Saponins associated with Panax notoginseng (P. notoginseng) demonstrate significant therapeutic efficacy across multiple diseases. However, certain high-yield saponins face limited clinical applications due to their reduced pharmacological efficacy. This study synthesized and evaluated 36 saponin-1,2,3-triazole derivatives of ginsenosides Rg1/Rb1 and notoginsenoside R1 for anti-adipogenesis activity in vitro. The research revealed that the ginsenosides Rg1-1,2,3-triazole derivative a17 demonstrates superior adipogenesis inhibitory effects. Structure-activity relationships (SARs) analysis indicates that incorporating an amidyl-substituted 1,2,3-triazole into the saponin side chain via Click reaction enhances anti-adipogenesis activity. Additionally, several other derivatives exhibit general adipogenesis inhibition. Compound a17 demonstrated enhanced potency compared to the parent ginsenoside Rg1. Mechanistic investigations revealed that a17 exhibits dose-dependent inhibition of adipogenesis in vitro, accompanied by decreased expression of preadipocytes. Peroxisome proliferator-activated receptor γ (PPARγ), fatty acid synthase (FAS), and fatty acid binding protein 4 (FABP4) adipogenesis regulators. These findings establish the ginsenoside Rg1-1,2,3-triazole derivative a17 as a promising adipocyte differentiation inhibitor and potential therapeutic agent for obesity and associated metabolic disorders. This research provides a foundation for developing effective therapeutic approaches for various metabolic syndromes.
Adipogenesis/drug effects* ; Triazoles/chemical synthesis* ; Ginsenosides/chemical synthesis* ; Saponins/chemical synthesis* ; Animals ; Mice ; Structure-Activity Relationship ; PPAR gamma/genetics* ; 3T3-L1 Cells ; Adipocytes/metabolism* ; Panax notoginseng/chemistry* ; Drug Design ; Molecular Structure ; Humans ; Cell Differentiation/drug effects* ; Fatty Acid-Binding Proteins/genetics*

Aging and age-related ailments have emerged as critical challenges and great burdens within the global contemporary society.Addressing these concerns is an imperative task,with the aims of postponing the aging process and finding effective treatments for age-related degenerative diseases.Recent investigations have highlighted the significant roles of nicotinamide adenine dinucleotide(NAD+)in the realm of anti-aging.It has been empirically evidenced that supplementation with nicotinamide mononucleotide(NMN)can elevate NAD+levels in the body,thereby ameliorating certain age-related degenerative diseases.The principal anti-aging mechanisms of NMN essentially lie in its impact on cellular energy metabolism,inhibition of cell apoptosis,modulation of immune function,and preservation of genomic stability,which collectively contribute to the deferral of the aging process.This paper critically reviews and evaluates existing research on the anti-aging mechanisms of NMN,elucidates the inherent limitations of current research,and proposes novel avenues for anti-aging investigations.

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

Objective:To design a modified S1PR3 specific agonist, GPS-725.017, and investigate its protective effect on acute lung injury by promoting macrophage clearance of bacteria.Methods:A short peptide derived from the intracellular region of S1PR3 receptor was named GPS725.017, which was modified with norleucine (Nle) and myristicacid (myr) at its N terminus. Mice were divided into the sham operation group, solvent group and GPS-725.017 treatment group. The acute lung injury model was induced by endotracheal injection of E. coli (5×10 6 CFU), and the experimental group was treated with GPS-725.017 (10 mg/kg). The 48-h survival rate of mice was recorded. After 5 h of modeling, the bacterial load and inflammatory cytokines in peripheral blood and lung were detected, and Vps34 protein content in alveolar macrophages was determined by Western blot. After 12-h of modeling, lung tissues were collected for H&E staining and pathological scores. Results:Compared with the solvent group, the survival rate of mice in the GPS-725.017 treatment group was significantly improved ( P<0.01), the bacterial CFU in blood and alveolar lavage fluid was significantly lower than that in the solvent group ( P<0.001), and the levels of TNF-α and IL-1β in blood and alveolar lavage fluid were significantly lower than those in the solvent group ( P<0.001). Western blot showed that the expression level of Vps34 protein in alveolar macrophages was significantly higher than that in the solvent group ( P<0.01). Histopathology result showed that the pathological damage of lung in the treatment group was significantly less than that in the solvent group ( P<0.001). Conclusions:The modified synthetic S1PR3 specific agonist GPS-725.017 could specifically activate the S1PR3 receptor on the membrane of alveolar macrophages and up-regulate the expression level of intracellular Vps34 protein, which can promote the removal of bacteria in alveolar macrophages, significantly reduce the degree of lung injury and improve the survival rate in ALI mice.

Objective:To evaluate the role of mitophagy in cognitive dysfunction in rats with sepsis-associated encephalopathy (SAE).Methods:Twenty-four clean-grade healthy male Sprague-Dawley rats, aged 13-14 weeks, weighing 230-250 g, were divided into 3 groups ( n=8 each) using a random number table method: sham operation group (Sham group), SAE group and SAE+ autophagy inhibitor 3-methyladenine (3-MA) group (3-MA group).The SAE models were developed by cecal ligation and puncture in anesthetized animals.3-MA 10 mg/kg was intraperitoneally injected at 30 min after developing the model in 3-MA group.Cognitive function was assessed by Morris water maze test, and the escape latency and ratio of the time of staying at the target quadrant were recorded.After the end of Morris water maze test, the rats were sacrificed and hippocampal tissues were collected for microscopic examination of the pathological changes which were scored after hematoxylin-eosin staining and for determination of the expression of autophagy-related proteins LC3, Beclin1 and p62 (by Western blot).The ratio of LC3Ⅱ/LC3Ⅰwas calculated.The hippocampal mitochondria were isolated to measure mitochondrial membrane potential (MMP), ATP content and ATPase activity by spectrophotometry. Results:Compared with Sham group, the escape latency was significantly prolonged, the ratio of the time of staying at the target quadrant was decreased, the pathological score of hippocampus was decreased, and the contents of MMP and ATP and ATPase activity were decreased in SAE and 3-MA groups, the ratio of LC3Ⅱ/LC3Ⅰwas significantly increased, the expression of Beclin1 was up-regulated, and the expression of p62 was down-regulated in SAE group, and the ratio of LC3Ⅱ/LC3Ⅰwas significantly decreased, and the expression of Beclin1 and p62 was up-regulated in 3-MA group ( P<0.05).Compared with SAE group, the escape latency was significantly prolonged, the ratio of the time of staying at the target quadrant was decreased, the pathological score of hippocampus was decreased, the ratio of LC3/LC3Ⅰwas decreased, the expression of Beclin1 was down-regulated, the expression of p62 was up-regulated, and the contents of MMP and ATP and ATPase activity were decreased in 3-MA group ( P<0.05). Conclusions:Hippocampal mitophagy is involved in cognitive dysfunction in the rats with SAE.

Objective:To evaluate the role of p38 mitogen-activated protein kinase (MAPK)/cyclic adenosine monophosphate response element-binding protein (CREB) signaling pathway in tetramethylpyrazine-induced reduction of hippocampal inflammatory responses in mice with sepsis-associated encephalopathy (SAE).Methods:Sixty healthy male C57BL6 mice, weighing 24-27 g, were divided into 4 groups ( n=15 each) using a random number table method: sham operation group (group Sham), sepsis group (group Sep), tetramethylpyrazine group (group TMP) and p38 MAPK inhibitor SB203580 group (group SB). The model of SAE was established by cecal ligation and puncture in anesthetized mice.Tetramethylpyrazine 10 mg/kg was injected intraperitoneally once a day at 3 days before the establishment of the model in TMP group, and SB203580 2.0 mg/kg was intraperitoneally injected at 30 min after the establishment of the model in SB group.The equal volume of normal saline was given intraperitoneally in Sham and Sep groups.At 1 day after operation, cognitive function was assessed by Morris water maze, and the escape latency and ratio of time spent in the target quadrant were recorded.The animals were sacrificed after the test, and hippocampal tissues were taken for determination of the contents of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and IL-6 (by enzyme-linked immunosorbent assay) and for detection of the expression of phosphorylation of p38 MAPK, GSK3 and CREB and expression of brain-derived neurotrophic factor (BDNF) (by Western blot). Results:Compared with group Sham, the escape latency was significantly prolonged, the ratios of time spent in the target quadrant were decreased, the contents of IL-1β, TNF-α and IL-6 were increased, the phosphorylation of hippocampus p38 MAPK was increased, the phosphorylation of GSK3 and CREB were decreased, and the expression of BDNF was down-regulated in Sep, TMP and SB groups ( P<0.05). Compared with group Sep, the escape latency was significantly shortened, the ratios of time spent in the target quadrant were increased, the contents of IL-1β, TNF-α and IL-6 were decreased, the phosphorylation of hippocampus p38 MAPK was decreased, the phosphorylation of GSK3 and CREB were increased, and the expression of BDNF was up-regulated in TMP and SB groups ( P<0.05). Compared with group TMP, no significant change was found in the parameters mentioned above in group SB ( P>0.05). Conclusion:p38 MAPK/CREB signaling pathway is involved in the process of tetramethylpyrazine-induced reduction of hippocampal inflammatory responses in mice with SAE.

Cashmere, also known as soft gold, is produced from the secondary hair follicles (SHFs) of cashmere goats. The number of SHFs determines the yield and quality of cashmere; therefore, it is of interest to investigate the transcriptional profiles present during cashmere goat hair follicle development. However, mechanisms underlying this development process remain largely unexplored, and studies regarding hair follicle development mostly use a murine research model. In this study, to provide a comprehensive understanding of cellular heterogeneity and cell fate decisions, single-cell RNA sequencing was performed on 19,705 single cells of the dorsal skin from cashmere goat fetuses at induction (embryonic day 60; E60), organogenesis (E90), and cytodifferentiation (E120) stages. For the first time, unsupervised clustering analysis identified 16 cell clusters, and their corresponding cell types were also characterized. Based on lineage inference, a detailed molecular landscape was revealed along the dermal and epidermal cell lineage developmental pathways. Notably, our current data also confirmed the heterogeneity of dermal papillae from different hair follicle types, which was further validated by immunofluorescence analysis. The current study identifies different biomarkers during cashmere goat hair follicle development and has implications for cashmere goat breeding in the future.

Objective:To evaluate the effect of tetramethylpyrazine on hippocampal inflammatory responses in rats with sepsis-associated encephalopathy.Methods:Sixty healthy male Sprague-Dawley rats, aged 12-14 weeks, weighing 240-270 g, were divided into 4 groups ( n=15 each) using a random number table method: sham operation group (group Sham), sepsis-associated encephalopathy group (group SAE), low-dose tetramethylpyrazine group (group L-TMP), and high-dose tetramethylpyrazine group (group H-TMP). Sepsis-associated encephalopathy was induced by cecal ligation and puncture (CLP) in anesthetized rats.Tetramethylpyrazine 5 and 20 mg/kg were intraperitoneally injected once a day in L-TMP and H-TMP groups, respectively, at 5 days prior to CLP.Morris water maze test was performed at 1-5 days after CLP to assess the cognitive function, and the escape latency and ratio of time spent in the target quadrant were recorded.Five rats were sacrificed at 1 day after CLP, the brains were removed, and the hippocampi were isolated for determination of the contents of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and IL-6 by enzyme-linked immunosorbent assay.Rats were sacrificed after the end of Morris water maze test, and hippocampi were removed for detection of the expression of Toll-like receptor 1 (TLR1), activated caspase-3, Bax and Bcl-2 by using Western blot. Results:Compared with group Sham, the escape latency was significantly prolonged, the ratios of time spent in the target quadrant were decreased, the expression of TLR1, activated caspase-3 and Bax was up-regulated, and the expression of Bcl-2 was down-regulated in group SAE, group L-TMP and group H-TMP, and the contents of IL-1β, TNF-α and IL-6 were significantly increased in group SAE and group L-TMP ( P<0.05). Compared with group SAE, the escape latency was significantly shortened, the ratio of time spent in the target quadrant was increased, the contents of IL-1β, TNF-α and IL-6 were decreased, the expression of TLR1, activated caspase-3 and Bax was down-regulated, and the expression of Bcl-2 was up-regulated in group L-TMP and group H-TMP ( P<0.05). Conclusion:The mechanism by which tetramethylpyrazine reduces sepsis-associated encephalopathy may be related to inhibiting hippocampal inflammatory responses in rats.

From January 15 to March 3, 2020, seven editions of the guidelines for the diagnosis and treatment of COVID-19 have been issued successively by the National Health Commission of the People's Republic of China, and the guidelines' name was changed from Guidelines for Diagnosis and Treatment of Novel Coronavirus Pneumonia to Diagnosis and Treatment for COVID-19. It optimized and perfected the etiology, clinical manifestations and types, diagnostic procedures and specific treatment measures of the disease, so that the clinical management of the cases was more scientific. In the revision process of guidelines for diagnosis and treatment, forensic medicine experts have also made some positive suggestions on clinical diagnosis and treatment. Especially regarding the pathological changes of COVID-19, they have repeatedly called for rapid autopsy at different levels. With the support, understanding and cooperation of all parties, pathological examination of more than ten cases of the remains were carried out, which made an important contribution to the understanding of the clinical characteristics and pathological characteristics of the disease and the improvement of treatment plans.
COVID-19 ; China ; Clinical Protocols ; Forensic Medicine ; Humans ; SARS-CoV-2

Objective To investigate the diagnostic value of 3.0T MR high field high-b-value diffusion weighted imaging (DWI) in prostate cancer (PCa) and to analyze its correlation with Gleason classification.Methods A total of 78 cases proved by operation and pathology were collected,including 41 cases of benign prostatic hyperplasia(BPH) and 37 cases of PCa.PCa patients were classified according to postoperative pathological scores,and their correlation with ADC values was analyzed subsequently.Parameter scanning was performed in all patients by using Philps 3.0T MR with b value at 0 s/mm2,1 000 s/mm2 and 1 500 s/mm2.The signal intensity and ADC value of PCa and BPH were compared under two kinds of high-b-values,and the correlation between ADC value and Gleason classification was analyzed.Results It was found that the specificity and accuracy of T2WI combined with b value of 1 500 s/mm2 were higher than these of T2WI combined with b value of 1 000 s/mm2 for the diagnosis of PCa.The ranking result of ADC value corresponding to Gleason score of PCa after operation was:2-4 points ＞ 5-6 points ＞7 points ＞ 8-10 points.Besides,the ADC value of the corresponding lesion with b value of 1 500 s/mm2 was lower than that with b value of 1 000 s/mm2,and the difference was statistically significant (P＜0.05).Conclusion High field high-b-value DWI combined with T2WI is of high value in differential diagnosis of PCa and BPH,and the specificity and accuracy of PCa and BPH improve obviously with the increase of the b value.Additionally,the ADC value is negatively correlated with the Gleason score.