Lingguizhugan Decoction (LGZG) demonstrates significant efficacy in treating various cardiovascular diseases clinically, yet its precise mechanism of action remains elusive. This study aimed to elucidate the potential mechanisms and effects of LGZG on isoproterenol (ISO) continuous stimulation-induced chronic heart failure (CHF) in mice, providing direct experimental evidence for further clinical applications. In vivo, continuous ISO infusion was administered to mice, and ventricular myocytes were utilized to explore LGZG?s potential mechanism of action on the ?1-adrenergic receptor (?1-AR)/Gs/G protein-coupled receptor kinases (GRKs)/?-arrestin signaling deflection system in the heart. The findings reveal that LGZG significantly reduced the messenger ribonucleic acid (mRNA) expression of hypertrophy-related biomarkers [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] and improved cardiac remodeling and left ventricular diastolic function in mice with ISO-induced CHF. Furthermore, LGZG inhibited the overactivation of Gs/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling and downregulated the downstream transcriptional activity of cAMP-response element binding protein (CREB) and the expression of the coactivator CBP/P300. Notably, LGZG downregulated the expression of ?-arrestin1 and GRK 2/3/5 while upregulating the expression of ?1-AR and ?-arrestin2. These results suggest that LGZG inhibits Gs/cAMP/PKA signaling and ?-arrestin/GRK-mediated desensitization and internalization of ?1-AR, potentially exerting cardioprotective effects through the synergistic regulation of the ?1-AR/Gs/GRKs/?-arrestin signaling deflection system via multiple pathways.
Animals ; Heart Failure/genetics* ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Mice ; Male ; G-Protein-Coupled Receptor Kinases/genetics* ; Mice, Inbred C57BL ; Humans ; Isoproterenol ; Arrestins/genetics* ; Chronic Disease

While multiple step saccades (MSS) are occasionally reported in the healthy population, they are more evident in patients with Parkinson's disease (PD). Therefore, MSS has been suggested as a biological marker for the diagnosis of PD. However, the lack of clarity on the neural mechanism underlying the generation of MSS largely impedes their application in the clinic. We have proposed recently that MSS are triggered by the discrepancy between desired and executed saccades. Accordingly, brain regions involved in saccadic planning and execution might play a role in the generation of MSS. To test this hypothesis, we explored the role of the prefrontal (PFC) and posterior parietal cortex (PPC) in generating MSS by conducting two experiments: electroencephalographic recording and single-pulse transcranial magnetic stimulation in the PFC or PPC of humans while participants were performing a gap saccade task. We found that the PFC and PPC are involved in the generation of MSS.
Humans ; Parietal Lobe/physiology* ; Saccades/physiology* ; Prefrontal Cortex/physiology* ; Male ; Transcranial Magnetic Stimulation ; Female ; Electroencephalography ; Adult ; Young Adult

Kashin-Beck disease (KBD), a common joint disorder that can lead to joint deformities and restricted mobility, significantly affects patients' quality of life. Traditional conservative treatments have shown limited efficacy. With advancements in total ankle replacement prosthesis and the successive updates of mobile and fixed -bearing in ankle prosthesis, more and more clinical trial results indicate that ankle prosthesis replacement is expected to become a new approach for treating KBD. This article reviews the progress in ankle prosthesis and studies their clinical application potential in KBD management.

Objectives:To investigate the protective effect of nicotinamide adenine dinucleotide (NAD?) against noise-induced cochlear damage and preliminarily explore its underlying transcriptional and metabolic regulatory mechanisms.Methods:During the study period (January 2023-February 2025), an oxidative stress model was established using House Ear Institute-organ of Corti 1 (HEI-OC1) cells, and cell viability was assessed using the Cell Counting Kit-8 (CCK8) assay. Flow cytometry was employed to analyze cell apoptosis. A mouse model of noise-induced hearing loss was developed, and the mice were divided into three groups: a noise-exposed saline group, a noise-exposed NAD? intervention group, and a noise-free control group. Hearing protection effects were evaluated by auditory brainstem response (ABR) and immunofluorescence. Metabolomics and transcriptomics were used to analyze the regulatory effects of NAD +on transcription and metabolism in mouse cochlea. Enzyme-linked immunosorbent assay, quantitative real-time PCR, and western blot were used to verify the differential transcription and metabolic molecules and their functions. Data were statistically analyzed with GraphPad Prism 9.3.0. Results:NAD +at concentrations ranging from 10-80 μM effectively restored cell viability and reduced apoptosis induced by H?O? in HEI-OC1 cells. NAD? intervention significantly improved 16-32 kHz ABR thresholds after noise exposure ( P<0.05), reduced outer hair cell loss rates ( P<0.05), and attenuated ribbon synapse damage ( P<0.000 1). Metabolomics analysis revealed a significant downregulation in the glycerophospholipid metabolism pathway, with decreased levels of lysophosphatidic acid (LPA) and its related metabolites. ELISA results showed that LPA levels in the NAD? intervention group were significantly lower ( P<0.05). LPA inhibitor (ATX inhibitor 1) exhibited a cell protective effect similar to that of NAD?. Transcriptomics analysis indicated a significant upregulation of key genes related to potassium ion channels, such as Kcnq4. qPCR and Western blot further confirmed the significant upregulation of Kcnq4 and its encoded protein in the NAD? intervention group ( P<0.05). In the presence of the KCNQ4 inhibitor (ML252), the protective effect of NAD? was inhibited. Conclusions:NAD? exerts effective protective effects against noise-induced cochlear injury. Its protective mechanism may be closely related to the inhibition of LPA metabolic pathway and the up-regulation of KCNQ4 channel function.

AIM:To evaluate the efficacy of inflix-imab in the maintenance of Perianal fstulizing Crohn's disease.METHODS:The clinical data of 24 patients with perianal fistula Crohn's disease(PFCD)treated with infliximab(IFX)in the Depart-ment of Anorectal Surgery of our hospital from No-vember 2020 to October 2023 were retrospectively collected.The clinical efficacy and safety were eval-uated by observing the clinical characteristics for 54 weeks.The fistula remission rate,clinical remis-sion rate,and endoscopic remission rate of pa-tients were calculated.The changes of laboratory indexes before and after treatment were recorded.Logistic regression was used to analyze the related factors of fistula remission.All adverse reactions oc-curred during IFX treatment were recorded.RE-SULTS:After 54 weeks of IFX treatment,the fistula remission rate,clinical remission rate,and endo-scopic remission rate were 37.5％,45.83％,and 33.33％,respectively.Fistula response at 14 weeks of treatment(OR=19.419,95％CI:1.267-297.559,P=0.033)was predictive factors for fistula remission at 54 weeks of treatment.The inflammatory index-es and nutritional indexes were significantly im-proved compared with those before treatment(P＜0.01).The scores of PDAI,CDAI and SES-CD were significantly different from those before treatment(P＜0.01).Five patients(20.83％)had adverse reac-tions,and the symptoms disappeared or improved after symptomatic treatment,and no patient had serious adverse reactions.CONCLUSION:IFX can ef-fectively promote the closure of PFCD fistula,im-prove the chronic inflammatory reaction of intesti-nal mucosa,alleviate clinical symptoms,and im-prove the quality of life of patients.IFX is effective and safe for PFCD maintenance treatment.

Kashin-Beck disease (KBD), a common joint disorder that can lead to joint deformities and restricted mobility, significantly affects patients' quality of life. Traditional conservative treatments have shown limited efficacy. With advancements in total ankle replacement prosthesis and the successive updates of mobile and fixed -bearing in ankle prosthesis, more and more clinical trial results indicate that ankle prosthesis replacement is expected to become a new approach for treating KBD. This article reviews the progress in ankle prosthesis and studies their clinical application potential in KBD management.

AIM:To evaluate the efficacy of inflix-imab in the maintenance of Perianal fstulizing Crohn's disease.METHODS:The clinical data of 24 patients with perianal fistula Crohn's disease(PFCD)treated with infliximab(IFX)in the Depart-ment of Anorectal Surgery of our hospital from No-vember 2020 to October 2023 were retrospectively collected.The clinical efficacy and safety were eval-uated by observing the clinical characteristics for 54 weeks.The fistula remission rate,clinical remis-sion rate,and endoscopic remission rate of pa-tients were calculated.The changes of laboratory indexes before and after treatment were recorded.Logistic regression was used to analyze the related factors of fistula remission.All adverse reactions oc-curred during IFX treatment were recorded.RE-SULTS:After 54 weeks of IFX treatment,the fistula remission rate,clinical remission rate,and endo-scopic remission rate were 37.5％,45.83％,and 33.33％,respectively.Fistula response at 14 weeks of treatment(OR=19.419,95％CI:1.267-297.559,P=0.033)was predictive factors for fistula remission at 54 weeks of treatment.The inflammatory index-es and nutritional indexes were significantly im-proved compared with those before treatment(P＜0.01).The scores of PDAI,CDAI and SES-CD were significantly different from those before treatment(P＜0.01).Five patients(20.83％)had adverse reac-tions,and the symptoms disappeared or improved after symptomatic treatment,and no patient had serious adverse reactions.CONCLUSION:IFX can ef-fectively promote the closure of PFCD fistula,im-prove the chronic inflammatory reaction of intesti-nal mucosa,alleviate clinical symptoms,and im-prove the quality of life of patients.IFX is effective and safe for PFCD maintenance treatment.

Objectives:To investigate the protective effect of nicotinamide adenine dinucleotide (NAD?) against noise-induced cochlear damage and preliminarily explore its underlying transcriptional and metabolic regulatory mechanisms.Methods:During the study period (January 2023-February 2025), an oxidative stress model was established using House Ear Institute-organ of Corti 1 (HEI-OC1) cells, and cell viability was assessed using the Cell Counting Kit-8 (CCK8) assay. Flow cytometry was employed to analyze cell apoptosis. A mouse model of noise-induced hearing loss was developed, and the mice were divided into three groups: a noise-exposed saline group, a noise-exposed NAD? intervention group, and a noise-free control group. Hearing protection effects were evaluated by auditory brainstem response (ABR) and immunofluorescence. Metabolomics and transcriptomics were used to analyze the regulatory effects of NAD +on transcription and metabolism in mouse cochlea. Enzyme-linked immunosorbent assay, quantitative real-time PCR, and western blot were used to verify the differential transcription and metabolic molecules and their functions. Data were statistically analyzed with GraphPad Prism 9.3.0. Results:NAD +at concentrations ranging from 10-80 μM effectively restored cell viability and reduced apoptosis induced by H?O? in HEI-OC1 cells. NAD? intervention significantly improved 16-32 kHz ABR thresholds after noise exposure ( P<0.05), reduced outer hair cell loss rates ( P<0.05), and attenuated ribbon synapse damage ( P<0.000 1). Metabolomics analysis revealed a significant downregulation in the glycerophospholipid metabolism pathway, with decreased levels of lysophosphatidic acid (LPA) and its related metabolites. ELISA results showed that LPA levels in the NAD? intervention group were significantly lower ( P<0.05). LPA inhibitor (ATX inhibitor 1) exhibited a cell protective effect similar to that of NAD?. Transcriptomics analysis indicated a significant upregulation of key genes related to potassium ion channels, such as Kcnq4. qPCR and Western blot further confirmed the significant upregulation of Kcnq4 and its encoded protein in the NAD? intervention group ( P<0.05). In the presence of the KCNQ4 inhibitor (ML252), the protective effect of NAD? was inhibited. Conclusions:NAD? exerts effective protective effects against noise-induced cochlear injury. Its protective mechanism may be closely related to the inhibition of LPA metabolic pathway and the up-regulation of KCNQ4 channel function.

[Objective] To investigate the functional differences and potential effects of chromatin spatial structure in patients with normal karyotype and complex karyotype multiple myeloma. [Methods] High-throughput chromosome conformational capture (Hi-C) analysis was performed on plasma cells of 1 case with 1q21 complex karyotype and 1 case with normal karyotype multiple myeloma, and the differences in three-dimensional genome structure between the two patients were analyzed, and the transcriptome characteristics of plasma cells were combined to investigate the differential features through gene functional enrichment. [Results] A/B switch occurred in 36% of the chromatin compartments in two cases, and 1 041 genes in patient with complex karyotype had B/A switch. About 3 500 topological association domains (TADs) were identified in each sample, and there was no significant difference. The number of loops identified in complex karyotype sample was 1 069, which was 1/6 of the normal sample, and there were significant differences in the number of three different types of loops, which to some extent reflected the loss of genome stability. Transcriptome analysis showed significant differences in expression profiles between the two patients, and a total of 6 150 differentially expressed genes (3 303 up-regulated genes and 2 847 down-regulated genes) were identified. [Conclusion] Compared with patient with normal karyotype, patient with 1q21 complex karyotype multiple myeloma exhibit significant changes in the spatial structure of plasma cell chromatin at different levels, which leads to changes in gene expression and activation of pathways related to cancer progression.

Objective:The outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndromes-evolved acute myeloid leukemia (MDS-AML) were explored.Methods:A retrospective review was conducted for 54 patients with MDS-AML treated with allo-HSCT in the Institute of Hematology and Blood Disease Hospital from January 2018 to August 2022. The clinical effects after transplantation were observed, and the related risk factors influencing prognosis were explored.Results:Of the total 54 patients, 26 males, 28 females, and 53 patients achieved hematopoietic reconstruction. After a median follow-up of 597 (15-1 934) days, the 1 year overall survival (OS) rate, disease-free survival (DFS) rate, relapse rate (CIR) and non-relapse mortality (NRM) rate were 75.8%±5.8%, 72.1%±6.1%, 12.7%±4.9%, and 17.1%±5.2%, respectively. The 3 year estimated OS, DFS, CIR, and NRM rates were 57.8%±7.5%, 58.1%±7.2%, 23.2%±6.6%, and 23.7%±6.6%, respectively. The cumulative incidence of acute graft-versus-host disease (aGVHD) was 57.5%±6.9%, and the cumulative incidence of chronic graft-versus-host disease (cGVHD) was 48.4%±7.7%. Hematopoietic cell transplantation comorbidity index (HCT-CI) before transplantation was ≥2, minimal residual disease (MRD) was positive on the day of reconstitution, grade Ⅲ/Ⅳ aGVHD, bacterial or fungal infection and no cGVHD after transplantation were adverse prognostic factors for OS ( P<0.05). COX regression model for multivariate analysis showed that HCT-CI score before transplantation, bone marrow MRD on the day of response, grade Ⅲ or Ⅳ aGVHD, and cGVHD after transplantation were the independent adverse factors for OS ( P=0.001, HR=6.981, 95% CI 2.186-22.300; P=0.010, HR=6.719, 95% CI 1.572-28.711; P=0.026, HR=3.386, 95% CI 1.158-9.901; P=0.006, HR=0.151, 95% CI 0.039-0.581) . Conclusion:For patients with MDS-AML and high risk of relapse, allogeneic transplantation must be considered as soon as possible. The enhanced management of post-transplantation complications and maintenance treatment should be provided whenever possible after transplantation.