ObjectiveTo evaluate the clinical efficacy of Shenqi Yangxin decoction in the treatment of ischemic cardiomyopathy （ICM） with Qi and Yin deficiency and blood stasis syndrome and its effect on serum hydrogen sulfide （H₂S） and calcium ion （Ca²⁺）. MethodsA total of 64 ICM patients with Qi and Yin deficiency and blood stasis syndrome who met the inclusion criteria were randomly divided into a control group （n=32） and a treatment group （n=32）. All patients received conventional Western medicine treatment. The treatment group was additionally given Shenqi Yangxin decoction. The TCM syndrome score， Minnesota Living with Heart Failure Questionnaire （MLHFQ） score， left ventricular ejection fraction （LVEF）， N-terminal pro-B-type natriuretic peptide （NT-proBNP）， 6-minute walk test （6MWT）， New York Heart Association （NYHA） cardiac function classification， and serum H₂S and Ca²⁺ levels were compared between the two groups pre- and post-treatment. ResultsTwo cases dropped out from each group during the study. Finally， 30 patients in each group were included in the analysis. There were no significant differences in age， gender， course of coronary heart disease， underlying diseases， and laboratory tests between the two groups. Compared with baseline， the TCM syndrome score， MLHFQ score， and NT-proBNP in both treatment group and control group decreased significantly （P<0.01）， LVEF， 6MWT， and H₂S increased significantly （P<0.01）， and serum Ca²⁺ increased （P<0.05）. Compared with the control group after treatment， the MLHFQ score and NT-proBNP in the treatment group decreased （P<0.05）， the TCM syndrome score decreased significantly （P<0.01）， LVEF， 6MWT， and serum Ca²⁺ increased （P<0.05）， and H₂S increased significantly （P<0.01）. The improvement degree of the NYHA cardiac function classification in the treatment group was higher than that in the control group， but there was no significant difference. ConclusionShenqi Yangxin decoction is effective in treating ICM patients with Qi and Yin deficiency and blood stasis， which could significantly improve cardiac function and quality of life， and its therapeutic effect may be related to the regulation of serum H₂S and Ca²⁺ levels.

Distinct from the complementary inhibition mechanism through binding to the target with three-dimensional conformation of small molecule inhibitors, targeted protein degradation technology takes tremendous advantage of endogenous protein degradation pathway inside cells to degrade plenty of “undruggable” target proteins, which provides a novel route for the treatment of many serious diseases, mainly including proteolysis-targeting chimeras, lysosome-targeting chimeras, autophagy-targeting chimeras, antibody-based proteolysis-targeting chimeras, etc. Unlike proteolysis-targeting chimeras first found in 2001, which rely on ubiquitin-proteasome system to mainly degrade intracellular proteins of interest, lysosome-targeting chimeras identified in 2020, which was act as the fastly developing technology, utilize cellular lysosomal pathway through endocytosis mediated by lysosome-targeting receptor to degrade both extracellular and membrane proteins. As an emerging biomedical technology, nucleic acid-driven lysosome-targeting chimeras utilize nucleic acids as certain components of chimera molecule to replace with ligand to lysosome-targeting receptor or protein of interest, exhibiting broad application prospects and potential clinical value in disease treatment and drug development. This review mainly introduced present progress of nucleic acid-driven lysosome-targeting chimeras technology, including its basic composition, its advantages compared with antibody or glycopeptide-based lysosome-targeting chimeras, and focused on its chief application, in terms of the type of lysosome-targeting receptors. Most research about the development of nucleic acid-driven lysosome-targeting chimeras focused on those which utilized cation-independent mannose-6-phosphonate receptor as the lysosome-targeting receptor. Both mannose-6-phosphonate-modified glycopeptide and nucleic aptamer targeting cation-independent mannose-6-phosphonate receptor, even double-stranded DNA molecule moiety can be taken advantage as the ligand to lysosome-targeting receptor. The same as classical lysosome-targeting chimeras, asialoglycoprotein receptor can also be used for advance of nucleic acid-driven lysosome-targeting chimeras. Another new-found lysosome-targeting receptor, scavenger receptor, can bind dendritic DNA molecules to mediate cellular internalization of complex and lysosomal degradation of target protein, suggesting the successful application of scavenger receptor-mediated nucleic acid-driven lysosome-targeting chimeras. In addition, this review briefly overviewed the history of lysosome-targeting chimeras, including first-generation and second-generation lysosome-targeting chimeras through cation-independent mannose-6-phosphonate receptor-mediated and asialoglycoprotein receptor-mediated endocytosis respectively, so that a clear timeline can be presented for the advance of chimera technique. Meantime, current deficiency and challenge of lysosome-targeting chimeras was also mentioned to give some direction for deep progress of lysosome-targeting chimeras. Finally, according to faulty lysosomal degradation efficiency, more cellular mechanism where lysosome-targeting chimeras perform degradation of protein of interest need to be deeply explored. In view of current progress and direction of nucleic acid-driven lysosome-targeting chimeras, we discussed its current challenges and development direction in the future. Stability of natural nucleic acid molecule and optimized chimera construction have a great influence on the biological function of lysosome-targeting chimeras. Discovery of novel lysosome-targeting receptors and nucleic aptamer with higher affinity to the target will greatly facilitate profound advance of chimera technique. In summary, nucleic acid-driven lysosome-targeting chimeras have many superiorities, such as lower immunogenicity, expedient synthesis of chimera molecules and so on, in contrast to classical lysosome-targeting chimeras, making it more valuable. Also, the chimera technology provides new ideas and methods for biomedical research, drug development and clinical treatment, and can be used more widely through further research and optimization.

OBJECTIVE To investigate the mechanism through which Danggui buxue decoction regulates neutrophil extracellular traps （NETs） to improve osteoporosis （OP） in rats with premature ovarian failure （POF）. METHODS Female SD rats were randomly divided into normal group， model group， calcitriol group， and Danggui buxue decoction low-dose， medium-dose and high-dose groups， with 9 rats in each group. Except for the normal group， all other groups were administered cisplatin via intraperitoneal injection on days 1 and 8 to establish a POF complicated with OP model. Each group received the corresponding drugs or normal saline intragastrically starting from day 5， once a day， for 4 consecutive weeks. After the last medication， serum levels of estradiol （E2）， NETs， 25-hydroxyvitamin D3 [25（OH）D3]， receptor activator of nuclear factor-κB ligand （RANKL）， and osteocalcin （BGP） were measured. The histopathological changes in bone tissue were observed. The expressions of vitamin D receptor （VDR）， myeloperoxidase （MPO）， neutrophil elastase （NE） and citrullinated histone H3 （CitH3） in bone tissue were detected； the protein expressions of 25-hydroxyvitamin D-1α-hydroxylase （CYP27B1） and 1α，25-dihydroxyvitamin D3-24-hydroxylase （CYP24A1） were also determined. RESULTS Compared with the normal group， the bone tissue of rats in the model group showed a significant reduction in the number of trabeculae， which was thinner broken and poorly connected， with significant destruction of the reticular structure， and an enlarged marrow cavity. Serum levels of NETs and RANKL， the protein expressions of MPO， NE， CitH3 and CYP24A1 in bone tissue were significantly increased or upregulated， while serum levels of E2， 25（OH）D3 and BGP as well as protein expressions of VDR and CYP27B1 were significantly decreased or downregulated （P＜0.05）. Compared with the model group， the histopathological changes in the bone tissue of rats in each administration group showed some degree of recovery， with significant improvements observed in most quantitative indicators （P＜0.05）. CONCLUSIONS Danggui buxue decoction can restore the E2 level in POF complicated with OP rats， and improve OP. The mechanism may be related to its ability to upregulate VD level and inhibit the formation of NETs.

AIM: To investigate the changes of retinal nerve fiber layer(RNFL)thickness, retinal thickness and blood flow density in different stages of diabetic retinopathy(DR)patients based on optical coherence tomography angiography(OCTA).METHODS: A retrospective analysis was conducted on 382 patients(382 eyes)diagnosed with DR in our hospital from February 2023 to February 2024. According to the staging criteria, the patients were divided into mild group(n=121), moderate group(n=133), severe group(n=72), and proliferative group(n=56). The general clinical data of the four groups of patients was compared; OCTA was used to scan and collect data from all patients, and the RNFL thickness, retinal thickness, and blood flow density were compared among the four groups of patients.RESULTS: There was no statistically significant difference in age, gender, hypertension, chronic kidney disease, and random blood glucose among patients in the mild, moderate, severe, and proliferative groups(all P>0.05). As the stage of DR worsened, the duration of the disease gradually prolonged(P<0.05). The thickness of the RNFL(superior, inferior, temporal, nasal, and average thickness)and retinal thickness significantly increased with the severity of DR(all P<0.001); however, there was no statistically significant difference in inferior RNFL thickness between the moderate and mild groups(P>0.05). The blood flow density in the superficial and deep retinal layers, as well as in the choroidal capillary layer, significantly decreased with the progression of DR(all P<0.05). Nevertheless, there was no statistically significant difference in superficial retinal blood flow density between the moderate and severe groups(P>0.05).CONCLUSION: OCTA can accurately observe the changes in RNFL thickness, retinal thickness, and blood flow density in patients with DR at different stages, which can serve as sensitive indicators for monitoring DR progression.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Objective: To understand the current status, international cooperation, research hotspots, and development trends of nutritional studies on patients with head and neck cancer from 2014 to 2024, and to predict future research trends. Methods: The Web of Science Core Collection database was searched to retrieve nutritional studies on patients with head and neck cancer from January 2014 to March 2024. The type of studies were “articles,” the language was English, CiteSpace 6.1 R6 software was used to conduct the bibliometric analysis, and the results were visualized to form a scientific knowledge map. Results: A total of 1 528 documents were retrieved, with a linear increase in the number of annual publications. The country with the highest number of publications was the United States, and the institution with the highest number of publications was the University of Queensland, with closer collaboration between authors and institutions. The most frequently cited publication was a set of nutrition guidelines, and the highest-impact articles were mainly concerned with performing percutaneous endoscopic gastrostomy. Keyword analysis showed that quality of life, radiotherapy, and weight loss were the keywords of highest interest. The keyword cluster analysis resulted in 17 clusters, which were divided into five main categories: head and neck cancer, treatment, outcome results, intervention modalities, and rehabilitation. Body composition, enteral nutrition, and accelerated postoperative rehabilitation were persistent research hotspots. Keyword highlighting revealed that “enhanced recovery after surgery” has been the focus of research in the last two years, with “index” and “model” emerging as theme words. Conclusion The number of publications in the literature related to nutrition for patients with head and neck cancer has increased annually over the past 10 years. The research hotspots mainly focus on the quality of life and weight loss during radiotherapy, the content and application prospect of body composition assessment, different modes of nutritional support interventions and enteral nutritional tube feeding routes, and perioperative nutritional management in enhanced recovery after surgery. The potential clinical value of preoperative nutritional intervention under the concept of enhanced recovery and the construction of new types of nutritional index are the trends of future research.

Neuropathic pain, often featuring allodynia, imposes significant physical and psychological burdens on patients, with limited treatments due to unclear central mechanisms. Addressing this challenge remains a crucial unsolved issue in pain medicine. Our previous study, using protein kinase C gamma (PKCγ)-tdTomato mice, highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia. However, the regulatory mechanisms governing this circuit necessitate further elucidation. We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin (5-HT) facilitation system on spinal PKCγ neurons. Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_2C receptors, disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia. Inhibiting spinal 5-HT_2C receptors restored the feedforward inhibitory circuit, effectively preventing neuropathic allodynia. These insights offer promising therapeutic targets for neuropathic allodynia management, emphasizing the potential of spinal 5-HT_2C receptors as a novel avenue for intervention.
Animals ; Neuralgia/physiopathology* ; Protein Kinase C/metabolism* ; Receptor, Serotonin, 5-HT2C/metabolism* ; Hyperalgesia/physiopathology* ; Mice, Transgenic ; Mice ; Spinal Cord/metabolism* ; Serotonin/metabolism* ; Male ; Neurons/metabolism* ; Mice, Inbred C57BL

Microglial functions are linked to Ca²⁺ signaling, with endoplasmic reticulum (ER) calcium stores playing a crucial role. Microglial abnormality is a hallmark of Alzheimer's disease (AD), but how ER Ca²⁺ receptors regulate microglial functions under physiological and AD conditions remains unclear. We found reduced ryanodine receptor 2 (Ryr2) expression in microglia from an AD mouse model. Modulation of RyR2 using S107, a RyR-Calstabin stabilizer, blunted spontaneous Ca²⁺ transients in controls and normalized Ca²⁺ transients in AD mice. S107 enhanced ATP-induced migration and phagocytosis while reducing ramification in control microglia; however, these effects were absent in AD microglia. Our findings indicate that RyR2 stabilization promotes an activation state shift in control microglia, a mechanism impaired in AD. These results highlight the role of ER Ca²⁺ receptors in both homeostatic and AD microglia, providing insights into microglial Ca²⁺ malfunctions in AD.
Animals ; Microglia/pathology* ; Alzheimer Disease/pathology* ; Phagocytosis/drug effects* ; Ryanodine Receptor Calcium Release Channel/metabolism* ; Disease Models, Animal ; Mice ; Cell Movement/drug effects* ; Mice, Transgenic ; Calcium Signaling/physiology* ; Calcium/metabolism* ; Mice, Inbred C57BL ; Male ; Endoplasmic Reticulum/metabolism*