Cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic disorders are the 3 major chronic diseases threatening human health, which are closely related and often coexist, significantly increasing the difficulty of disease management. In response, the American Heart Association (AHA) proposed a novel disease concept of “cardiovascular-kidney-metabolic (CKM) syndrome” in October 2023, which has triggered widespread concern about the co-treatment of heart and kidney diseases and the prevention and treatment of metabolic disorders around the world. This review posits that effectively managing CKM syndrome requires a new and multidimensional paradigm for diagnosis and risk prediction that integrates biological insights, advanced technology and social determinants of health (SDoH). We argue that the core pathological driver is a “metabolic toxic environment”, fueled by adipose tissue dysfunction and characterized by a vicious cycle of systemic inflammation and oxidative stress, which forms a common pathway to multi-organ injury. The at-risk population is defined not only by biological characteristics but also significantly impacted by adverse SDoH, which can elevate the risk of advanced CKM by a factor of 1.18 to 3.50, underscoring the critical need for equity in screening and care strategies. This review systematically charts the progression of diagnostic technologies. In diagnostics, we highlight a crucial shift from single-marker assessments to comprehensive multi-marker panels. The synergistic application of traditional biomarkers like NT-proBNP (reflecting cardiac stress) and UACR (indicating kidney damage) with emerging indicators such as systemic immune-inflammation index (SII) and Klotho protein facilitates a holistic evaluation of multi-organ health. Furthermore, this paper explores the pivotal role of non-invasive monitoring technologies in detecting subclinical disease. Techniques like multi-wavelength photoplethysmography (PPG) and impedance cardiography (ICG) provide a real-time window into microcirculatory and hemodynamic status, enabling the identification of early, often asymptomatic, functional abnormalities that precede overt organ failure. In imaging, progress is marked by a move towards precise, quantitative evaluation, exemplified by artificial intelligence-powered quantitative computed tomography (AI-QCT). By integrating AI-QCT with clinical risk factors, the predictive accuracy for cardiovascular events within 6 months significantly improves, with the area under the curve (AUC) increasing from 0.637 to 0.688, demonstrating its potential for reclassifying risk in CKM stage 3. In the domain of risk prediction, we trace the evolution from traditional statistical tools to next-generation models. The new PREVENT equation represents a major advancement by incorporating key kidney function markers (eGFR, UACR), which can enhance the detection rate of CKD in primary care by 20%-30%. However, we contend that the future lies in dynamic, machine learning-based models. Algorithms such as XGBoost have achieved an AUC of 0.82 for predicting 365-day cardiovascular events, while deep learning models like KFDeep have demonstrated exceptional performance in predicting kidney failure risk with an AUC of 0.946. Unlike static calculators, these AI-driven tools can process complex, multimodal data and continuously update risk profiles, paving the way for truly personalized and proactive medicine. In conclusion, this review advocates for a paradigm shift toward a holistic and technologically advanced framework for CKM management. Future efforts must focus on the deep integration of multimodal data, the development of novel AI-driven biomarkers, the implementation of refined SDoH-informed interventions, and the promotion of interdisciplinary collaboration to construct an efficient, equitable, and effective system for CKM screening and intervention.

Acupotomy therapy demonstrates the definite clinical efficacy on knee osteoarthritis (KOA). After reviewing systematically the mechanism studies on acupotomy for KOA over the past 5 years, It is revealed that acupotomy synergistically intervenes in the pathological progression of KOA through multi-target approaches, such as regulating cartilage homeostasis, restoring skeletal muscle function, alleviating synovial inflammatory responses, remodeling subchondral bone, and neuromodulation. But the current research still limits to single-tissue phenotypic observation, and is insufficiency in the in-depth exploration of multi-tissue synergistic interactions and molecular upstream-downstream regulatory mechanisms. Future studies should focus on the inheritance and innovation of acupotomy theory, and integrating multi-omics analytical technologies, artificial intelligence, and novel biochemical detection methods. The mechanism research targets on the interaction mechanisms among tissues, direct effects of acupotomy, immune-inflammatory regulatory mechanisms, and analgesic mechanisms, so as to comprehensively elucidate the therapeutic mechanism of acupotomy for KOA.
Humans ; Acupuncture Therapy ; Osteoarthritis, Knee/genetics* ; Animals

This study aims to investigate the effects of renin inhibitor aliskiren on kidney injury in human angiotensinogen-renin (AGT-REN) double transgenic hypertensive (dTH) mice and explore its possible mechanism. The dTH mice were divided into hypertension group (HT group) and aliskiren intervention group (HT+Aliskiren group), while wild-type C57BL/6 mice were served as the control group (WT group). Blood pressure data of mice in HT+Aliskiren group were collected after 28 d of subcutaneous penetration of aliskiren (20 mg/kg), and the damage of renal tissue structure and collagen deposition were observed by HE, Masson and PAS staining. The ultrastructure of kidney was observed by transmission electron microscope. Coomassie bright blue staining and biochemical analyzer were used to detect renal function injury. The expression of renin-angiotensin system (RAS) was determined by ELISA and immunohistochemistry. The contents of superoxide dismutase (SOD) and malondialdehyde (MDA) in kidney were determined by chemiluminescence method. The content of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47^phox, inducible nitric oxide synthase (iNOS), 3-nitrotyrosine (3-NT), NADPH oxidase 2 (NOX2) and NADPH oxidase 4 (NOX4) were detected by Western blot analysis. The results showed that compared with WT group, the blood pressure of mice in HT group was significantly increased. The renal tissue structure in HT group showed glomerular sclerosis, severe interstitial tubular injury, and increased collagen deposition. In addition, 24 h urinary protein, serum creatinine and urea levels increased. Serum and renal tissue levels of angiotensin II (Ang II) were increased, serum angiotensin-(1-7) [Ang-(1-7)] expression was decreased, and renal Ang-(1-7) expression was elevated. The expressions of ACE, Ang II type 1 receptor (AT₁R) and MasR in renal tissue were increased, while the expression of ACE2 was decreased. MDA content increased, SOD content decreased, and the expressions of p47^phox, iNOS, 3-NT, NOX2 and NOX4 were increased. However, aliskiren reduced blood pressure in dTH mice, improved renal structure and renal function, reduced Ang II and Ang-(1-7) levels in serum and renal tissue, reduced the expression of ACE and AT₁R in renal tissue, increased the expression of ACE2 and MasR in renal tissue, and decreased the above levels of oxidative stress indexes in dTH mice. These results suggest that aliskiren may play a protective role in hypertensive renal injury by regulating the balance between ACE-Ang II-AT₁R and ACE2-Ang-(1-7)-MasR axes and inhibiting oxidative stress.
Animals ; Fumarates/therapeutic use* ; Mice ; Renin/antagonists & inhibitors* ; Amides/therapeutic use* ; Mice, Inbred C57BL ; Hypertension/physiopathology* ; Mice, Transgenic ; Kidney/pathology* ; Angiotensinogen/genetics* ; Renin-Angiotensin System/drug effects* ; NADPH Oxidases/metabolism* ; Male ; Antihypertensive Agents/pharmacology* ; Humans ; Superoxide Dismutase/metabolism* ; NADPH Oxidase 4

Jiuwei Xifeng Granules have become a Chinese patent medicine in the market. Because the formula contains Os Draconis, a top-level protected fossil of ancient organisms, the formula was to be improved by replacing Os Draconis with Ostreae Concha. To evaluate whether the improved formula has the same effectiveness and safety as the original formula, a randomized, double-blind, parallel-controlled, equivalence clinical trial was conducted. This study enrolled 288 tic disorder(TD) of children and assigned them into two groups in 1∶1. The treatment group and control group took the modified formula and original formula, respectively. The treatment lasted for 6 weeks, and follow-up visits were conducted at weeks 2, 4, and 6. The primary efficacy endpoint was the difference in Yale global tic severity scale(YGTSS)-total tic severity(TTS) score from baseline after 6 weeks of treatment. The results showed that after 6 weeks of treatment, the declines in YGTSS-TSS score showed no statistically significant difference between the two groups. The difference in YGTSS-TSS score(treatment group-control group) and the 95%CI of the full analysis set(FAS) were-0.17[-1.42, 1.08] and those of per-protocol set(PPS) were 0.29[-0.97, 1.56], which were within the equivalence boundary [-3, 3]. The equivalence test was therefore concluded. The two groups showed no significant differences in the secondary efficacy endpoints of effective rate for TD, total score and factor scores of YGTSS, clinical global impressions-severity(CGI-S) score, traditional Chinese medicine(TCM) response rate, or symptom disappearance rate, and thus a complete evidence chain with the primary outcome was formed. A total of 6 adverse reactions were reported, including 4(2.82%) cases in the treatment group and 2(1.41%) cases in the control group, which showed no statistically significant difference between the two groups. No serious suspected unexpected adverse reactions were reported, and no laboratory test results indicated serious clinically significant abnormalities. The results support the replacement of Os Draconis by Ostreae Concha in the original formula, and the efficacy and safety of the modified formula are consistent with those of the original formula.
Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Male ; Double-Blind Method ; Drugs, Chinese Herbal/therapeutic use* ; Tic Disorders/drug therapy* ; Treatment Outcome

This study aims to investigate the molecular mechanism by which naringin alleviates cerebral ischemia/reperfusion(CI/R) injury through DRP1/LRRK2/MCU signaling axis. A total of 60 SD rats were randomly divided into the sham group, the model group, the sodium Danshensu group, and low-, medium-, and high-dose(50, 100, and 200 mg·kg~(-1)) naringin groups, with 10 rats in each group. Except for the sham group, a transient middle cerebral artery occlusion/reperfusion(tMCAO/R) model was established in SD rats using the suture method. Longa 5-point scale was used to assess neurological deficits. 2,3,5-Triphenyl tetrazolium chloride(TTC) staining was used to detect the volume percentage of cerebral infarction in rats. Hematoxylin-eosin(HE) staining and Nissl staining were employed to assess neuronal structural alterations and the number of Nissl bodies in cortex, respectively. Western blot was used to determine the protein expression levels of B-cell lymphoma-2 gene(Bcl-2), Bcl-2-associated X protein(Bax), cleaved cysteine-aspartate protease-3(cleaved caspase-3), mitochondrial calcium uniporter(MCU), microtubule-associated protein 1 light chain 3(LC3), and P62. Mitochondrial structure and autophagy in cortical neurons were observed by transmission electron microscopy. Immunofluorescence assay was used to quantify the fluorescence intensities of MCU and mitochondrial calcium ion, as well as the co-localization of dynamin-related protein 1(DRP1) with leucine-rich repeat kinase 2(LRRK2) and translocase of outer mitochondrial membrane 20(TOMM20) with LC3 in cortical mitochondria. The results showed that compared with the model group, naringin significantly decreased the volume percentage of cerebral infarction and neurological deficit score in tMCAO/R rats, alleviated the structural damage and Nissl body loss of cortical neurons in tMCAO/R rats, inhibited autophagosomes in cortical neurons, and increased the average diameter of cortical mitochondria. The Western blot results showed that compared to the sham group, the model group exhibited increased levels of cleaved caspase-3, Bax, MCU, and the LC3Ⅱ/LC3Ⅰ ratio in the cortex and reduced protein levels of Bcl-2 and P62. However, naringin down-regulated the protein expression of cleaved caspase-3, Bax, MCU and the ratio of LC3Ⅱ/LC3Ⅰ ratio and up-regulated the expression of Bcl-2 and P62 proteins in cortical area. In addition, immunofluorescence analysis showed that compared with the model group, naringin and positive drug treatments significantly decreased the fluorescence intensities of MCU and mitochondrial calcium ion. Meanwhile, the co-localization of DRP1 with LRRK2 and TOMM20 with LC3 in cortical mitochondria was also decreased significantly after the intervention. These findings suggest that naringin can alleviate cortical neuronal damage in tMCAO/R rats by inhibiting DRP1/LRRK2/MCU-mediated mitochondrial fragmentation and the resultant excessive mitophagy.
Animals ; Rats, Sprague-Dawley ; Reperfusion Injury/genetics* ; Flavanones/administration & dosage* ; Rats ; Dynamins/genetics* ; Male ; Brain Ischemia/genetics* ; Protein Serine-Threonine Kinases/genetics* ; Signal Transduction/drug effects* ; Humans ; Drugs, Chinese Herbal/administration & dosage*

Biomedical big data, characterized by its massive scale, multi-dimensionality, and heterogeneity, offers novel perspectives for disease research, elucidates biological principles, and simultaneously prompts changes in related research methodologies. Biomedical ontology, as a shared formal conceptual system, not only offers standardized terms for multi-source biomedical data but also provides a solid data foundation and framework for biomedical research. In this review, we summarize enrichment analysis and deep learning for biomedical ontology based on its structure and semantic annotation properties, highlighting how technological advancements are enabling the more comprehensive use of ontology information. Enrichment analysis represents an important application of ontology to elucidate the potential biological significance for a particular molecular list. Deep learning, on the other hand, represents an increasingly powerful analytical tool that can be more widely combined with ontology for analysis and prediction. With the continuous evolution of big data technologies, the integration of these technologies with biomedical ontologies is opening up exciting new possibilities for advancing biomedical research.
Deep Learning ; Biological Ontologies ; Humans ; Big Data ; Biomedical Research

Case 1: A 19-day-old male infant presented with poor feeding and decreased activity for 2 weeks, worsening with poor responsiveness for 3 days. At 5 days old, he developed poor feeding and poor responsiveness, was hospitalized, and was found to have elevated blood ammonia and thrombocytopenia. Whole-genome genetic analysis revealed a pathogenic homozygous mutation in the PCCA gene, NM-000282.4: c.1834-1835del (p.Arg612AspfsTer44), leading to a diagnosis of propionic acidemia. Case 2: A 4-day-old male infant presented with poor responsiveness and feeding difficulties since birth, with elevated blood ammonia for 1 day. He showed weak sucking and deteriorating responsiveness, with blood ammonia >200 µmol/L. Genetic testing identified two heterozygous mutations in the MMUT gene: NM_000255.4: c.1677-1G>A and NM_000255.4: ex.5del, confirming methylmalonic acidemia. Case 3: A 20-day-old male infant presented with poor feeding for 15 days and skin petechiae for 8 days. He developed feeding difficulties at 5 days old and lower limb petechiae at 12 days old, with blood ammonia measured at 551.6 µmol/L. Genetic analysis found two heterozygous mutations in the PCCA gene: NM_000282.4: c.1118T>A (p.Met373Lys) and NM_000282.4: ex.16-18del, confirming propionic acidemia. In the first two cases, continuous hemodiafiltration was performed for 30 hours and 20 hours, respectively, before administering carglumic acid. In the third case, carglumic acid was administered orally without continuous hemodiafiltration, resulting in a decrease in blood ammonia from 551.6 µmol/L to 72.0 µmol/L within 6 hours, with a reduction rate of approximately 20-25 µmol/(kg·h), similar to the first two cases. Carglumic acid was effective in all three cases, suggesting it may help optimize future treatment protocols for organic acidemia.
Humans ; Male ; Infant, Newborn ; Propionic Acidemia/drug therapy* ; Amino Acid Metabolism, Inborn Errors/genetics* ; Mutation ; Methylmalonyl-CoA Decarboxylase/genetics* ; Citrates/administration & dosage* ; Carbon-Carbon Ligases/genetics* ; Glutamates

OBJECTIVE: To investigate the effect of piperlongumine(PL) on the proliferation and ferroptosis of human adriamycin-resistant chronic myeloid leukemia K562/ADR cells, and to explore its possible molecular mechanism. METHODS: CCK-8 assay was used to detect the effect of PL on the survival rate of K562/ADR cells and to screen the appropriate drug concentration. After K562/ADR cells were treated with low, medium and high concentrations of PL(2, 4, and 6 μmol/L), EdU proliferation assay and plate colony formation assay were used to detect cell proliferation and colony formation ability. CCK-8 assay was used to detect the effects of different inhibitors (Fer-1, Z-VAD, Nec-1) combined with PL on cell proliferation. The intracellular Fe²⁺, ROS, malondialdehyde(MDA) and glutathine(GSH) contents were respectively detected by iron ion colorimetry, DCFH-DA fluorescent probe, MDA and GSH kits. RT-qPCR and Western blot were respectively used to detect the expression level of GPX4 mRNA and protein in cells. Bioinformatics websites predicted miRNA that could target and regulate GPX4 . RT-qPCR was used to detect the effects of different concentrations of PL on the expression levels of the predicted miRNA. Dual luciferase gene reporter assay was used to verify the targeting relationship between miR-214-3p and GPX4 . After treating cells with PL or PL+miR-214-3p inhibitor, the Fe²⁺, ROS, MDA, GSH centents and GPX4 protein expression levels in cells were detected. RESULTS: PL inhibited K562/ADR cell proliferation in a concentration-dependent manner（r =0.979）. Compared with the blank control group, the survival rate, EdU positive cells rate in low, medium and high concentration PL groups were significantly decreased (P < 0.01). Compared with the PL group alone, the survival rate of cells in the Z-VAD+PL group was increased slightly (P < 0.05). The cell survival rate was significantly increased in medium or high concentration PL+Fer-1 group (P < 0.01). Compared with blank control group, ROS expression level in low concentration PL group was slightly increased (P < 0.05), and GSH content was slightly decreased (P < 0.05). In medium and high concentration PL groups, the contents of Fe²⁺, ROS and MDA were significantly increased (P < 0.01), while the contents of GSH, expression of GPX4 mRNA and protein were significantly decreased(P < 0.01). Bioinformatics prediction and double luciferase reporter gene experiment confirmed the targeting relationship between GPX4 and miR-214-3p. Compared with the blank control group, the expression level of miR-214-3p in cells of medium and high concentration PL groups was significantly increased (P < 0.01). Compared with PL group alone, the intracellular Fe²⁺, ROS and MDA contents in PL+miR-214-3p inhibitor group were all decreased (P < 0.01), while GSH content and GPX4 protein expression levels were significantly increased (P < 0.01). CONCLUSION Medium and high concentrations of PL can inhibit the proliferation of K562/ADR cells by inducing ferroptosis, which is related to the regulation of miR-214-3p pathway.
Humans ; Ferroptosis/drug effects* ; MicroRNAs/metabolism* ; Dioxolanes/pharmacology* ; Cell Proliferation/drug effects* ; K562 Cells ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Reactive Oxygen Species ; Doxorubicin/pharmacology* ; Signal Transduction ; Piperidones

OBJECTIVE: Photodynamic therapy has become an important method in clinical tumor treatment. This study aimed to investigate the effects of hematoporphyrin on multiple myeloma (MM) and its potential applications. METHODS: The MM cell line RPMI 8226 was treated with hematoporphyrin derivative (HPD), and CCK-8 assay was used to determine cell viability, apoptosis was detected by flow cytometry, intracellular reactive oxygen species (ROS) levels were measured using a detection kit combined with flow cytometry, and Western blot assay was used to detect apoptosis-related proteins and key signaling pathway protein levels. RESULTS: The optimal incubation time for the maximum absorption of HPD in RPMI 8226 cells was 4 hours. HPD significantly inhibited the proliferation of RPMI 8226 cells in a dose- and illumination time-dependent manner ( r =0.981; r =0.961). Additionally, HPD induced apoptosis in RPMI 8226 cells, but had no significant inhibitory effect on peripheral blood mononuclear cells derived from healthy individuals. HPD combined with illumination treatment significantly increased the intracellular ROS level, upregulated the expression of apoptosis-related proteins such as cleaved PARP, cleaved caspase-3 and Bax, and down-regulated the expression of proteins that maintain cell survival, such as NF-κB and Akt. CONCLUSION The HPD can inhibit the proliferation and induce apoptosis of multiple myeloma cells.
Humans ; Multiple Myeloma/pathology* ; Hematoporphyrins/pharmacology* ; Apoptosis/drug effects* ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism* ; Cell Proliferation/drug effects* ; Photochemotherapy ; Cell Survival/drug effects* ; Signal Transduction