridine group （100 mg·kg^-1）， and the low， medium， and high dose groups of DH （1.2， 2.4， and 4.8 g·kg^-1）. The efficacy of the treatment was assessed through the general condition of the mice， histopathological examination， and the expression levels of inflammatory markers in the colon. The effect of DH on angiogenesis was explored by messenger RNA （mRNA） detection of colonic angiogenesis-related mediators， vascular endothelial growth factor （VEGF） immunohistochemistry， microvessel density （MVD） detection， and transmission electron microscopy. The phosphatidylinositol-3-kinase （PI3K）-protein kinase B （Akt） signaling pathway proteins were quantitatively analyzed through Western blot to assess whether the suppression of pathological angiogenesis by DH is associated with this pathway. ResultsNetwork pharmacological analysis yielded 112 potential core therapeutic targets for the treatment of UC with DH， of which the core targets were tumor protein 53 （TP53）， JUN， interleukin （IL）-6， Akt1， and tumor necrosis factor （TNF）. Compared with the normal group， mice in the model group showed significant weight loss， colon shortening， and high DAI score， increased expression of inflammatory factors IL-6， IL-1β， and TNF-α， as well as increased mRNA expression levels of angiogenesis-related mediators VEGF， vascular cell adhesion molecule 1 （VCAM1）， angiotensin 1 （Ang1）， matrix metalloproteinase （MMP）-1， MMP-2， and MMP-9. The positive expression of CD31 and VEGF in colonic tissue increased， and the protein expression of the PI3K/Akt pathway was increased （P<0.05）. The endothelial cells of the colonic mucosa and the colonic vasculature were severely damaged. Compared with the model group， mice in the DH groups had significantly reduced weight loss and colon shortening， lower DAI scores， and a significant decrease in mRNA expression of inflammatory factors and angiogenesis-related mediators. In addition， there was decreased positive expression of CD31 and VEGF in colonic tissue and decreased protein expression of the PI3K/Akt pathway （P<0.05）. ConclusionNetwork pharmacology， molecular docking， and experimental validation are applied to explore the mechanism of action of DH in the treatment of UC， and it is found that DH is able to improve the symptoms of colitis and inhibit the pathological angiogenesis in UC mice. Its action might be related to affecting the PI3K/Akt pathway.

Objective:To investigate the role of umbilical cord mesenchymal stem cell (MSC) -derived nanovesicles in hair regeneration.Methods:(1) Nanovesicles were prepared by continuously extruding umbilical cord MSCs through polycarbonate membranes, and were identified using transmission electron microscopy and nanoparticle tracking analysis. (2) Six C57BL/6 female mice with full-thickness skin wounds were randomly divided into a nanovesicle group (subcutaneously injected with nanovesicles once at the wound margin) and a control group (subcutaneously injected with an equal volume of phosphate-buffered saline [PBS] at the wound margin) ; skin samples were collected on day 16 for hematoxylin-eosin (HE) staining to assess wound healing and hair follicle regeneration. (3) Human hair follicle dermal papilla cells (DPCs) were isolated using a two-step enzyme method; the uptake of PKH26-pre-labeled nanovesicles by DPCs was observed by fluorescence microscopy; the proliferative activity of DPCs co-cultured with nanovesicles was evaluated using cell counting kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. (4) Six healthy C57BL/6 female mice were randomly divided into two groups after anesthesia, and subcutaneously injected with either fluorescent dye DIR-pre-labeled nanovesicles or PBS; an in vivo imaging system was used to observe the uptake and metabolism of nanovesicles in the mouse skin. (5) Twenty-four C57BL/6 female mice with depilated backs were randomly divided into a nanovesicle group (subcutaneously injected with nanovesicles on days 0, 8, and 15) and a control group (subcutaneously injected with an equal volume of PBS at the same time points) ; skin samples were collected on days 4, 18, and 21 for HE staining to analyze differences in hair follicle cycling; transcriptome sequencing was performed on skin samples collected on day 4. Statistical analyses were conducted using the t test. Results:(1) Transmission electron microscopy showed that nanovesicles exhibited a spherical membranous structure with diameters of 141.3 ± 60.0 nm. (2) In 6 C57BL/6 female mice with full-thickness skin wounds, the wound area on day 12 was significantly smaller in the nanovesicle group (1.27 ± 0.50 mm 2) than in the control group (4.13 ± 1.03 mm 2, t = 4.34, P = 0.012). (3) Fluorescence microscopy revealed that nanovesicles were taken up by DPCs within 20 hours; the absorbance of DPCs was significantly higher in the nanovesicle group than in the control group ( t = 20.23, P < 0.001), and the percentage of EdU-positive cells was also significantly higher in the nanovesicle group (49.62% ± 6.45%) than in the control group (37.58% ± 3.42%, t = 3.69, P = 0.006). (4) In vivo imaging of the 6 C57BL/6 female mice showed strong fluorescence in the back of mice in the nanovesicle group on day 0, which markedly decreased by day 8, while no fluorescence was observed in the control group throughout the experiment. (5) Hair follicle cycle experiments on the 24 C57BL/6 female mice with depilated backs showed that the hair follicle length on day 4 after depilation was significantly longer in the nanovesicle group (368.00 ± 63.17 μm) than in the control group (266.90 ± 34.41 μm, t = 9.87, P < 0.001), and the hair bulb diameter was also significantly longer in the nanovesicle group (54.83 ± 10.32 μm) than in the control group (39.12 ± 7.54 μm, t = 16.02, P < 0.001) ; on day 18, the nanovesicle group showed a significantly higher hair follicle density (19.12 ± 0.90) compared with the control group (11.07 ± 1.51, t = 7.92, P = 0.001) ; on day 21, 46.13% ± 8.64% of hair follicles in the nanovesicle group remained in the anagen phase Ⅵ to the catagen phase Ⅱ, and 46.24% ± 3.29% were in the catagen phases Ⅲ to Ⅳ, while 78.89% ± 18.36% of hair follicles in the control group were in the telogen phases Ⅶ to Ⅷ. Transcriptome sequencing showed that differentially expressed genes in the nanovesicle group were significantly positively enriched in the keratinization process (NES = 2.23, P < 0.001) . Conclusion:Umbilical cord MSC-derived nanovesicles could promote the proliferation of DPCs, advance the entry of hair follicles into the anagen phase, delay their entry into the catagen phase, and induce hair regeneration.

Middle compartment defects,a common subtype of pelvic floor dysfunction(PFD),are primarily characterized by the prolapse of the uterus or vaginal vault.Magnetic resonance imaging(MRI)has emerged as a valuable diagnostic tool for PFD,offering superior soft tissue resolution while eliminating exposure to ionizing radiation.This review comprehensive summarizes current applications of MRI in the diagnosis and treatment of PFD,covering measurement methods,manifestations of three-level structural defects,postoperative efficacy evaluation,vaginal axial assessment,and evaluation of the mesh status.The authors suggest that MRI enables precise preoperative evaluation of three-level defects,thereby facilitating the development of personalized treatment plans.Additionally,MRI provides an accurate postoperative assessment of surgical outcomes and mesh status,offering a new basis for postoperative assessment.MRI demonstrates unique value in the diagnosis and treatment of middle compartment defects.

Objective To evaluate the perioperative safety and mid-term outcomes of laparoscopic sacrocolpopexy(LSC)and laparoscopic pectopexy(LP)for pelvic organ prolapse(POP).Methods A retrospective analysis was conducted on 274 POP patients,including 178 who underwent LSC and 96 who underwent LP,between August 2017 and January 2023.The extent of prolapse and anatomical restoration were assessed preoperatively and postoperatively using the Pelvic Organ Prolapse Quantification(POP-Q)system.Quality of life outcomes were evaluated with validated questionnaires,including Pelvic Floor Distress Inventory-short form 20(PFDI-20),Pelvic Floor Impact Questionnaire-short form 7(PFIQ-7),and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12(PISQ-12).Postoperative patient satisfaction was assessed during follow-ups.Postoperative anatomical restoration,perioperative status,and postoperative complications,recurrence,and quality of life were compared between the two groups.Multivariate logistic regression was performed to identify postoperative risk factors for recurrence.Results The operative time in the LSC group was significantly shorter than that in the LP group(P<0.05).Intraoperative blood loss was higher in the LSC group compared to that in the LP group(P<0.05).The LSC group also exhibited higher rates of de novo stress urinary incontinence and constipation(P<0.05).The mean follow-up duration was(35.91±16.90)months.The positions of the indicator points(Aa,Ba,C,Ap,and Bp)in the POP-Q classification after the operation were all better than those before the operation.The PFDI-20 score,PFIQ-7 score,and PISQ-12 score all improved compared to those before the operation(P<0.05).Comparison of preoperative and postoperative PFDI-20,PFIQ-7,and PISQ-12 scores showed no intergroup differences.Compared with the LP group,the LSC group had the lower preoperative POP-Q measurements at points Aa and Ba(P<0.05),but superior postoperative measurements for all the indicator points(Aa,Ba,C,Ap,and Bp)(P<0.05).Recurrence occurred in 28 cases in the LP group and 4 cases in the LSC group,with the LP group presenting a significantly higher anatomical recurrence rate than the LSC group did(31.46%[28/89]vs.2.41%[4/166],P<0.05).The subjective cure rate(100%)and objective cure rate(97.59%)in the LSC group were superior to those in the LP group(88.76%and 68.54%,respectively;P<0.05).The results of the multivariate logistic regression analysis showed that,after adjusting for the confounding factors,including age,gravidity,parity,body mass index,and duration of POP,the risk of recurrence after LSC surgery was 0.044 times that after LP(odds ratio[OR],0.044;95%CI,0.015-0.133;P<0.001).Conclusion Mid-term outcomes of LP with partial cervical preservation appear inferior to those of LSC,with LSC demonstrating superior anatomical restoration and lower rates of anatomical recurrence.However,improvements in sexual function and quality of life are comparable between the two procedures.Further evaluation with larger sample sizes and longer follow-up is warranted to better characterize long-term outcomes.

Objective:To investigate the role of umbilical cord mesenchymal stem cell (MSC) -derived nanovesicles in hair regeneration.Methods:(1) Nanovesicles were prepared by continuously extruding umbilical cord MSCs through polycarbonate membranes, and were identified using transmission electron microscopy and nanoparticle tracking analysis. (2) Six C57BL/6 female mice with full-thickness skin wounds were randomly divided into a nanovesicle group (subcutaneously injected with nanovesicles once at the wound margin) and a control group (subcutaneously injected with an equal volume of phosphate-buffered saline [PBS] at the wound margin) ; skin samples were collected on day 16 for hematoxylin-eosin (HE) staining to assess wound healing and hair follicle regeneration. (3) Human hair follicle dermal papilla cells (DPCs) were isolated using a two-step enzyme method; the uptake of PKH26-pre-labeled nanovesicles by DPCs was observed by fluorescence microscopy; the proliferative activity of DPCs co-cultured with nanovesicles was evaluated using cell counting kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. (4) Six healthy C57BL/6 female mice were randomly divided into two groups after anesthesia, and subcutaneously injected with either fluorescent dye DIR-pre-labeled nanovesicles or PBS; an in vivo imaging system was used to observe the uptake and metabolism of nanovesicles in the mouse skin. (5) Twenty-four C57BL/6 female mice with depilated backs were randomly divided into a nanovesicle group (subcutaneously injected with nanovesicles on days 0, 8, and 15) and a control group (subcutaneously injected with an equal volume of PBS at the same time points) ; skin samples were collected on days 4, 18, and 21 for HE staining to analyze differences in hair follicle cycling; transcriptome sequencing was performed on skin samples collected on day 4. Statistical analyses were conducted using the t test. Results:(1) Transmission electron microscopy showed that nanovesicles exhibited a spherical membranous structure with diameters of 141.3 ± 60.0 nm. (2) In 6 C57BL/6 female mice with full-thickness skin wounds, the wound area on day 12 was significantly smaller in the nanovesicle group (1.27 ± 0.50 mm 2) than in the control group (4.13 ± 1.03 mm 2, t = 4.34, P = 0.012). (3) Fluorescence microscopy revealed that nanovesicles were taken up by DPCs within 20 hours; the absorbance of DPCs was significantly higher in the nanovesicle group than in the control group ( t = 20.23, P < 0.001), and the percentage of EdU-positive cells was also significantly higher in the nanovesicle group (49.62% ± 6.45%) than in the control group (37.58% ± 3.42%, t = 3.69, P = 0.006). (4) In vivo imaging of the 6 C57BL/6 female mice showed strong fluorescence in the back of mice in the nanovesicle group on day 0, which markedly decreased by day 8, while no fluorescence was observed in the control group throughout the experiment. (5) Hair follicle cycle experiments on the 24 C57BL/6 female mice with depilated backs showed that the hair follicle length on day 4 after depilation was significantly longer in the nanovesicle group (368.00 ± 63.17 μm) than in the control group (266.90 ± 34.41 μm, t = 9.87, P < 0.001), and the hair bulb diameter was also significantly longer in the nanovesicle group (54.83 ± 10.32 μm) than in the control group (39.12 ± 7.54 μm, t = 16.02, P < 0.001) ; on day 18, the nanovesicle group showed a significantly higher hair follicle density (19.12 ± 0.90) compared with the control group (11.07 ± 1.51, t = 7.92, P = 0.001) ; on day 21, 46.13% ± 8.64% of hair follicles in the nanovesicle group remained in the anagen phase Ⅵ to the catagen phase Ⅱ, and 46.24% ± 3.29% were in the catagen phases Ⅲ to Ⅳ, while 78.89% ± 18.36% of hair follicles in the control group were in the telogen phases Ⅶ to Ⅷ. Transcriptome sequencing showed that differentially expressed genes in the nanovesicle group were significantly positively enriched in the keratinization process (NES = 2.23, P < 0.001) . Conclusion:Umbilical cord MSC-derived nanovesicles could promote the proliferation of DPCs, advance the entry of hair follicles into the anagen phase, delay their entry into the catagen phase, and induce hair regeneration.

Periarticular fracture of the shoulder is a common type of fractures in the elderly. Postoperative adverse events such as internal fixation failure, humeral head ischemic necrosis and upper limb dysfunction occur frequently, which seriously endangers the exercise and health of the elderly. Compared with the fracture with normal bone mass, the osteoporotic periarticular fracture of the shoulder is complicated with slow healing and poor rehabilitation, so the clinical management becomes more difficult. At present, there is no targeted guideline or consensus for this type of fracture in China. In such context, experts from Youth Osteoporosis Group of Chinese Orthopedic Association, Orthopedic Expert Committee of Geriatrics Branch of Chinese Association of Gerontology and Geriatrics, Osteoporosis Group of Youth Committee of Chinese Association of Orthopedic Surgeons and Osteoporosis Committee of Shanghai Association of Chinese Integrative Medicine developed the Chinese expert consensus on the diagnosis and treatment of osteoporotic periarticular fracture of the shoulder in the elderly ( version 2023). Nine recommendations were put forward from the aspects of diagnosis, treatment strategies and rehabilitation of osteoporotic periarticular fracture of the shoulder, hoping to promote the standardized, systematic and personalized diagnosis and treatment concept and improve functional outcomes and quality of life in elderly patients with osteoporotic periarticular fracture of the shoulder.

SARS-CoV-2 Omicron variant (B.1.1.529) was first discovered in South Africa in November 2021 and has since become a mainstream strain worldwide. Omicron variant was defined as the fifth "variant of concern (VOC)" by World Health Organization on November 26, 2021. This paper illustrates the mutation trends of Omicron variants in terms of SARS-CoV-2 genome and protein structure as well as nucleic acid site mutations and amino acid site mutations, describes the features of Omicron mutation sites in terms of lineage comparison among the VOCs and Omicron sublineages, and further highlights the influences of Omicron site mutations from the aspects of immune escape, virulence and transmission ability. Moreover, this paper also reviews the development of direct antiviral agents, antibodies and vaccines, aiming to provide reference for further investigation.

Objectives:To explore changes in the quality of life(QoL)in patients with non-severe aplastic anemia(NSAA)after 2 years of cyclosporine A(CsA)therapy, and possible factors may affect the QoL.Methods:Patients with de novo NSAA from January 2014 to 2016 who had been treated with only CsA for at least 2 years in the outpatient department of Peking Union Medical College Hospital were instructed to fill-in the SF-36 form before and after 2 years of CsA treatment. Data from NSAA were compared with those of normal controls; patients’ information such as age, sex, education, annual income, type of payment, and compliance were collected, disease severity and response to treatment were also evaluated.Results:A total of 52 patients were included in our study with 27(51.9%)men and 25(48.1%)women, with the medium age of 48(21-85)years. After 2 years of treatment, 15(28.8%)patients achieved complete response(CR), 25(48.1%)achieved partial response(PR), and 12(23.1%)patients had no response(NR). The overall response rate(ORR)was 76.9%. Before the therapy, SF-36 scores in patients with NSAA were significantly lower than that of normal controls either in physical or mental component summaries( P<0.05). However, after 2 years of therapy, patients with NSAA had significant improvement of mental component summaries and recovered to normal with even higher scores in mental health(MH)(65.9±17.6 vs 59.7±22.9, P=0.014)and energy/vitality(VT)(58.8±20.1 vs 52.3±20.9, P=0.023)compared with normal controls, although they still had comparatively lower scores in physical component summaries. No associations were found between QoL and age, sex, educational level, family income, type of payment, patient adherence, or transfusion dependency. Patients with higher ECOG (the Eastern Cooperative Oncology Group score)at the beginning experienced greater progress in QoL compared to those with lower ECOG. Both patients with CR and PR had shown significant improvement in QoL. Conclusion:Patients with NSAA had impaired QoL compared with normal patients. CsA treatment can improve the QoL, especially in mental component summaries. Patients can benefit from the treatment regardless of their social status, and patients with lower ECOG at the beginning seem to benefit more from the therapy.