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1.
J Tradit Chin Med ; 44(3): 437-447, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38767627

ABSTRACT

OBJECTIVE: To evaluate the analgesic effects of total flavonoids of Longxuejie (Resina Dracaenae Cochinchinensis) (TFDB) and explore the possible analgesic mechanism associated with transient receptor potential vanilloid 1 (TRPV1). METHODS: Whole-cell patch clamp technique was used to observe the effects of TFDB on capsaicin-induced TRPV1 currents. Rat experiments in vivo were used to observe the analgesic effects of TFDB. Western blot and immunofluorescence experiments were used to test the change of TRPV1 expression in DRG neurons induced by TFDB. RESULTS: Results showed that TFDB inhibited capsaicin-induced TRPV1 receptor currents in acutely isolated dorsal root ganglion (DRG) neurons of rats and the half inhibitory concentration was (16.7 ± 1.6) mg/L. TFDB (2-20 mg/kg) showed analgesic activity in the phase Ⅱ of formalin test and (0.02-2 mg per paw) reduced capsaicin-induced licking times of rats. TFDB (20 mg/kg) was fully efficacious on complete Freund's adjuvant (CFA)-induced inflammatory thermal hyperalgesia and capsaicin could weaken the analgesic effects. The level of TRPV1 expressions of DRG neurons was also decreased in TFDB-treated CFA-inflammatory pain rats. CONCLUSION: All these results indicated that the analgesic effect of TFDB may contribute to their modulations on both function and expression of TRPV1 channels in DRG neurons.


Subject(s)
Analgesics , Flavonoids , Ganglia, Spinal , Rats, Sprague-Dawley , TRPV Cation Channels , Animals , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolism , Rats , Flavonoids/pharmacology , Analgesics/pharmacology , Analgesics/chemistry , Male , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Ganglia, Spinal/cytology , Humans , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Neurons/drug effects , Neurons/metabolism , Pain/drug therapy , Pain/metabolism
2.
J Tradit Chin Med ; 44(3): 458-467, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38767629

ABSTRACT

OBJECTIVE:To elucidate the mechanism by which Huoxue Jiedu Huayu recipe (, HJHR) regulates angiogenesis in the contralateral kidney of unilateral ureteral obstruction (UUO) rats and the mechanism by which it reduces of renal fibrosis. METHODS: Male Wistar rats were randomly divided into 4 groups: the sham group, UUO group (180 d of left ureter ligation), UUO plus eplerenone (EPL) group, and UUO plus HJHR group. After 180 d of oral drug administration, blood and contralateral kidneys were collected for analysis. Angiogenesis- and fibrosis-related indexes were detected. RESULTS: HJHR and EPL improved structural damage and renal interstitial fibrosis in the contralateral kidney and reduced the protein expression levels of α-smooth muscle actin (α-SMA), vimentin and collagen I. Moreover, these treatments could reduce the expression of vascular endothelial growth factor-A (VEGFA) by inhibiting the infiltration of macrophages. Furthermore, HJHR and EPL significantly reduced the expression of CD34 and CD105 by downregulating VEGFA production, which inhibited angiogenesis. Finally, the coexpressions of CD34, CD105 and α-SMA were decreased in the HJHR and EPL groups, indicating that endothelial-to-mesenchymal transition was inhibited. CONCLUSIONS: These findings confirm that HJHR alleviates contralateral renal fibrosis by inhibiting VEGFA-induced angiogenesis, encourage the use of HJHR against renal interstitial fibrosis and provide a theoretical basis for the clinical management of patients with CKD.


Subject(s)
Drugs, Chinese Herbal , Fibrosis , Kidney , Macrophages , Rats, Wistar , Ureteral Obstruction , Vascular Endothelial Growth Factor A , Animals , Male , Ureteral Obstruction/metabolism , Ureteral Obstruction/drug therapy , Ureteral Obstruction/genetics , Rats , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/genetics , Kidney/drug effects , Kidney/metabolism , Macrophages/drug effects , Macrophages/metabolism , Drugs, Chinese Herbal/administration & dosage , Humans , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Kidney Diseases/drug therapy , Kidney Diseases/metabolism , Kidney Diseases/etiology , Kidney Diseases/genetics , Angiogenesis
3.
J Tradit Chin Med ; 44(3): 448-457, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38767628

ABSTRACT

OBJECTIVE: Exploring the effect of Optimized New Shengmai powder (, ONSMP) on myocardial fibrosis in heart failure (HF) based on rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular regulated protein kinases (ERK) signaling pathway. METHODS: Randomized 70 Sprague-Dawley rats into sham (n = 10) and operation (n = 60) groups, then established the HF rat by ligating the left anterior descending branch of the coronary artery. We randomly divided the operation group rats into the model, ONSMP [including low (L), medium (M), and high (H) dose], and enalapril groups. After the 4-week drug intervention, echocardiography examines the cardiac function and calculates the ratios of the whole/left heart to the rat's body weight. Finally, we observed the degree of myocardial fibrosis by pathological sections, determined myocardium collagen (COL) I and COL Ⅲ content by enzyme-linked immunosorbent assay, detected the mRNA levels of COL I, COL Ⅲ, α-smooth muscle actin (α-SMA), and c-Fos proto-oncogene (c-Fos) by universal real-time, and detected the protein expression of p-RAS, p-RAF, p-MEK1/2, p-ERK1/2, p-ETS-like-1 transcription factor (p-ELK1), p-c-Fos, α-SMA, COL I, and COL Ⅲ by Western blot. RESULTS: ONSMP can effectively improve HF rat's cardiac function, decrease cardiac organ coefficient, COL volume fraction, and COL I/Ⅲ content, down-regulate the mRNA of COL I/Ⅲ, α-SMA and c-Fos, and the protein of p-RAS, p-RAF, p-MEK1/ 2, p-ERK1/2, p-ELK1, c-Fos, COL Ⅰ/Ⅲ, and α-SMA. CONCLUSIONS: ONSMP can effectively reduce myocardial fibrosis in HF rats, and the mechanism may be related to the inhibition of the RAS/RAF/MEK/ERK signaling pathway.


Subject(s)
Drug Combinations , Drugs, Chinese Herbal , Fibrosis , Heart Failure , Rats, Sprague-Dawley , Animals , Drugs, Chinese Herbal/administration & dosage , Rats , Heart Failure/drug therapy , Heart Failure/genetics , Heart Failure/metabolism , Heart Failure/physiopathology , Heart Failure/etiology , Male , Fibrosis/drug therapy , Humans , Myocardium/metabolism , Myocardium/pathology , Extracellular Signal-Regulated MAP Kinases/metabolism , Extracellular Signal-Regulated MAP Kinases/genetics , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinase Kinases/genetics , Signal Transduction/drug effects , Sarcoma/drug therapy , Sarcoma/genetics , Sarcoma/metabolism
4.
J Tradit Chin Med ; 44(3): 489-495, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38767632

ABSTRACT

OBJECTIVE: To explore the multi-component synergistic mechanism of Zuogui Wan (, ZGW) in treating postmenopausal osteoporosis (PMOP). METHODS: The main components and target genes of ZGW were screened via the Traditional Chinese Medicine Systems Pharmacology (TCMSP). In addition, the target gene sets of PMOP were derived from the GeneCards and Online Mendelian Inheritance in Man databases. The search tool for recurring instances of neighbouring genes (STRING) 11.0 software was used to analyze the interaction among intersecting genes. Cytoscape 3.6.1 software and the Matthews correlation coefficient (MCC) algorithm were used to screen the core genes. Fifty Sprague-Dawley female rats were randomly divided into the sham-operated (Sham) group and the four ovariectomized (OVX) subgroups. Rats subjected to Sham or OVX were administered with the vehicle (OVX, 1 mL water/100 g weight), 17ß-estradiol (E2, 50 µg·kg-1·d-1), and lyophilized powder of ZGW at a low dose of 2.3 (ZGW-L) and high dose of 4.6 (ZGW-H) g·kg-1·d-1 for three months. The bone density and bone strength were assessed using dual-energy X-ray and three-point bending tests, respectively. Furthermore, enzyme-linked immun-osorbent assay, Hematoxylin-eosin staining, and western blot analysis were used to determine the potential pharmacological mechanisms of action of ZGW in PMOP. RESULTS: A total of 117 active compounds of ZGW were screened from the TCMSP. Furthermore, 108 intersecting genes of drugs and diseases were identified. Using STRING software and the MCC algorithm, ten core genes, including C-X-C chemokine living 8 (CXCL8), C-C chemokine receptor type 2 (CCR2), alpha-2a active receptor (ADRA2A), melatonin receptor type 1B (MTNR1B), and amyloid-beta A4 protein (APP), were identified. The anti-osteoporosis regulation network of ZGW was constructed using the Cytoscape software. The animal experiments demonstrated that ZGW groups significantly reduced the serum levels of ß-C-terminal telopeptide of type I collagen (ß-CTX) and increased serum levels of bone-specific alkaline phosphatase (BALP) (P < 0.05, P < 0.01). The OVX group exhibited a significant decrease in bone mineral density and bone strength compared with the Sham group (P < 0.01). Moreover, treatment with ZGW resulted in increased trabecular thickness, improved arrangement of trabecular structure, and reduced empty bone lacunae. Furthermore, treatment with ZGW significantly increased the protein expression of CXCL8, ADRA2A, and CCR2 (P < 0.05, P < 0.01), and significantly decreased the protein expression of Runx2 (P < 0.01). Furthermore, the ZGW and E2 groups demonstrated significantly increased BMD (P < 0.05, P < 0.01), improved bone strength (P < 0.05, P < 0.01), reduced expression of CXCL8, ADRA2A, and CCR2, and increased runt-related transcription factor 2 levels in bone tissue (P < 0.05, P < 0.01) compared with the OVX group. However, there were no significant differences in MTNR1B and APP expression among the groups. CONCLUSION: ZGW shows synergistic mechanisms in PMOP through multiple components, targets, and pathways.


Subject(s)
Bone Density , Drugs, Chinese Herbal , Osteoporosis, Postmenopausal , Rats, Sprague-Dawley , Drugs, Chinese Herbal/administration & dosage , Female , Animals , Osteoporosis, Postmenopausal/drug therapy , Osteoporosis, Postmenopausal/genetics , Osteoporosis, Postmenopausal/physiopathology , Osteoporosis, Postmenopausal/metabolism , Rats , Humans , Bone Density/drug effects
5.
PLoS One ; 19(5): e0303189, 2024.
Article in English | MEDLINE | ID: mdl-38768165

ABSTRACT

OBJECTIVES: To establish a rat model that accurately replicates the clinical characteristics of male infertility (MI) with Liver Depression and Kidney Deficiency (LD & KD) and investigate the pathogenesis. METHODS: After subjecting the rats to chronic restraint stress (CRS) and adenine treatment, a series of tests were conducted, including ethological assessments, evaluations of reproductive characteristics, measurements of biochemical parameters, histopathological examinations, and analyses of urinary metabolites. Additionally, bioinformatics predictions were performed for comprehensive analysis. RESULTS: Compared to the control, the model exhibited significant manifestations of MI with LD & KD, including reduced responsiveness, diminished frequency of capturing estrous female rats, and absence of mounting behavior. Additionally, the kidney coefficient increased markedly, while the coefficients of the testis and epididymis decreased significantly. Sperm counts and viabilities decreased notably, accompanied by an increase in sperm abnormalities. Dysregulation of reproductive hormone levels in the serum was observed, accompanied by an upregulation of proinflammatory cytokines expressions in the liver and kidney, as well as exacerbated oxidative stress in the penile corpus cavernosum and testis. The seminiferous tubules in the testis exhibited a loose arrangement, loss of germ cells, and infiltration of inflammatory cells. Furthermore, utilizing urinary metabolomics and bioinformatics analysis, 5 key biomarkers and 2 crucial targets most closely linked to MI were revealed. CONCLUSION: The study successfully established a clinically relevant animal model of MI with LD & KD. It elucidates the pathogenesis of the condition, identifies key biomarkers and targets, and provides a robust scientific foundation for the prediction, diagnosis, and treatment of MI with LD & KD.


Subject(s)
Biomarkers , Disease Models, Animal , Infertility, Male , Animals , Male , Rats , Biomarkers/metabolism , Infertility, Male/metabolism , Infertility, Male/etiology , Testis/metabolism , Testis/pathology , Kidney/metabolism , Kidney/pathology , Rats, Sprague-Dawley , Liver/metabolism , Liver/pathology , Oxidative Stress , Liver Diseases/metabolism , Liver Diseases/pathology , Renal Insufficiency/metabolism , Renal Insufficiency/pathology , Renal Insufficiency/etiology
6.
Int J Nanomedicine ; 19: 4321-4337, 2024.
Article in English | MEDLINE | ID: mdl-38770103

ABSTRACT

Purpose: Cannabidiol (CBD) is a promising therapeutic drug with low addictive potential and a favorable safety profile. However, CBD did face certain challenges, including poor solubility in water and low oral bioavailability. To harness the potential of CBD by combining it with a transdermal drug delivery system (TDDS). This innovative approach sought to develop a transdermal patch dosage form with micellar vesicular nanocarriers to enhance the bioavailability of CBD, leading to improved therapeutic outcomes. Methods: A skin-penetrating micellar vesicular nanocarriers, prepared using nano emulsion method, cannabidiol loaded transdermal nanocarriers-12 (CTD-12) was presented with a small particle size, high encapsulation efficiency, and a drug-loaded ratio for CBD. The skin permeation ability used Strat-M™ membrane with a transdermal diffusion system to evaluate the CTD and patch of CTD-12 (PCTD-12) within 24 hrs. PCTD-12 was used in a preliminary pharmacokinetic study in rats to demonstrate the potential of the developed transdermal nanocarrier drug patch for future applications. Results: In the transdermal application of CTD-12, the relative bioavailability of the formulation was 3.68 ± 0.17-fold greater than in the free CBD application. Moreover, PCTD-12 indicated 2.46 ± 0.18-fold higher relative bioavailability comparing with free CBD patch in the ex vivo evaluation. Most importantly, in the pharmacokinetics of PCTD-12, the relative bioavailability of PCTD-12 was 9.47 ± 0.88-fold higher than in the oral application. Conclusion: CTD-12, a transdermal nanocarrier, represents a promising approach for CBD delivery, suggesting its potential as an effective transdermal dosage form.


Subject(s)
Administration, Cutaneous , Biological Availability , Cannabidiol , Drug Carriers , Nanoparticles , Skin Absorption , Transdermal Patch , Cannabidiol/pharmacokinetics , Cannabidiol/chemistry , Cannabidiol/administration & dosage , Animals , Skin Absorption/drug effects , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Male , Nanoparticles/chemistry , Rats , Rats, Sprague-Dawley , Particle Size , Skin/metabolism , Skin/drug effects , Micelles
7.
Proc Natl Acad Sci U S A ; 121(22): e2318859121, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38771880

ABSTRACT

Megalin (low-density lipoprotein receptor-related protein 2) is a giant glycoprotein of about 600 kDa, mediating the endocytosis of more than 60 ligands, including those of proteins, peptides, and drug compounds [S. Goto, M. Hosojima, H. Kabasawa, A. Saito, Int. J. Biochem. Cell Biol. 157, 106393 (2023)]. It is expressed predominantly in renal proximal tubule epithelial cells, as well as in the brain, lungs, eyes, inner ear, thyroid gland, and placenta. Megalin is also known to mediate the endocytosis of toxic compounds, particularly those that cause renal and hearing disorders [Y. Hori et al., J. Am. Soc. Nephrol. 28, 1783-1791 (2017)]. Genetic megalin deficiency causes Donnai-Barrow syndrome/facio-oculo-acoustico-renal syndrome in humans. However, it is not known how megalin interacts with such a wide variety of ligands and plays pathological roles in various organs. In this study, we elucidated the dimeric architecture of megalin, purified from rat kidneys, using cryoelectron microscopy. The maps revealed the densities of endogenous ligands bound to various regions throughout the dimer, elucidating the multiligand receptor nature of megalin. We also determined the structure of megalin in complex with receptor-associated protein, a molecular chaperone for megalin. The results will facilitate further studies on the pathophysiology of megalin-dependent multiligand endocytic pathways in multiple organs and will also be useful for the development of megalin-targeted drugs for renal and hearing disorders, Alzheimer's disease [B. V. Zlokovic et al., Proc. Natl. Acad. Sci. U.S.A. 93, 4229-4234 (1996)], and other illnesses.


Subject(s)
Cryoelectron Microscopy , Low Density Lipoprotein Receptor-Related Protein-2 , Low Density Lipoprotein Receptor-Related Protein-2/metabolism , Low Density Lipoprotein Receptor-Related Protein-2/genetics , Animals , Humans , Rats , Ligands , Endocytosis , Agenesis of Corpus Callosum/metabolism , Agenesis of Corpus Callosum/genetics , Renal Tubular Transport, Inborn Errors , Myopia , Hernias, Diaphragmatic, Congenital , Proteinuria , Hearing Loss, Sensorineural
8.
Chem Biol Drug Des ; 103(5): e14556, 2024 May.
Article in English | MEDLINE | ID: mdl-38772881

ABSTRACT

Histone deacetylase 6 (HDAC6), as the key regulatory enzyme, plays an important role in the development of the nervous system. More and more studies indicate that HDAC6 has become a promising therapeutic target for CNS diseases. Herein we designed and synthesized a series of novel HDAC6 inhibitors with benzothiadiazinyl systems as cap groups and evaluated their activity in vitro and in vivo. Among them, compound 3 exhibited superior selective inhibitory activity against HDAC6 (IC50 = 5.1 nM, about 30-fold selectivity over HDAC1). The results of docking showed that compound 3 can interact well with the key amino acid residues of HDAC6. Compound 3 showed lower cytotoxicity (20 µM to SH-SY5Y cells, inhibition rate = 25.75%) and better neuroprotective activity against L-glutamate-induced SH-SY5Y cell injury model in vitro. Meanwhile, compound 3 exhibited weak cardiotoxicity (10 µM hERG inhibition rate = 17.35%) and possess good druggability properties. Especially, compound 3 could significantly reduce cerebral infarction from 49.87% to 32.18%, and similar with butylphthalide in MCAO model, indicating potential clinical application prospects for alleviating ischemic stroke-induced brain infarction.


Subject(s)
Drug Design , Histone Deacetylase 6 , Histone Deacetylase Inhibitors , Molecular Docking Simulation , Neuroprotective Agents , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase 6/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/chemical synthesis , Animals , Structure-Activity Relationship , Cell Line, Tumor , Male , Mice , Binding Sites , Rats
9.
Pharm Biol ; 62(1): 456-471, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38773737

ABSTRACT

CONTEXT: The mechanisms of Traditional Chinese Medicine (TCM) Guizhi-Gancao Decoction (GGD) remain unknown. OBJECTIVE: This study explores the mechanisms of GGD against cardiac hypertrophy. MATERIALS AND METHODS: Network pharmacology analysis was carried out to identify the potential targets of GGD. In vivo experiments, C57BL/6J mice were divided into Con, phenylephrine (PE, 10 mg/kg/d), 2-chloroadenosine (CADO, the stable analogue of adenosine, 2 mg/kg/d), GGD (5.4 g/kg/d) and GGD (5.4 g/kg/d) + CGS15943 (a nonselective adenosine receptor antagonist, 4 mg/kg/d). In vitro experiments, primary neonatal rat cardiomyocytes (NRCM) were divided into Con, PE (100 µM), CADO (5 µM), GGD (10-5 g/mL) and GGD (10-5 g/mL) + CGS15943 (5 µM). Ultrasound, H&E and Masson staining, hypertrophic genes expression and cell surface area were conducted to verify the GGD efficacy. Adenosine receptors (ADORs) expression were tested via real-time polymerase chain reaction (PCR), western blotting and immunofluorescence analysis. RESULTS: Network pharmacology identified ADORs among those of the core targets of GGD. In vitro experiments demonstrated that GGD attenuated PE-induced increased surface area (with an EC50 of 5.484 × 10-6 g/mL). In vivo data shown that GGD attenuated PE-induced ventricular wall thickening. In vitro and in vivo data indicated that GGD alleviated PE-induced hypertrophic gene expression (e.g., ANP, BNP and MYH7/MYH6), A1AR over-expression and A2aAR down-expression. Moreover, CADO exerts effects similar to GGD, whereas CGS15943 eliminated most effects of GGD. DISCUSSION AND CONCLUSIONS: Our findings suggest the mechanism by which GGD inhibits cardiac hypertrophy, highlighting regulation of ADORs as a potential therapeutic strategy for HF.


Subject(s)
Cardiomegaly , Drugs, Chinese Herbal , Mice, Inbred C57BL , Myocytes, Cardiac , Network Pharmacology , Phenylephrine , Animals , Drugs, Chinese Herbal/pharmacology , Phenylephrine/pharmacology , Cardiomegaly/drug therapy , Cardiomegaly/chemically induced , Mice , Male , Rats , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Myocytes, Cardiac/metabolism , Rats, Sprague-Dawley , Cells, Cultured , Disease Models, Animal , Medicine, Chinese Traditional/methods
10.
Comb Chem High Throughput Screen ; 27(5): 786-796, 2024.
Article in English | MEDLINE | ID: mdl-38773797

ABSTRACT

OBJECTIVE: Diabetic osteoporosis (DOP) belongs to the group of diabetes-induced secondary osteoporosis and is the main cause of bone fragility and fractures in many patients with diabetes. The aim of this study was to determine whether Ziyin Bushen Fang (ZYBSF) can improve DOP by inhibiting autophagy and oxidative stress. METHODS: Type 1 diabetes mellitus (T1DM) was induced in rats using a high-fat high-sugar diet combined with streptozotocin. Micro-CT scanning was used to quantitatively observe changes in the bone microstructure in each group. Changes in the serum metabolites of DOP rats were analyzed using UHPLC-QTOF-MS. The DOP mouse embryonic osteoblast precursor cell model (MC3T3-E1) was induced using high glucose levels. RESULTS: After ZYBSF treatment, bone microstructure significantly improved. The bone mineral density, trabecular number, and trabecular thickness in the ZYBSF-M and ZYBSF-H groups significantly increased. After ZYBSF treatment, the femur structure of the rats was relatively intact, collagen fibers were significantly increased, and osteoporosis was significantly improved. A total of 1239 metabolites were upregulated and 1527 were downregulated in the serum of T1DM and ZYBSF-treated rats. A total of 20 metabolic pathways were identified. In cellular experiments, ZYBSF reduced ROS levels and inhibited the protein expression of LC3II / I, Beclin-1, and p-ERK. CONCLUSION: ZYBSF may improve DOP by inhibiting the ROS/ERK-induced autophagy signaling pathway.


Subject(s)
Autophagy , Drugs, Chinese Herbal , Osteoporosis , Oxidative Stress , Animals , Autophagy/drug effects , Oxidative Stress/drug effects , Osteoporosis/drug therapy , Osteoporosis/metabolism , Rats , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Mice , Diabetes Mellitus, Experimental/drug therapy , Male , Rats, Sprague-Dawley , Streptozocin , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/complications , Bone Density/drug effects
11.
Gen Physiol Biophys ; 43(3): 221-230, 2024 May.
Article in English | MEDLINE | ID: mdl-38774922

ABSTRACT

The aim of this study was to improve insulin sensitivity in fructose-treated animals by ingestion of flavonoid quercetin. Several signs of insulin resistance have been developed in rats by drinking 10% fructose solution for 9 weeks. The effect of 6-week-gavage-administrated quercetin (20 mg/kg/day in 1% methyl cellulose solution) was monitored. Rats of the control groups received methyl cellulose vehicle as well. The most striking result of the quercetin treatment was the normalization of the fructose solution drinking to the level of drinking water intake. In addition, quercetin supplementation considerably decreased the plasma glucose and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index in rats consuming fructose. Surprisingly, fructose ingestion did not elevate plasma uric acid, thiobarbituric acid reactive substances, nitrotyrosine, or advanced glycation end products fluorescence. Instead, a reduction of the above parameters was observed. In summary, these results indicate that quercetin supplementation reduces fructose drinking and decreases plasma glucose and the HOMA-IR index. Furthermore, methyl cellulose, in combination with fructose, causes uric acid - lowering, antioxidant and anti-glycation effects. Thus, methyl cellulose possibly shifts fructose metabolism in favor of the utilization of antioxidant features of fructose. Our results call for using methyl cellulose in sweetened beverages and other sweetened food.


Subject(s)
Fructose , Insulin Resistance , Quercetin , Rats, Wistar , Uric Acid , Animals , Fructose/administration & dosage , Quercetin/pharmacology , Quercetin/administration & dosage , Uric Acid/blood , Rats , Male , Thiobarbituric Acid Reactive Substances/metabolism , Drinking/drug effects , Antioxidants/pharmacology , Antioxidants/metabolism , Blood Glucose/metabolism , Blood Glucose/drug effects
12.
Gen Physiol Biophys ; 43(3): 263-271, 2024 May.
Article in English | MEDLINE | ID: mdl-38774925

ABSTRACT

Lithium (Li) is a mood-stabilizing drug. Although one of the potential mechanisms underlying the neuroprotective effects of lithium is related to its antioxidative effect, its mechanisms of action are not fully understood. Herein we aimed to investigate the impact of varied dosages of long-term lithium therapy on oxidative stress parameters in the brains of healthy rats, and on anxiety-like behaviors, and whether any changes in behavior can be attributed to modifications in oxidative stress levels within the brain. Thirty-two adult Wistar albino male rats were randomly assigned to four treatment groups. While the control (C) group was fed with a standard diet, low Li (1.4 g/kg/diet), moderate Li (1.8 g/kg/diet), and high Li (2.2 g/kg/diet) groups were fed with lithium bicarbonate (Li2CO3) for 30 days. Malondialdehyde increased, while superoxide dismutase and catalase levels decreased in the brains of the high Li group animals. In addition, anxiety-like behaviors of animals increased in the high Li group considering fewer entries to and less time spent in the open arms of the elevated plus maze test. Our findings underscore the potential adverse effects of prolonged lithium treatment, especially at doses approaching the upper therapeutic range. The induction of toxicity, manifested through heightened oxidative stress, appears to be a key mechanism contributing to the observed increase in anxiety-like behaviors. Consequently, caution is warranted when considering extended lithium therapy at higher doses, emphasizing the need for further research to delineate the precise mechanisms underlying these effects and to inform safer therapeutic practices.


Subject(s)
Anxiety , Brain , Dose-Response Relationship, Drug , Oxidative Stress , Rats, Wistar , Animals , Oxidative Stress/drug effects , Male , Rats , Anxiety/chemically induced , Anxiety/drug therapy , Brain/drug effects , Brain/metabolism , Lithium/pharmacology , Lithium/administration & dosage , Behavior, Animal/drug effects , Drug Administration Schedule , Lithium Compounds/pharmacology , Lithium Compounds/administration & dosage
13.
Gen Physiol Biophys ; 43(3): 231-242, 2024 May.
Article in English | MEDLINE | ID: mdl-38774923

ABSTRACT

Vascular endothelial cell functions affect lower extremity arteriosclerosis obliterans (LEASO), while alpha-2-macroglobulin (A2M) and CCCTC-binding factor (CTCF) are closely related to the function of such cells. This paper aims to identify the influences of CTCF on vascular endothelial cells in LEASO by regulating A2M. A rat model of LEASO was established to measure intima-media ratio, blood lipid, and inflammatory factor levels. By constructing LEASO cell models, cell viability and apoptosis were assayed, while autophagy-related proteins, CTCF and A2M levels in femoral artery tissues and HUVECs were determined. The transcriptional regulation of CTCF on A2M was verified. In LEASO rat models, femoral artery lumen was narrowed and endothelial cells were disordered; levels of total cholesterol, IL-1, and TNF-α enhanced, and HDL-C decreased, with strong expression of A2M and low expression of CTCF. The viability of ox-LDL-treated HUVECs was decreased, together with higher apoptosis, lower LC3II/I expression, and higher p62 expression, which were reversed by sh-A2M transfection. Overexpression of CTCF inhibited A2M transcription, promoted the viability and autophagy of HUVECs, and decreased apoptosis. Collectively, CTCF improves the function of vascular endothelial cells in LEASO by inhibiting A2M transcription.


Subject(s)
Arteriosclerosis Obliterans , CCCTC-Binding Factor , Human Umbilical Vein Endothelial Cells , Rats , CCCTC-Binding Factor/metabolism , Animals , Humans , Arteriosclerosis Obliterans/metabolism , Male , Human Umbilical Vein Endothelial Cells/metabolism , Endothelial Cells/metabolism , Transcription, Genetic , Rats, Sprague-Dawley , Lower Extremity/blood supply , Apoptosis , Pregnancy-Associated alpha 2-Macroglobulins/metabolism , Cell Survival , Autophagy
14.
FASEB J ; 38(10): e23677, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38775792

ABSTRACT

Although the use of Doxorubicin (Dox) is extensive in the treatment of malignant tumor, the toxic effects of Dox on the heart can cause myocardial injury. Therefore, it is necessary to find an alternative drug to alleviate the Dox-induced cardiotoxicity. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin, which is an active ingredient of Artemisia annua. The study investigates the effects of DHA on doxorubicin-induced cardiotoxicity and ferroptosis, which are related to the activation of Nrf2 and the regulation of autophagy. Different concentrations of DHA were administered by gavage for 4 weeks in mice. H9c2 cells were pretreated with different concentrations of DHA for 24 h in vitro. The mechanism of DHA treatment was explored through echocardiography, biochemical analysis, real-time quantitative PCR, western blotting analysis, ROS/DHE staining, immunohistochemistry, and immunofluorescence. In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes. In vitro, DHA attenuated oxidative stress and cardiomyocyte ferroptosis, activated Nrf2, promoted clearance of autophagosomes, and reduced lysosomal destruction. The changes of ferroptosis and Nrf2 depend on selective degradation of keap1 and recovery of lysosome. We found for the first time that DHA could protect the heart from the toxic effects of Dox-induced cardiotoxicity. In addition, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.


Subject(s)
Artemisinins , Autophagy , Cardiotoxicity , Doxorubicin , Ferroptosis , Myocytes, Cardiac , NF-E2-Related Factor 2 , Artemisinins/pharmacology , Animals , NF-E2-Related Factor 2/metabolism , Autophagy/drug effects , Doxorubicin/adverse effects , Doxorubicin/toxicity , Mice , Ferroptosis/drug effects , Cardiotoxicity/etiology , Cardiotoxicity/prevention & control , Cardiotoxicity/metabolism , Male , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Oxidative Stress/drug effects , Mice, Inbred C57BL , Cell Line , Rats
15.
J Neuroimmune Pharmacol ; 19(1): 23, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38775885

ABSTRACT

Hyperbilirubinemia is one of the most common occurrence in newborns and is toxic to the brain, resulting in neurological sequelae such as auditory impairment, with potential to evolve to chronic bilirubin encephalopathy and long-term cognitive impairment in adults. In the early postnatal period, neurogenesis is rigorous and neuroinflammation is detrimental to the brain. What are the alterations in neurogenesis and the underlying mechanisms of bilirubin encephalopathy during the early postnatal period? This study found that, there were a reduction in the number of neuronal stem/progenitor cells, an increase in microglia in the dentate gyrus (DG) and an inflammatory state in the hippocampus, characterized by increased levels of IL-6, TNF-α, and IL-1ß, as well as a decreased level of IL-10 in a rat model of bilirubin encephalopathy (BE). Furthermore, there was a significant decrease in the number of newborn neurons and the expression of neuronal differentiation-associated genes (NeuroD and Ascl1) in the BE group. Additionally, cognitive impairment was observed in this group. The administration of minocycline, an inhibitor of microglial activation, resulted in a reduction of inflammation in the hippocampus, an enhancement of neurogenesis, an increase in the expression of neuron-related genes (NeuroD and Ascl1), and an improvement in cognitive function in the BE group. These results demonstrate that microglia play a critical role in reduced neurogenesis and impaired brain function resulting from bilirubin encephalopathy model, which could inspire the development of novel pharmaceutical and therapeutic strategies.


Subject(s)
Hippocampus , Kernicterus , Microglia , Minocycline , Neurogenesis , Animals , Neurogenesis/drug effects , Neurogenesis/physiology , Microglia/drug effects , Microglia/metabolism , Rats , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Male , Minocycline/pharmacology , Disease Models, Animal , Rats, Sprague-Dawley , Inflammation/metabolism , Inflammation/pathology , Neuroinflammatory Diseases/drug therapy
16.
JCI Insight ; 9(9)2024 May 08.
Article in English | MEDLINE | ID: mdl-38716725

ABSTRACT

IgA nephropathy (IgAN) represents the main cause of renal failure, while the precise pathogenetic mechanisms have not been fully determined. Herein, we conducted a cross-species single-cell survey on human IgAN and mouse and rat IgAN models to explore the pathogenic programs. Cross-species single-cell RNA sequencing (scRNA-Seq) revealed that the IgAN mesangial cells (MCs) expressed high levels of inflammatory signatures CXCL12, CCL2, CSF1, and IL-34 and specifically interacted with IgAN macrophages via the CXCL12/CXCR4, CSF1/IL-34/CSF1 receptor, and integrin subunit alpha X/integrin subunit alpha M/complement C3 (C3) axes. IgAN macrophages expressed high levels of CXCR4, PDGFB, triggering receptor expressed on myeloid cells 2, TNF, and C3, and the trajectory analysis suggested that these cells derived from the differentiation of infiltrating blood monocytes. Additionally, protein profiling of 21 progression and 28 nonprogression IgAN samples revealed that proteins CXCL12, C3, mannose receptor C-type 1, and CD163 were negatively correlated with estimated glomerular filtration rate (eGFR) value and poor prognosis (30% eGFR as composite end point). Last, a functional experiment revealed that specific blockade of the Cxcl12/Cxcr4 pathway substantially attenuated the glomerulus and tubule inflammatory injury, fibrosis, and renal function decline in the mouse IgAN model. This study provides insights into IgAN progression and may aid in the refinement of IgAN diagnosis and the optimization of treatment strategies.


Subject(s)
Disease Progression , Glomerulonephritis, IGA , Macrophages , Single-Cell Analysis , Adult , Animals , Female , Humans , Male , Mice , Rats , Chemokine CXCL12/metabolism , Disease Models, Animal , Glomerular Filtration Rate , Glomerulonephritis, IGA/immunology , Glomerulonephritis, IGA/pathology , Interleukins , Macrophages/immunology , Macrophages/metabolism , Mesangial Cells/pathology , Mesangial Cells/metabolism , Mesangial Cells/immunology , Receptors, CXCR4/metabolism , Receptors, CXCR4/genetics , Rats, Wistar
17.
PLoS One ; 19(5): e0302906, 2024.
Article in English | MEDLINE | ID: mdl-38718039

ABSTRACT

Osteoarthritis is the most prevalent type of degenerative arthritis. It is characterized by persistent pain, joint dysfunction, and physical disability. Pain relief and inflammation control are prioritised during osteoarthritis treatment Mume Fructus (Omae), a fumigated product of the Prunus mume fruit, is used as a traditional medicine in several Asian countries. However, its therapeutic mechanism of action and effects on osteoarthritis and articular chondrocytes remain unknown. In this study, we analyzed the anti-osteoarthritis and articular regenerative effects of Mume Fructus extract on rat chondrocytes. Mume Fructus treatment reduced the interleukin-1ß-induced expression of matrix metalloproteinase 3, matrix metalloproteinase 13, and a disintegrin and metalloproteinase with thrombospondin type 1 motifs 5. Additionally, it enhanced collagen type II alpha 1 chain and aggrecan accumulation in rat chondrocytes. Furthermore, Mume Fructus treatment regulated the inflammatory cytokine levels, mitogen-activated protein kinase phosphorylation, and nuclear factor-kappa B activation. Overall, our results demonstrated that Mume Fructus inhibits osteoarthritis progression by inhibiting the nuclear factor-kappa B and mitogen-activated protein kinase pathways to reduce the levels of inflammatory cytokines and prevent cartilage degeneration. Therefore, Mume Fructus may be a potential therapeutic option for osteoarthritis.


Subject(s)
Cartilage, Articular , Chondrocytes , Interleukin-1beta , NF-kappa B , Osteoarthritis , Plant Extracts , Animals , Chondrocytes/drug effects , Chondrocytes/metabolism , Interleukin-1beta/metabolism , Rats , Cartilage, Articular/drug effects , Cartilage, Articular/metabolism , NF-kappa B/metabolism , Osteoarthritis/drug therapy , Osteoarthritis/metabolism , Osteoarthritis/pathology , Plant Extracts/pharmacology , Prunus/chemistry , Rats, Sprague-Dawley , Down-Regulation/drug effects , Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase 13/genetics , Collagen Type II/metabolism , Mitogen-Activated Protein Kinases/metabolism , Matrix Metalloproteinase 3/metabolism , Matrix Metalloproteinase 3/genetics , Fruit/chemistry , Aggrecans/metabolism , ADAMTS5 Protein/metabolism , ADAMTS5 Protein/genetics , Cells, Cultured , Male , MAP Kinase Signaling System/drug effects
18.
PLoS One ; 19(5): e0300292, 2024.
Article in English | MEDLINE | ID: mdl-38718051

ABSTRACT

The aim of the study was to investigate the effect of returning to a balanced diet combined with chromium picolinate (CrPic) or chromium nanoparticles (CrNPs) supplementation at a pharmacologically relevant dose of 0.3 mg/kg body weight on the expression level of selected genes and bone turnover markers in the blood and bones of rats fed an obese diet. The results of the study showed that chronic intake of a high-fat obesogenic diet negatively affects bone turnover by impairing processes of both synthesis and degradation of bones. The switch to a healthy diet proved insufficient to regulate bone metabolism disorders induced by an obesogenic diet, even when it was supplemented with chromium, irrespective of its form. Supplementation with CrPic with no change in diet stimulated bone metabolism only at the molecular level, towards increased osteoclastogenesis (bone resorption). In contrast, CrNPs added to the high-fat diet effectively regulated bone turnover by increasing both osteoblastogenesis and osteoclastogenesis, with these changes directed more towards bone formation. The results of the study suggest that unfavourable changes in bone metabolism induced by chronic intake of a high-fat diet can be mitigated by supplementation with CrNPs, whereas a change in eating habits fails to achieve a similar effect.


Subject(s)
Bone Remodeling , Chromium , Diet, High-Fat , Animals , Diet, High-Fat/adverse effects , Rats , Chromium/administration & dosage , Chromium/pharmacology , Male , Bone Remodeling/drug effects , Nanoparticles/chemistry , Dietary Fiber/pharmacology , Picolinic Acids/pharmacology , Picolinic Acids/administration & dosage , Dietary Supplements , Bone and Bones/metabolism , Bone and Bones/drug effects , Rats, Wistar , Metal Nanoparticles/chemistry , Metal Nanoparticles/administration & dosage , Osteogenesis/drug effects
19.
Sci Adv ; 10(19): eadl1230, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38718109

ABSTRACT

The spinal cord is crucial for transmitting motor and sensory information between the brain and peripheral systems. Spinal cord injuries can lead to severe consequences, including paralysis and autonomic dysfunction. We introduce thin-film, flexible electronics for circumferential interfacing with the spinal cord. This method enables simultaneous recording and stimulation of dorsal, lateral, and ventral tracts with a single device. Our findings include successful motor and sensory signal capture and elicitation in anesthetized rats, a proof-of-concept closed-loop system for bridging complete spinal cord injuries, and device safety verification in freely moving rodents. Moreover, we demonstrate potential for human application through a cadaver model. This method sees a clear route to the clinic by using materials and surgical practices that mitigate risk during implantation and preserve cord integrity.


Subject(s)
Spinal Cord Injuries , Spinal Cord , Animals , Spinal Cord/physiology , Rats , Spinal Cord Injuries/therapy , Spinal Cord Injuries/physiopathology , Humans , Electric Stimulation/methods , Electrodes, Implanted
20.
Sci Adv ; 10(19): eadl3549, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38718121

ABSTRACT

Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed after TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. In addition, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid cycle intermediates, enhance energy production, and restore glutathione redox balance. Our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis during cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.


Subject(s)
Mice, Knockout , Myocytes, Cardiac , Proline , Ventricular Remodeling , Animals , Proline/metabolism , Myocytes, Cardiac/metabolism , Mice , Rats , Proline Oxidase/metabolism , Proline Oxidase/genetics , Energy Metabolism , Myocardium/metabolism , Myocardium/pathology , Cardiomegaly/metabolism , Cardiomegaly/pathology , Cardiomegaly/etiology , Disease Models, Animal , Oxidation-Reduction , Male , Metabolic Reprogramming
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