BACKGROUND:Previous studies have found that neohesperidin can delay bone loss in ovariectomized mice and has the potential to treat osteoporosis,but its specific mechanism of action remains to be explored. OBJECTIVE:To explore the key targets and possible mechanisms of neohesperidin in the treatment of osteoporosis based on bioinformatics and cell experiments in vitro. METHODS:The gene expression dataset related to osteoporosis was obtained from GEO database,and the differentially expressed genes were screened and analyzed in R language.The osteoporosis-related targets were screened from GeneCards and DisGeNET databases,and the neohesperidin-related targets were screened from ChEMBL and PubChem databases,and the common targets were obtained by intersection of the three.The String database was used to construct the PPI network of intersection genes,and the key targets were screened.The DAVID database was used for GO and KEGG enrichment analysis.The AutoDock software was used to verify the molecular docking between the neohesperidin and the target protein.The effect of neohesperidin on osteogenic differentiation of C57 mouse bone marrow mesenchymal stem cells was detected.Complete medium was used as blank control group;osteogenic induction medium was used as the control group;and osteogenic induction medium containing different concentrations of neohesperidin(25,50 μmol/L)was used as experimental group.The expression of alkaline phosphatase,the degree of mineralization,the expression of osteogenic-related genes and target genes during osteogenic differentiation of cells were measured at corresponding time points. RESULTS AND CONCLUSION:(1)9 253 differentially expressed genes,2 161 osteoporosis-related targets,and 326 neohesperidin-related targets were screened.There were 53 common targets among the three.All 53 genes were up-regulated in osteoporosis samples.The PPI network screened the target gene PRKACA of research significance.GO function and KEGG pathway enrichment analysis showed that neohesperidin's treatment of osteoporosis through PRKACA target mainly depended on biological processes such as protein phosphorylation and protein autophosphorylation,acting on endocrine resistance,proteoglycan in cancer,and estrogen signaling pathway to play a therapeutic role.Molecular docking results showed that neohesperidin had a certain binding ability to the protein corresponding to the target PRKACA.(2)The results of alkaline phosphatase staining showed that neohesperidin could promote the expression of alkaline phosphatase in the early stage of osteogenic differentiation of mesenchymal stem cells.Alizarin red staining showed that neohesperidin could promote the mineralization of osteogenic differentiation of mesenchymal stem cells.RT-qPCR results showed that neohesperidin could increase the mRNA expression of alkaline phosphatase,PRKACA,and osteocalcin.(3)These results indicate that neohesperidin may promote osteogenic differentiation through PRKACA target on the estrogen signaling pathway to prevent and treat osteoporosis.

Background: Older adults undergoing surgery frequently have multiple comorbidities and reduced physical and cognitive reserves. This study aims to assess the effect of physical and cognitive frailty on long-term mortality in older patients undergoing elective non-cardiac surgery in a tertiary center. Methods: Patients aged ≥65 years old admitted to surgical wards at the University of Malaya Medical Centre were recruited. Physical frailty and cognitive status were assessed using the Fried Frailty Index (FFI) and the Montreal Cognitive Assessment, respectively. Patients were stratified into six groups based on their frailty and cognitive status: Group 1, normal cognition and non-frail (reference group); Group 2, normal cognition and frail; Group 3, mild cognitive impairment (MCI) and non-frail; Group 4, MCI and frail; Group 5, dementia and non-frail; and Group 6, dementia and frail. Results: A total of 406 patients with a mean FFI score of 1.1±1.2 were recruited. Predictors of mortality include male sex (hazard ratio [HR]=1.96; 95% confidence interval [CI], 1.14–3.37; p=0.015), presence of active malignancy (HR=3.86; 95% CI, 2.14–6.95; p<0.001), and high FFI scores (1.8±1.2 vs. 1.0±1.1; p=0.013). Compared to Group 1, long-term mortality risk was significantly increased in Group 4 (HR=3.17; 95% CI, 1.36–7.38) and Group 6 (HR=3.91; 95% CI, 1.62–9.43) patients. Conclusion The combination of physical frailty and cognitive impairment was associated with long-term mortality risk among older patients who underwent elective non-cardiac surgery. This highlights the importance of assessing physical frailty and cognitive function of all older surgical patients to guide targeted intervention, especially for those with impairments which may be potentially reversible.

Background: Older adults undergoing surgery frequently have multiple comorbidities and reduced physical and cognitive reserves. This study aims to assess the effect of physical and cognitive frailty on long-term mortality in older patients undergoing elective non-cardiac surgery in a tertiary center. Methods: Patients aged ≥65 years old admitted to surgical wards at the University of Malaya Medical Centre were recruited. Physical frailty and cognitive status were assessed using the Fried Frailty Index (FFI) and the Montreal Cognitive Assessment, respectively. Patients were stratified into six groups based on their frailty and cognitive status: Group 1, normal cognition and non-frail (reference group); Group 2, normal cognition and frail; Group 3, mild cognitive impairment (MCI) and non-frail; Group 4, MCI and frail; Group 5, dementia and non-frail; and Group 6, dementia and frail. Results: A total of 406 patients with a mean FFI score of 1.1±1.2 were recruited. Predictors of mortality include male sex (hazard ratio [HR]=1.96; 95% confidence interval [CI], 1.14–3.37; p=0.015), presence of active malignancy (HR=3.86; 95% CI, 2.14–6.95; p<0.001), and high FFI scores (1.8±1.2 vs. 1.0±1.1; p=0.013). Compared to Group 1, long-term mortality risk was significantly increased in Group 4 (HR=3.17; 95% CI, 1.36–7.38) and Group 6 (HR=3.91; 95% CI, 1.62–9.43) patients. Conclusion The combination of physical frailty and cognitive impairment was associated with long-term mortality risk among older patients who underwent elective non-cardiac surgery. This highlights the importance of assessing physical frailty and cognitive function of all older surgical patients to guide targeted intervention, especially for those with impairments which may be potentially reversible.

Background: Older adults undergoing surgery frequently have multiple comorbidities and reduced physical and cognitive reserves. This study aims to assess the effect of physical and cognitive frailty on long-term mortality in older patients undergoing elective non-cardiac surgery in a tertiary center. Methods: Patients aged ≥65 years old admitted to surgical wards at the University of Malaya Medical Centre were recruited. Physical frailty and cognitive status were assessed using the Fried Frailty Index (FFI) and the Montreal Cognitive Assessment, respectively. Patients were stratified into six groups based on their frailty and cognitive status: Group 1, normal cognition and non-frail (reference group); Group 2, normal cognition and frail; Group 3, mild cognitive impairment (MCI) and non-frail; Group 4, MCI and frail; Group 5, dementia and non-frail; and Group 6, dementia and frail. Results: A total of 406 patients with a mean FFI score of 1.1±1.2 were recruited. Predictors of mortality include male sex (hazard ratio [HR]=1.96; 95% confidence interval [CI], 1.14–3.37; p=0.015), presence of active malignancy (HR=3.86; 95% CI, 2.14–6.95; p<0.001), and high FFI scores (1.8±1.2 vs. 1.0±1.1; p=0.013). Compared to Group 1, long-term mortality risk was significantly increased in Group 4 (HR=3.17; 95% CI, 1.36–7.38) and Group 6 (HR=3.91; 95% CI, 1.62–9.43) patients. Conclusion The combination of physical frailty and cognitive impairment was associated with long-term mortality risk among older patients who underwent elective non-cardiac surgery. This highlights the importance of assessing physical frailty and cognitive function of all older surgical patients to guide targeted intervention, especially for those with impairments which may be potentially reversible.

BACKGROUND: The effects of acupuncture have varied in different randomized controlled trials (RCTs), and there are many factors that influence treatment effect of acupuncture in different outcomes, with conflicting results. OBJECTIVE: To identify factors and their impact on the treatment effect of acupuncture in different outcomes. METHODS: Acupuncture RCTs were searched from 7 databases including Medline (PubMed), Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang Database, VIP Database, and China Biology Medicine disc between January 1st, 2015 and December 31st, 2019. Eligible studies must compare acupuncture to no acupuncture, sham acupuncture, or waiting lists, and report at least 1 patient-important outcome. A multi-level meta-regression was conducted using a 3-level robust mixed model and univariate analyses were performed for all independent variables, even those excluded from the multivariable model due to collinearities. We used thresholds of 0.2 and 0.4 for the difference of standardized mean differences (SMDs), categorising them as small (<0.2), moderate (0.2-0.4), or large (>0.4) effects. RESULTS: The pain construct analysis involved 211 effect estimates from 153 studies and 14 independent variables. High-frequency acupuncture treatment sessions produced larger effects compared to low-frequency sessions [large magnitude, the difference of adjusted SMDs 0.46, 95% confidence interval (CI) 0.07 to 0.84; P=0.02]. The non-pain symptoms construct analysis comprised 323 effect estimates from 231 studies and 15 independent variables. Penetrating acupuncture showed moderately larger effects when compared to non-penetrating acupuncture (0.30, 95% CI 0.06 to 0.53; P=0.01). The function construct analysis included 495 effect estimates from 274 studies and 14 independent variables. Penetrating acupuncture and the flexible acupuncture regimen showed moderately larger effects, compared to non-penetrating acupuncture and fixed regimen, respectively (0.40, 95% CI 0 to 0.80; P=0.05; 0.29, 95% CI 0.06 to 0.53; P=0.01). CONCLUSIONS High-frequency acupuncture sessions appear to be a more effective approach to managing painful symptoms. Penetrating acupuncture demonstrated greater effect in relieving non-painful symptoms. Both penetrating acupuncture type and flexible acupuncture regimen were linked to significant treatment effects in function outcomes. Future studies should consider the factors that are significantly associated with the effects of acupuncture in patient-important outcomes.
Humans ; Randomized Controlled Trials as Topic ; Acupuncture Therapy/methods* ; Pain ; Pain Management ; China

The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.
Humans ; Prions ; Neurodegenerative Diseases/pathology* ; Amyloid beta-Peptides ; Alzheimer Disease ; alpha-Synuclein ; tau Proteins ; Parkinson Disease

Umbilical cord mesenchymal stem cells (UC-MSCs) have been widely used in regenerative medicine, but there is limited research on the stability of UC-MSCs formulation during production. This study aims to assess the stability of the cell stock solution and intermediate product throughout the production process, as well as the final product following reconstitution, in order to offer guidance for the manufacturing process and serve as a reference for formulation reconstitution methods. Three batches of cell formulation were produced and stored under low temperature (2-8 ℃) and room temperature (20-26 ℃) during cell stock solution and intermediate product stages. The storage time intervals for cell stock solution were 0, 2, 4, and 6 h, while for intermediate products, the intervals were 0, 1, 2, and 3 h. The evaluation items included visual inspection, viable cell concentration, cell viability, cell surface markers, lymphocyte proliferation inhibition rate, and sterility. Additionally, dilution and culture stability studies were performed after reconstitution of the cell product. The reconstitution diluents included 0.9% sodium chloride injection, 0.9% sodium chloride injection + 1% human serum albumin, and 0.9% sodium chloride injection + 2% human serum albumin, with dilution ratios of 10-fold and 40-fold. The storage time intervals after dilution were 0, 1, 2, 3, and 4 h. The reconstitution culture media included DMEM medium, DMEM + 2% platelet lysate, 0.9% sodium chloride injection, and 0.9% sodium chloride injection + 1% human serum albumin, and the culture duration was 24 h. The evaluation items were viable cell concentration and cell viability. The results showed that the cell stock solution remained stable for up to 6 h under both low temperature (2-8 ℃) and room temperature (20-26 ℃) conditions, while the intermediate product remained stable for up to 3 h under the same conditions. After formulation reconstitution, using sodium chloride injection diluted with 1% or 2% human serum albumin maintained a viability of over 80% within 4 h. It was observed that different dilution factors had an impact on cell viability. After formulation reconstitution, cultivation in medium with 2% platelet lysate resulted in a cell viability of over 80% after 24 h. In conclusion, the stability of cell stock solution within 6 h and intermediate product within 3 h meets the requirements. The addition of 1% or 2% human serum albumin in the reconstitution diluent can better protect the post-reconstitution cell viability.

Cold and heat belong to the eight-principal syndrome differentiation of traditional Chinese medicine， which can reflect the rise and fall of Yin and Yang in the body and the Yin and Yang nature of the disease. At present， traditional Chinese medicine has an inconsistent understanding of cold and heat in acute coronary syndrome. The emphasis on pathogenic factors of cold and heat is biased， and the elements of cold and heat syndrome are not fully reflected in the scale. Therefore， the literature has been reviewed from the perspectives of etiology， pathogenesis， symptom elements， and test signs with drugs. From the perspective of etiology， both cold evil and heat evil can increase the risk of acute coronary syndrome. It was previously believed that acute coronary syndrome occurs frequently in cold climates such as winter and spring. Based on this understanding， hot weather can also induce acute coronary syndrome， and different temperatures have different effects on patients of different ages and with different underlying diseases. In addition， artificial pathogenic factors such as excessive consumption of cold food and refrigeration air conditioners were added. From the perspective of pathogenesis， on the basis of the traditional ''asthenia in origin and asthenia in superficiality'' and ''phlegm stagnation''， it is found that Yin-cold and fire-heat can both cause paralysis of the heart chakra and pain induced by the blockage. The pathogenesis of acute coronary syndrome characterized by heat stagnation and coldness featuring heartburn should be distinguished from gastroesophageal reflux disease. Moreover， the pathogenesis of Yin cold coagulation and pulse stagnation and wind obstruction are different. The acute coronary syndrome is in line with the wind characteristics of frequent changes and can be treated with wind medicine. From the perspective of syndrome elements， the syndrome elements such as cold condensation， heat accumulation， and toxicity are analyzed， and the use of basic syndrome elements and their combination forms facilitates clinical and scientific research. In addition， according to the test sign with the drug， it can be seen that the attributes of cold and heat of traditional Chinese medicine prescriptions for acute coronary syndrome can be explained according to the temperature-sensitive transient receptor potential （TRP） ion channel， thus proving the pathogenesis of cold and heat of acute coronary syndrome.

Humans ; Vascular Stiffness ; Coal Mining ; Occupational Diseases/epidemiology* ; Risk Factors ; Coal ; Miners

Objective To observe the clinical efficacy of the modified Huangan Lipi Decoction(mainly composed of Sclerotium Poriae Pararadicis,Paeoniae Radix Alba,Atractylodis Macrocephalae Rhizoma,Polygalae Radix,Acori Tatarinowii Rhizoma,and Curcumae Radix)combined with acupuncture at Sifeng(EX-UE10)points in the treatment of children with tic disorders(TD).Methods Seventy cases of TD children with spleen deficiency and liver hyperactivity syndrome were randomly divided into the treatment group and the control group,with 35 cases in each group.The control group was treated with conventional western medicine of Tiapride Hydrochloride Tablets,while the treatment group was treated with the combination of the modified Huangan Lipi Decoction and acupuncture at Sifeng points.Both groups were treated for 8 weeks.The changes of the Yale Global Tic Severity Scale(YGTSS)item scores of tic muscle group,tic frequency,tic intensity,complexity and interference degree as well as their total scores in the two groups were observed before and after treatment.Moreover,the clinical efficacy and safety in the two groups were evaluated.Results(1)After 8 weeks of treatment,the total effective rate of the treatment group was 88.57%(31/35),and that of the control group was 68.57%(24/35).The intergroup comparison showed that the total effective rate(tested by chi-square test)and the overall therapeutic efficacy(tested by rank-sum test)of the treatment group were significantly superior to those of the control group,and the differences were statistically significant(P＜0.05).(2)After treatment,the YGTSS item scores of tic muscle group,tic frequency,tic intensity,complexity and interference degree as well as their total scores in the two groups were significantly lower than those before treatment(P＜0.01),and the effect on lowering the above scores of the treatment group was significantly superior to that of the control group,the differences being all statistically significant(P＜0.01).(3)During the treatment,the incidence of adverse reactions in the treatment group was 2.86%(1/35)and that in the control group was 8.57%(3/35).The intergroup comparison showed that the incidence of adverse reactions in the treatment group tended to be lower than that of the control group,but the difference was not statistically significant(P＞0.05).Conclusion Modified Huangan Lipi Decoction combined with acupuncture at Sifeng points exert certain effect in the treatment of TD children with spleen deficiency and liver hyperactivity syndrome,and its efficacy is superior to that of the western medicine Tiapride Hydrochloride Tablets.