The pathogenesis of Parkinson's disease is closely related to genetic factors. This article has systematically reviewed the research progress of molecular genetic mechanism on Parkinson's disease by focusing on the role of six high-penetrance pathogenic genes (SNCA, LRRK2, PRKN, PINK1, PARK7, and VPS35) and some risk genes (such as GBA1). These genetic variants eventually converge in three core pathogenic biological pathways, including lysosomal-autophagy pathway disorder, mitochondrial quality control disorder and α-synuclein metabolic abnormality. In-depth understanding of these molecular mechanisms is of great significance for the development of targeted therapy and realization of precision medicine for this disease.
Humans ; Parkinson Disease/metabolism* ; alpha-Synuclein/genetics* ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics* ; Genetic Predisposition to Disease ; Protein Kinases/genetics* ; Animals ; Glucosylceramidase/genetics* ; Ubiquitin-Protein Ligases/genetics*

To investigate the mechanism of action of Syngnathus extract in treating knee osteoarthritis of rats, forty-eight male SD rats were randomly divided into the blank group, model group, positive drug group, as well as low-dose, medium-dose, and high-dose groups of Syngnathus extract. The rat model of knee osteoarthritis was constructed by intra-articular injection of sodium iodoacetate. After successful modeling, celecoxib(18 mg·kg~(-1)·d~(-1)) and Syngnathus extract(0.4, 0.8, and 1.6 g·kg~(-1)·d~(-1)) were given in different groups by gavage intervention for two weeks. Hematoxylin-eosin(HE) staining was used to observe the histopathological changes of cartilage in knee joints, and enzyme-linked immunosorbent assay(ELISA) was used to detect the expression level of inflammatory factors in serum. Real-time fluorescence quantitative PCR, Western blot, and immunohistochemistry were used to detect the levels of phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target protein of rapamycin(mTOR) pathway-related mRNA and protein expression. The results showed that, comparied with the blank group, the cartilage surface of the knee joints of rats in the model group was uneven, with disorganized levels and defective cartilage tissue. The serum levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) and the mRNA levels of PI3K, Akt, and mTOR in cartilage tissue, as well as the protein expression levels of phosphorylated PI3K(p-PI3K)/PI3K, phosphorylated Akt(p-Akt)/Akt, phosphorylated mTOR(p-mTOR)/mTOR, and P62 were significantly increased. Beclin1 protein expression was decreased. Comparied with the model group, the number of chondrocytes in the knee joint of rats in each group of Syngnathus extract increased, and the arrangement of chondrocytes was relatively neat. The cartilage layer was restored, and the serum levels of IL-1β, IL-6, and TNF-α, as well as the mRNA expression levels of PI3K, Akt, and mTOR in cartilage tissue were significantly reduced. The protein expression levels of p-PI3K/PI3K, p-Akt/Akt, p-mTOR/mTOR, and P62 were significantly reduced in the rats in the middle-dose and high-dose groups of Syngnathus extract, and the Beclin1 protein expression was significantly increased. The protein expression levels of p-PI3K/PI3K, p-Akt/Akt, and P62 in rats in the low-dose group of Syngnathus extract were significantly reduced. In summary, Syngnathus extract may be used to treat knee osteoarthritis by inhibiting the expression of PI3K/Akt/mTOR signaling pathway, so as to alleviate the inflammatory response in the organism, enhance the autophagy activity of chondrocytes, and reduce the apoptosis of chondrocytes.
Animals ; TOR Serine-Threonine Kinases/genetics* ; Male ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/genetics* ; Rats ; Osteoarthritis, Knee/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Phosphatidylinositol 3-Kinases/genetics* ; Humans

This study explored the mechanism of Xiangsha Liujunzi Decoction(XSLJZD) in the treatment of functional dyspepsia(FD) based on inositol-requiring enzyme 1(IRE1)/apoptosis signal-regulating kinase 1(ASK1)/c-Jun N-terminal kinase(JNK) pathway-mediated autophagy in interstitial cells of Cajal(ICC). Forty-eight SPF-grade male SD suckling rats were randomly divided into a blank group and a modeling group, and the integrated modeling method(iodoacetamide gavage + disturbance of hunger and satiety + swimming exhaustion) was used to replicate the FD rat model. After the model replications were successfully completed, the rats were divided into a model group, high-dose, medium-dose, and low-dose groups of XSLJZD(12, 6, and 3 g·kg~(-1)·d~(-1)), and a positive drug group(mosapride of 1.35 mg·kg~(-1)·d~(-1)), and the intervention lasted for 14 days. The gastric emptying rate and intestinal propulsion rate of rats in each group were measured. The histopathological changes in the gastric sinus tissue of rats in each group were observed by hematoxylin-eosin(HE) staining. The ultrastructure of ICC was observed by transmission electron microscopy. The immunofluorescence double staining technique was used to detect the protein expression of phospho-IRE1(p-IRE1), TNF receptor associated factors 2(TRAF2), phospho-ASK1(p-ASK1), phospho-JNK(p-JNK), p62, and Beclin1 in ICC of gastric sinus tissue of rats in each group. Western blot was used to detect the related protein expression of gastric sinus tissue of rats in each group. Compared with those in the blank group, the rats in the model group showed decreased body weight, gastric emptying rate, and intestinal propulsion rate, and transmission electron microscopy revealed damage to the endoplasmic reticulum structure and increased autophagosomes in ICC. Immunofluorescence staining revealed that the ICC of gastric sinus tissue showed a significant elevation of p-IRE1, TRAF2, p-ASK1, p-JNK, and Beclin1 proteins and a significant reduction of p62 protein. Western blot revealed that the expression levels of relevant proteins in gastric sinus tissue were consistent with those of proteins in ICC. Compared with the model group, the body weight of rats in the high-dose and medium-dose groups of XSLJZD was increased, and the gastric emptying rate and intestinal propulsion rate were increased. Transmission electron microscopy observed amelioration of structural damage to the endoplasmic reticulum of ICC and reduction of autophagosomes, and the p-IRE1, TRAF2, p-ASK1, p-JNK, and Beclin1 proteins in the ICC of gastric sinus tissue were significantly decreased. The p62 protein was significantly increased. Western blot revealed that the expression levels of relevant proteins in gastric sinus tissue were consistent with those of proteins in ICC. XSLJZD can effectively treat FD, and its specific mechanism may be related to the inhibition of the expression of molecules related to the endoplasmic reticulum stress IRE1/ASK1/JNK pathway in ICC and the improvement of autophagy to promote gastric motility in ICC.
Animals ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Autophagy/drug effects* ; Rats ; Rats, Sprague-Dawley ; Interstitial Cells of Cajal/metabolism* ; Dyspepsia/physiopathology* ; Protein Serine-Threonine Kinases/genetics* ; MAP Kinase Kinase Kinase 5/genetics* ; MAP Kinase Signaling System/drug effects* ; Humans ; Endoribonucleases/genetics* ; Multienzyme Complexes

This study aims to evaluate the therapeutic effect of Alpiniae Oxyphyllae Fructus-Saposhnikoviae Radix(AOF-SR) in a diabetic kidney disease(DKD) mouse model, explore its potential mechanism in regulating the NOD-like receptor protein 3(NLRP3) inflammasome via phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR) signaling pathway, and provide new theoretical support for traditional Chinese medicine(TCM) intervention in DKD. Using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), the active ingredients and potential targets of AOF-SR were screened and its molecular mechanisms were investigated through molecular docking, molecular dynamics simulations, and experimental validation. The db/db mice were randomly divided into four groups: model group, low-dose AOF-SR group, high-dose AOF-SR group, and canagliflozin group. The db/m mice served as normal group. After one week of acclimatization, the mice underwent drug intervention. Starting from one week after treatment, body weight, blood glucose levels, and 24-hour urinary protein(24hUP) were measured every two weeks. After 13 weeks of administration, tissue collection and indicator detection were performed. Blood glucose, 24hUP, urinary microalbumin(mAlb), serum creatinine(Scr), and blood urea nitrogen(BUN) levels were determined. Pathological changes in kidney tissue were observed using hematoxylin-eosin(HE) staining. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of serum IL-1β, IL-18, and caspase-1, while RT-qPCR was employed to measure the mRNA expression levels of IL-1β, IL-18, caspase-1, and NLRP3. Western blot was used to assess the protein expression levels of NLRP3, PI3K, p-Akt, Akt, p-mTOR, and mTOR. Network pharmacology analysis indicated that wogonin, pinocembrin, hancinol, and kaempferol were the core compounds for drug treatment of the disease. Molecular docking and molecular dynamics simulations showed that core compounds, particularly wogonin, could specifically bind to PIK3R1, thereby regulating the PI3K/Akt/mTOR pathway. The experimental results indicated that both low and high doses of AOF-SR and canagliflozin significantly reduced blood glucose, 24hUP, mAlb, Scr, and BUN levels in db/db mice, while improving kidney pathological damage and inflammatory cell infiltration. Moreover, the treatments reduced the mRNA expression levels of caspase-1, IL-1β, and IL-18 in the kidneys of db/db mice, as well as the secretion of these factors in the serum. The drugs also inhibited the mRNA and protein expression levels of NLRP3 in the kidneys of db/db mice and decreased the protein levels of PI3K, p-Akt/Akt, and p-mTOR/mTOR. In conclusion, AOF-SR may improve kidney inflammation in DKD mice by regulating the PI3K/Akt/mTOR signaling pathway and inhibiting NLRP3 inflammasome activation.
Animals ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Signal Transduction/drug effects* ; Phosphatidylinositol 3-Kinases/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; Diabetic Nephropathies/metabolism* ; Inflammasomes/drug effects* ; Male ; Drugs, Chinese Herbal/chemistry* ; Humans ; Mice, Inbred C57BL

Osteoarthritis (OA) is the most common degenerative joint disease. Its pathological process is related to inflammatory response, chondrocyte apoptosis, and cartilage degeneration. Hippo-yes-associate protein(YAP) signaling pathway plays an important role in mediating organ size and tissue homeostasis. In recent years, the key effector protein YAP in the Hippo-YAP pathway has become a research hotspot in osteoarthritis. This article introduces the activation process of Hippo-YAP signaling pathway and the biological role of YAP. It reviews the progress of YAP in regulating osteoarthritis by influencing the proliferation and differentiation of mesenchymal stem cells and the proliferation, differentiation, and apoptosis of articular chondrocytes. It analyzed the problems encountered in YAP research in OA, introduces the research potential of YAP in other orthopedic diseases, and provides new ideas for subsequent research in Osteoarthritis.
Osteoarthritis/metabolism* ; Humans ; Signal Transduction ; Protein Serine-Threonine Kinases/physiology* ; Hippo Signaling Pathway ; YAP-Signaling Proteins ; Adaptor Proteins, Signal Transducing/physiology* ; Animals ; Transcription Factors ; Chondrocytes/cytology* ; Cell Cycle Proteins

Objective To study the impacts of curcumin on the proliferation, migration and cisplatin (DDP) resistance of bladder cancer cells by regulating the liver kinase B1-AMP activated protein kinase-microtubule-associated protein 1 light chain 3 (LKB1-AMPK-LC3) signaling pathway. Methods Human bladder cancer cell line T24 was cultured in vitro, and its DDP resistant T24/DDP cells were induced by cisplatin (DDP). After treating T24 and T24/DDP cells with different concentrations of curcumin, the optimal concentration of curcumin was screened by MTT assay. T24 cells were randomly grouped into control group, curcumin group, metformin group, and combination group of curcumin and metformin. After treatment with curcumin and LKB1-AMPK activator metformin, the proliferation, autophagy, migration, and apoptosis of T24 cells in each group were detected by MTT assay, monodansylcadavrine (MDC) fluorescence staining, cell scratch assay, and flow cytometry, respectively. Western blot was used to detect the expression of proteins related to LKB1-AMPK-LC3 signaling pathway in T24 cells of each group. T24/DDP cells were randomly assigned into control group, curcumin group, metformin group, and combination group of curcumin and metformin. Cells were treated with curcumin and metformin according to grouping and treated with different concentrations of DDP simultaneously. Then, the effect of curcumin on the DDP resistance coefficient of T24/DDP cells was detected by MTT assay. T24/DDP cells were randomly grouped into control group, DDP group, combination groups of DDP and curcumin, DDP and metformin, DDP, curcumin and metformi. After treatment with DDP, curcumin, and metformin, the proliferation, autophagy, migration, apoptosis, drug resistance, and the expression of proteins related to LKB1-AMPK-LC3 signaling pathway in T24/DDP cells of each group were detected with the same methods. Results Compared with the control group, the activity of T24 cells, relative number of autophagosomes, migration rate, Phosphorylated-LKB1 (p-LKB1)/LKB1, Phosphorylated-AMPK (p-AMPK)/AMPK, LC3II/LC3I, and the DDP resistance coefficient of T24/DDP cells in the curcumin group were lower, and the apoptosis rate of T24 cells was higher; the changes in various indicators in the metformin group were opposite to those in the curcumin group. Compared with the curcumin group, the activity of T24 cells, relative number of autophagosomes, migration rate, p-LKB1/LKB1, p-AMPK/AMPK, LC3II/LC3I, and the DDP resistance coefficient of T24/DDP cells in the combination group of curcumin and metformin were higher, and the apoptosis rate of T24 cells was lower. Compared with the control group, there were no obvious changes in various indicators of T24/DDP cells in the DDP group. Compared with the control group and DDP group, the viability of T24/DDP cells, relative number of autophagosomes, migration rate, P-glycoprotein (P-gp) protein expression, p-LKB1/LKB1, p-AMPK/AMPK, and LC3II/LC3I in the combination group of DDP and curcumin were lower, and the apoptosis rate of T24/DDP cells was higher; the changes in the above indicators in the combination group of DDP and metformin were opposite to those in the combination group of DDP and curcumin. Compared with the combination group of DDP and curcumin, the viability of T24/DDP cells, relative number of autophagosomes, migration rate, P-gp protein expression, p-LKB1/LKB1, p-AMPK/AMPK, and LC3II/LC3I in the combination group of DDP, curcumin and metformin were higher, and the apoptosis rate of T24/DDP cells was lower. Conclusion Curcumin can reduce the activity of LKB1-AMPK-LC3 signaling pathway, thereby inhibiting autophagy, proliferation and migration of bladder cancer cells, promoting their apoptosis, and weakening their resistance to DDP.
Humans ; Cisplatin/pharmacology* ; Curcumin/pharmacology* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects* ; Protein Serine-Threonine Kinases/genetics* ; AMP-Activated Protein Kinases/metabolism* ; Drug Resistance, Neoplasm/drug effects* ; Urinary Bladder Neoplasms/pathology* ; Cell Line, Tumor ; Cell Movement/drug effects* ; AMP-Activated Protein Kinase Kinases ; Microtubule-Associated Proteins/metabolism* ; Apoptosis/drug effects* ; Antineoplastic Agents/pharmacology* ; Metformin/pharmacology* ; Autophagy/drug effects*

Objective To investigate the effects and molecular mechanism of Homer protein homolog 1a (Homer 1a) overexpression on nerve injury in mice with traumatic brain injury (TBI). Methods Sixty male C57BL/6 mice were randomly divided into five groups: sham group, TBI group, empty lentivirus (Lv-NC) group, Homer 1a overexpression lentivirus (Lv-Homer 1a) group and Lv-Homer 1a + 740 Y-P group, with 12 mice in each group. The lentivirus was orthotopic injected into the cerebral cortex of mice 5 d before modeling, while 740 Y-P was injected intraperitoneally 1 d before modeling. The TBI model was established using the free-fall impact method, and the modified neurological severity scores (mNSS) of the mice was assessed 72 h post-surgery. The water content of brain tissue was quantified, and the histopathological damage and neuronal loss in brain tissue were assessed using HE staining and Nissl staining respectively. The formation of autophagosomes in brain tissue was observed by transmission electron microscopy. The protein expression levels of Homer 1a, microtubule-associated protein 1 light chain 3B (LC3B), Beclin 1, phosphatidylinositol 3-kinase (PI3K), phosphorylation PI3K(p-PI3K), protein kinase B (AKT), p-AKT, mammalian target of rapamycin (mTOR), and p-mTOR in brain tissue were detected by Western blot analysis. Results Compared to the sham group, the mice in the TBI group exhibited a significant increase in mNSS and cerebral water content. Moreover, severe brain tissue pathological damage was observed, accompanied by a substantial loss of neurons and an increase in autophagosome formation. The protein expressions of Homer 1a and Beclin 1, as well as the protein ratio of LC3B-II/LC3B-I, in brain tissues were significantly elevated, while the protein ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR were significantly reduced. Compared to the TBI group, the Lv-Homer 1a group exhibited reduced mNSS and brain water content. Additionally, there was an improvement in pathological brain tissue damage and neuron loss. Furthermore, there was an increase in autophagosome formation and expression of autophagy-related proteins, while the protein ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR were decreased. Compared to the Lv-Homer 1a group, the nerve injury in the Lv-Homer 1a+740 Y-P group was exacerbated, accompanied by a reduction in autophagosome formation and expression of autophagy-related proteins, while the PI3K/AKT/mTOR signaling pathway was activated. Conclusion Overexpression of Homer 1a effectively mitigates neurological damage in TBI mice, potentially through modulation of autophagy mediated by the PI3K/AKT/mTOR signaling pathway.
Animals ; TOR Serine-Threonine Kinases/genetics* ; Autophagy ; Brain Injuries, Traumatic/pathology* ; Male ; Proto-Oncogene Proteins c-akt/genetics* ; Phosphatidylinositol 3-Kinases/genetics* ; Homer Scaffolding Proteins/metabolism* ; Mice, Inbred C57BL ; Signal Transduction ; Mice

Mannose-binding lectin-associated serine protease 2(MASP-2) is a member of serine protease family and plays a crucial role in activating the complement lectin pathway. When mannose residues on the surface of a pathogen are recognized by mannose-binding lectins (MBL) or fibrinogen collagen (FCN), MASP-2 is activated. This activation then triggers the cleavage of C4 and C2 to form C3 convertase, thereby initiating the lectin pathway of the complement system. Numerous studies have demonstrated that MASP-2 gene polymorphisms and serum levels are closely related with various diseases, including tumors, infectious diseases, autoimmune diseases and so on. In this review, we summarize the relationships between MASP-2 and tumors, infectious diseases, autoimmune diseases. We aim to provide a theoretical basis for the early diagnosis, prognosis evaluation and clinical treatment of various diseases.
Humans ; Mannose-Binding Protein-Associated Serine Proteases/metabolism* ; Neoplasms/metabolism* ; Autoimmune Diseases/genetics* ; Animals ; Polymorphism, Genetic ; Communicable Diseases/genetics*

Objective To explore the role and mechanism of mammalian target of rapamycin (mTOR) in oxidized low-density lipoprotein (oxLDL)-induced ferroptosis in vascular smooth muscle cells (VSMCs). Methods A model of oxLDL-induced VSMC ferroptosis was established. VSMCs were co-treated with either the mTOR inhibitor rapamycin or the autophagy inducer carbonyl cyanide m-chlorophenylhydrazone (CCCP), followed by detection of autophagy and ferroptosis-related indexes. Quantitative real-time PCR and Western blot were used respectively to analyze the expression of mTOR, glutathione peroxidase 4 (GPX4), sequestosome 1 (p62), and microtubule-associated protein 1 light chain 3 (LC3). Flow cytometry was employed to assess VSMC death. C11 BODIPY fluorescent staining was used to measure cellular lipid peroxidation levels. Colorimetric assays were performed to determine the contents of malondialdehyde (MDA), ferrous ion (Fe²⁺) and glutathione (GSH). Results oxLDL significantly upregulated mTOR expression in VSMCs, while increasing p62 expression and reducing LC3 expression, thereby suppressing VSMC autophagy. Compared with oxLDL treatment alone, rapamycin co-treatment reversed oxLDL-induced VSMC ferroptosis, as characterized by reduced VSMC death, increased GPX4 expression and GSH contents, along with decreased MDA content, Fe²⁺ content and lipid peroxidation levels. Similarly, CCCP co-treatment activated autophagy characterized by reduced p62 expression and elevated LC3 expression, which subsequently alleviated oxLDL-induced ferroptosis, showing reduced VSMC death, increased GPX4 expressions and GSH contents, and decreased MDA content, Fe²⁺ content and lipid peroxidation levels. Moreover, mTOR inhibition by rapamycin significantly reversed the oxLDL-induced upregulation of p62 and downregulation of LC3. Conclusion mTOR may promote oxLDL-induced VSMC ferroptosis by suppressing autophagy.
Ferroptosis/drug effects* ; Lipoproteins, LDL/metabolism* ; TOR Serine-Threonine Kinases/physiology* ; Autophagy/drug effects* ; Muscle, Smooth, Vascular/metabolism* ; Animals ; Rats ; Myocytes, Smooth Muscle/cytology* ; Cells, Cultured ; Lipid Peroxidation/drug effects* ; Sequestosome-1 Protein/genetics* ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism* ; Microtubule-Associated Proteins/genetics* ; Sirolimus/pharmacology*

OBJECTIVES: To explore the protective effect of vitexin-4 ″-O-glucoside (VOG) against acetaminophen-induced acute liver injury in mice and its underlying mechanism. METHODS: C57BL/6 mice were randomly divided into 4 groups: normal control group, model control group, low-dose group of VOG (30 mg/kg), and high-dose group of VOG (60 mg/kg). Acute liver injury was induced by intraperitoneal injection of acetaminophen (500 mg/kg). VOG was administrated by gavage 2 h before acetaminophen treatment in VOG groups. The protective effect of VOG against acute liver injury was evaluated by detecting alanine transaminase (ALT), aspartate transaminase (AST) levels and hematoxylin and eosin staining. The malondialdehyde (MDA) content, superoxide dismutase (SOD) and catalase (CAT) activity in liver were detected to evaluate the hepatic oxidative stress. The expression levels of tumor necrosis factor (TNF)-α, Il-1β, and Il-6 in liver were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression levels of phosphorylated c-jun N-terminal kinase (JNK)/JNK, phosphorylated p38/p38, inositol-requiring enzyme 1 alpha (IRE-1α), X-box binding protein 1s (XBP1s), and glucose-regulated protein 78 (GRP78) in liver were detected by Western blotting. An endoplasmic reticulum stress model was established in AML-12 cells using tunicamycin. Cell viability was assessed using the CCK-8 assay, and the degree of cell damage was detected by lactate dehydrogenase (LDH) assay. The gene expression levels of Ire-1α, Xbp1s, and Grp78 in the cells were detected using qRT-PCR. RESULTS: In the animal experiments, compared with the model control group, VOG significantly improved plasma ALT and AST levels, liver MDA content, as well as SOD and CAT activities. VOG also reduced the expression levels of Tnf-α, Il-1β, and Il-6 in the liver, and improved protein phosphorylation levels of JNK and p38, as well as the protein expression levels of IRE-1α, XBP1s, and GRP78. In cell experiments, VOG pretreatment enhanced cell viability, reduced LDH release and decreased the mRNA expression of Ire-1α, Xbp1s, and Grp78. CONCLUSIONS VOG can suppress inflammation and oxidative stress, and alleviate acetaminophen-induced acute liver injury in mice by suppressing endoplasmic reticulum stress and modulating the MAPK signaling pathway.
Animals ; Endoplasmic Reticulum Chaperone BiP ; Mice ; Acetaminophen/adverse effects* ; Mice, Inbred C57BL ; Chemical and Drug Induced Liver Injury/prevention & control* ; Glucosides/therapeutic use* ; Oxidative Stress/drug effects* ; Male ; Apigenin/therapeutic use* ; Liver/drug effects* ; Tumor Necrosis Factor-alpha/metabolism* ; Endoplasmic Reticulum Stress/drug effects* ; X-Box Binding Protein 1 ; Endoribonucleases/metabolism* ; Interleukin-1beta/metabolism* ; Interleukin-6/metabolism* ; Protein Serine-Threonine Kinases