Naringenin modulates oxidative stress and lipid metabolism: Insights from network pharmacology, mendelian randomization, and molecular docking.

Background: Previous studies have demonstrated that naringenin possesses lipid-lowering effects; however, the underlying mechanisms, particularly its specific molecular targets, remain uncertain. Methods: Using bioinformatics, three traditional Chinese medicine databases and one human disease database were integrated to establish two naringenin-target-hyperlipidemia modules: naringenin-oxidative stress (OS) and naringenin-lipid metabolism (LM). Data on 1,850 proteins from 1,871 genetic instruments were sourced from seven previous studies. Using Mendelian randomization based on data from the Integrative Epidemiology Unit genome-wide association study (case, n = 5,153; control, n = 344,069), we identified potential drug targets that were subsequently validated in the UK Biobank (396,565 individuals) and FinnGen (412,181 individuals) cohorts. Using molecular docking and molecular dynamics simulation to verify the binding ability of naringenin and causal protein. Results: In plasma, every standard deviation increase in apolipoprotein B (APOB) was associated with an increased risk of hyperlipidemia (odds ratio [OR] = 9.37, 95% confidence interval [CI], 5.12-17.12; P = 3.58e-13; posterior probability of hypothesis 4 [PPH4] = 0.997), and the same was observed for proprotein convertase subtilisin/kexin type 9 (OR = 1.81, 95% CI, 1.51-2.16; P = 6.87e-11; PPH4 = 1) and neurocan (OR = 2.34, 95% CI, 1.82-3.01; P = 4.09e-11; PPH4 = 0.932). The intersection of two modules and Mendelian randomization result identified APOB as a key regulatory target of naringenin in the treatment of hyperlipidemia. The binding energy between naringenin and APOB was determined to be -7.7 kcal/mol. Additionally, protein-protein interactions and protein-disease networks were analyzed to uncover potential connections between proteins and hyperlipidemia. Conclusion: This Mendelian randomization-based combined analysis offers a robust framework for elucidating the pharmacological effects of naringenin and identifying candidate proteins for further investigation in the context of hyperlipidemia treatment.

Plexiform schwannomas of the sciatic nerve:a case report and review of the literature.

Background: Schwannomas grow slowly, mainly in the head and spine. The extremities schwannomas are rare and easily missed, particularly in patients who also have lumbar disc herniation in addition to sciatic schwannomas. We present a unique case of sciatic schwannoma , which has been considered as a lumbar disease in the past until an MRI of the thigh. Case presentation: A 43-year-old female complained of pain in her low back and left thigh for 10 years. Physical examination showed that her left thigh was swollen and positive Tinel sign. On MRI, we found a series of tumors suspected of schwannomas at the back of her left thigh. After obtaining the patient's consent, we performed intracapsular excision of her tumors. Histological examination of the tumors were consistent with plexiform schwannomas. The patient recovered well after operation and there was no sign of nerve injury or recurrence after follow-up for 11 months. We searched the Pubmed database and found 31 published reports about sciatic schwannomas. Conclusions: Sciatic schwannomas usually occur in middle-aged women, and the main symptom is pain. In addition to palpation, we should pay attention to Tinel sign during physical examination. MRI is very helpful for diagnosis, but histological examination is the only way to make a final diagnosis. Intracapsular resection is the best method for the treatment of schwannomas, although there is still the possibility of recurrence after operation.

Nephro-protective effect of Daphnetin in hyperoxaluria-induced rat renal injury via alterations of the gut microbiota.

It is well proved that hyperoxaluria induces the renal injury and finally causes the end stage kidney disease. Daphnetin (coumarin derivative) already confirmed renal protective effect in renal model, but hyperoxaluria protective effect still unexplore. The objective of this research was to scrutinize the renal protective effect of daphnetin against ethylene glycol (GC)-induced hyperoxaluria via altering the gut microbiota. GC (1% v/v) was used for the induction of hyperoxaluria in the rats and the rats were received the oral administration of daphnetin (5, 10 and 15 mg/kg). The body and renal weight were assessed. Urine, renal, inflammatory cytokines, antioxidant, inflammatory parameters, and gut microbiota were appraised. Daphnetin effectually improved the body weight and reduced the renal weight. Its also remarkably boosted the magnesium, calcium, citrate level and suppressed the level of uric acid and oxalate formation. Daphnetin significantly (p < .001) ameliorate the level of urinary kidney injury molecule 1 (KIM-1), blood urea nitrogen (BUN), urea, serum creatinine (Scr), neutrophil gelatinase-associated lipocalin (NGAL) and uric acid along with inflammatory cytokines and inflammatory mediators. Daphnetin considerably repressed the malonaldehyde (MDA) level, protein carbonyl and improved the level of glutathione reductase (GR), superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT). Daphnetin treatment considerably altered the microbial composition of different bacteria at phylum, genus and family level. Daphnetin significantly suppressed the Firmicutes relative abundance and boosted the Bacteroidetes relative abundance. Our result clearly indicated that daphnetin remarkably ameliorates the GC induced hyperoxaluria in rats via altering the oxidative stress, inflammatory reaction and gut microbiota. PRACTICAL APPLICATION: Nephrotoxicity is a serious health disease worldwide. We induce the renal toxicity in the experimental rats using the ethylene glycol and scrutinized the renal protective effect of daphnetin. Daphnetin considerably suppress the renal, urine parameters. For estimation the underlying mechanism, we estimated the gut microbiota in all group rats. Daphnetin remarkably altered the level of gut microbiota and suggesting the renal protective effect.

Plasma periostin as a biomarker of osteoporosis in postmenopausal women with type 2 diabetes.

INTRODUCTION: Periostin, as an emerging biomarker, is involved in multiple steps in bone metabolism. This study aimed to investigate the correlation between periostin levels and bone mineral density as well as bone turnover markers in postmenopausal women with type 2 diabetes (T2DM). MATERIALS AND METHODS: This study was a cross-sectional study that included 164 postmenopausal women with T2DM as study subjects and 32 age-matched nondiabetic postmenopausal women with normal bone mineral density (BMD) as healthy control subjects. A total of 164 subjects with T2DM were then divided into three groups according to BMD: the normal BMD group (n = 29), the osteopenia group (n = 70), and the osteoporosis group (n = 65). The clinical data of all subjects along with the relevant biochemical parameter data were collected. Plasma periostin was detected using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Plasma periostin levels were significantly increased in T2DM patients with normal BMD compared with healthy controls (p < 0.05). In the diabetic group, plasma periostin levels were significantly elevated with decreased BMD, were positively correlated with osteocalcin levels (r = 0.162, p = 0.039) and were inversely associated with femoral neck BMD (r = - 0.308, p < 0.001) and total femur BMD (r = - 0.295, p < 0.001). In the case of chronic complications, periostin levels were slightly increased in individuals with complications of diabetic retinopathy, diabetic nephropathy and fracture (p > 0.05). CONCLUSIONS: The current study demonstrated that plasma periostin levels were significantly associated with BMD in patients with T2DM, and periostin might act as a novel biochemical marker of osteoporosis in postmenopausal women with type 2 diabetes.

Protective effect of apigenin on d-galactosamine/LPS-induced hepatocellular injury by increment of Nrf-2 nucleus translocation.

Apigenin has a protective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced mouse liver injury through the increments of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and peroxisome proliferator-activated receptor γ (PPARγ) expressions, but its exact mechanisms are still uncertain. This study aimed to further verify its protective effect on hepatocytes and to determine its target of action. The results showed that after treatment of D-GalN/LPS-stimulated hepatocytes with 2.5-20 µM apigenin, the supernatant alanine aminotransferase, aspartate aminotransferasein, tumor necrosis factor-α, and malondialdehyde levels and intracellular nuclear factor-κB protein expression were decreased, while the supernatant superoxide dismutase (SOD) and catalase (CAT) levels, intracellular PPARγ and inhibitor of kappa B-alpha protein expressions, and nucleus Nrf-2 protein expression were increased. After pretreatment with BML-111 or GW9662, the apigenin-induced nucleus Nrf-2 or intracellular PPARγ protein expressions were completely inhibited, respectively, but the both pretreatment differently affected the protective effect of apigenin on hepatocytes. The former completely canceled the protective effect, whereas the latter did not. These findings further demonstrate that apigenin can exert a protective effect on D-GalN/LPS-induced hepatocellular injury via the increment of Nrf-2 nucleus translocation, which may increase the SOD and CAT levels and PPARγ protein expression and subsequently inhibit the inflammatory response.

PPARα/γ antagonists reverse the ameliorative effects of osthole on hepatic lipid metabolism and inflammatory response in steatohepatitic rats.

Our previous studies have indicated that osthole may ameliorate the hepatic lipid metabolism and inflammatory response in nonalcoholic steatohepatitic rats, but the underlying mechanisms remain unclear. This study aimed to determine whether the effects of osthole were mediated by the activation of hepatic peroxisome proliferator-activated receptor α/γ (PPARα/γ). A rat model with steatohepatitis was induced by orally feeding high-fat and high-sucrose emulsion for 6 weeks. These experimental rats were then treated with osthole (20 mg/kg), PPARα antagonist MK886 (1 mg/kg) plus osthole (20 mg/kg), PPARγ antagonist GW9662 (1 mg/kg) plus osthole (20 mg/kg) and MK886 (1 mg/kg) plus GW9662 (1 mg/kg) plus osthole (20 mg/kg) for 4 weeks. The results showed that after osthole treatment, the hepatic triglycerides, free fatty acids, tumor necrosis factor-α, monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-8 and liver index decreased by 52.3, 31.0, 32.4, 28.9, 36.3, 29.3 and 29.9%, respectively, and the score of steatohepatitis also decreased by 70.0%, indicating that osthole improved the hepatic steatosis and inflammation. However, these effects of osthole were reduced or abrogated after simultaneous addition of the specific PPARα antagonist MK886 or/and the PPARγ antagonist GW9662, especially in the co-PPARα/γ antagonists-treated group. Importantly, the osthole-induced hepatic expressions of PPARα/γ proteins were decreased, and the osthole-regulated hepatic expressions of lipogenic and inflammatory gene proteins were also reversed by PPARα/γ antagonist treatment. These findings demonstrated that the ameliorative effect of osthole on nonalcoholic steatohepatitis was mediated by PPARα/γ activation, and osthole might be a natural dual PPARα/γ activator.

Apigenin inhibits d-galactosamine/LPS-induced liver injury through upregulation of hepatic Nrf-2 and PPARγ expressions in mice.

Apigenin is a natural flavonoid compound widely distributed in a variety of vegetables, medicinal plants and health foods. This study aimed to examine the protective effect of apigenin against d-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced mouse liver injury and to investigate the potential biochemical mechanisms. The results showed that after oral administration of apigenin 100-200 mg/kg for 7 days, the levels of serum alanine aminotransferase and aspartate aminotransferase were decreased, and the severity of liver injury was alleviated. Importantly, apigenin pretreatment increased the levels of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and peroxisome proliferator-activated receptor γ (PPARγ) protein expressions as well as superoxide dismutase, catalase, glutathione S-transferase and glutathione reductase activities, decreased the levels of hepatic nuclear factor-κB (NF-κB) protein expression and tumor necrosis factor-α. These findings demonstrated that apigenin could prevent the D-GalN/LPS-induced liver injury in mice, and its mechanisms might be associated with the increments of Nrf-2-mediated antioxidative enzymes and modulation of PPARγ/NF-κB-mediated inflammation.

Apigenin protects against alcohol-induced liver injury in mice by regulating hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression.

Alcohol is a major cause of liver injury, and there are currently no ideal pharmacological reagents that can prevent or reverse this disease. Apigenin is one of the most common flavonoids present in numerous plants and has many beneficial effects. But whether or not apigenin may protect against alcohol-induced liver injury remains unknown. Our aim was to examine the effect and potential mechanisms. The experimental mice were given 56% erguotou wine or simultaneously given apigenin 150-300 mg/kg by gavage for 30 days. The results showed that in the apigenin-treated mice, the expression of hepatic cytochrome P450 2E1 (CYP2E1) and nuclear factor kappa B proteins as well as contents of hepatic malondialdehyde and tumor necrosis factor-alpha were reduced, while the levels of hepatic reduced glutathione, glutathione reductase, glutathione peroxidase, and glutathione S-transferase were increased, especially in the 300 mg/kg group. A significant change in hepatic steatosis was also observed in the apigenin 300 mg/kg group. Apigenin pretreatment could increase the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase-1 proteins, and decrease the expression of hepatic sterol regulatory element binding protein-1c, fatty acid synthase, and diacylglycerol acyltransferase proteins. These findings demonstrated that apigenin might exert a protective effect on alcohol-induced liver injury, and its mechanisms might be related to the regulations of hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression.

Antinociceptive effect of intrathecal microencapsulated human pheochromocytoma cell in a rat model of bone cancer pain.

Human pheochromocytoma cells, which are demonstrated to contain and release met-enkephalin and norepinephrine, may be a promising resource for cell therapy in cancer-induced intractable pain. Intrathecal injection of alginate-poly (l) lysine-alginate (APA) microencapsulated human pheochromocytoma cells leads to antinociceptive effect in a rat model of bone cancer pain, and this effect was blocked by opioid antagonist naloxone and alpha 2-adrenergic antagonist rauwolscine. Neurochemical changes of cerebrospinal fluid are in accordance with the analgesic responses. Taken together, these data support that human pheochromocytoma cell implant-induced antinociception was mediated by met-enkephalin and norepinephrine secreted from the cell implants and acting at spinal receptors. Spinal implantation of microencapsulated human pheochromocytoma cells may provide an alternative approach for the therapy of chronic intractable pain.