Modifiable risk factors for mild cognitive impairment among cognitively normal community-dwelling older adults: A systematic review and meta-analysis.

Although numerous studies have investigated modifiable risk factors for mild cognitive impairment (MCI) among community-dwelling seniors, no meta-analysis has summarized these findings. Five databases were searched from January 1, 2000, to December 30, 2023. The protocol was registered with PROSPERO. Data were extracted and reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant meta-analyses of modifiable risk factors were performed. The evidence of each factor was assessed by the GRADE for cohort studies. Of 16,651 citations, 87 studies involving 225,584 community-dwelling seniors were included. Fourteen meta-analyses involving 20 studies with 44,199 participants were performed. The analyses revealed low-to-moderate-quality evidence supporting that diabetes, 2 or more comorbidities, anxiety, apathy, depressive symptoms, and physical frailty were risk factors for incident MCI in older adults. Conversely, hypertension, agitation, and irritability might not be risk factors. Additionally, moderate-quality evidence supports the protective effect of engaging in cognitive-demanding activities on the onset of MCI. Collectively, this study constitutes the first extensive compilation of evidence regarding the various risk factors for the development of MCI in older adults. Our findings hold significant potential to guide the formulation of prevention and management strategies to either prevent or potentially reverse the onset of MCI.

Comparative effectiveness of non-pharmacological interventions on sleep in individuals with chronic musculoskeletal pain: A systematic review with network meta-analysis.

This network meta-analysis aimed to estimate the comparative effectiveness of non-pharmacological interventions on sleep in individuals with chronic musculoskeletal pain. Seven databases were systematically searched up to February 2023. A random-effects network meta-analysis in a frequentist framework was performed to synthesize continuous data as standardized mean differences (SMD) along with a 95% confidence interval (95% CI). A total of 15,641 records were identified, and 107 randomized controlled trials involving 8,121 participants were included. Of 14 identified interventions, eight were significantly more effective than passive control in improving sleep quality at immediate post-intervention (SMDs = 0.67-0.74), with cognitive behavioral therapy (CBT) being the most effective treatment (SMD = 0.74, 95% CI: 0.45-1.03). Only CBT demonstrated sustained effects at short-term (SMD = 1.56; 95% CI: 0.62-2.49) and mid-term (SMD = 1.23; 95% CI: 0.44-2.03) follow-ups. Furthermore, CBT significantly improved subjective (SMD = 0.64; 95% CI: 0.25-1.03) and objective (SMD = 0.30; 95% CI: 0.01-0.59) sleep efficiency compared with passive control at immediate post-intervention. Our findings support CBT as the first-line treatment for improving sleep in individuals with chronic musculoskeletal pain, given its superior effectiveness across multiple sleep outcomes and its sustainable effects until mid-term follow-up. However, the certainty of evidence for these interventions in improving sleep quality was very low to low.

The differential effects of sleep deprivation on pain perception in individuals with or without chronic pain: A systematic review and meta-analysis.

Many experimental sleep deprivation (SD) studies were conducted to clarify the causal relationship between sleep and pain. This systematic review and meta-analysis aimed to update the evidence regarding the effects of different experimental SD paradigms on various pain outcomes. Five databases were searched from their inception to June 2022. Separate random-effects models were used to estimate the pooled effect sizes (ES) of different experimental SD paradigms on various pain outcomes. Thirty-one studies involving 699 healthy individuals and 47 individuals with chronic pain were included. For healthy individuals, limited evidence substantiated that total SD significantly reduced pain threshold and tolerance (ES 0.74-0.95), while moderate evidence supported that partial SD significantly increased spontaneous pain intensity (ES 0.30). Very limited to moderate evidence showed that sleep fragmentation significantly increased peripheral and central sensitization in healthy individuals (ES 0.42-0.79). Further, there was very limited evidence that total or partial SD significantly aggravated spontaneous pain intensity in people with chronic pain. Our results accentuated that different SD paradigms differentially increased subjective pain intensity and worsened peripheral/central pain sensitization in healthy individuals, whereas the corresponding findings in people with chronic pain remain uncertain. Further rigorous studies are warranted to quantify their relationships in clinical populations.

Potential mechanisms underlying the accelerated cognitive decline in people with chronic low back pain: A scoping review.

A growing body of evidence has shown that people with chronic low back pain (CLBP) demonstrate significantly greater declines in multiple cognitive domains than people who do not have CLBP. Given the high prevalence of CLBP in the ever-growing aging population that may be more vulnerable to cognitive decline, it is important to understand the mechanisms underlying the accelerated cognitive decline observed in this population, so that proper preventive or treatment approaches can be developed and implemented. The current scoping review summarizes what is known regarding the potential mechanisms underlying suboptimal cognitive performance and cognitive decline in people with CLBP and discusses future research directions. Five potential mechanisms were identified based on the findings from 34 included studies: (1) altered activity in the cortex and neural networks; (2) grey matter atrophy; (3) microglial activation and neuroinflammation; (4) comorbidities associated with CLBP; and (5) gut microbiota dysbiosis. Future studies should deepen the understanding of mechanisms underlying this association so that proper prevention and treatment strategies can be developed.

Simultaneous characterization of multiple Psoraleae Fructus bioactive compounds in rat plasma by ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry for application in sex-related differences in pharmacokinetics.

A method for the simultaneous quantification of 13 bioactive compounds (psoralen, isopsoralen, isobavachin, bakuchalcone, neobabaisoflavone, bavachin, corylin, psoralidin, isobavachalcone, bavachinin, corylifol A, bavachalcone, and bakuchiol) by ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry has been developed and validated in rat plasma. Osthol was used as an internal standard and plasma samples were pretreated with one-step liquid-liquid extraction. These analytes were separated using a gradient mobile phase system of water and acetonitrile at a flow rate of 0.2 mL/min on a reverse-phase C18 column and analyzed in the selected multiple reactions monitoring mode. All calibration curves were linear (r > 0.9952) over the tested ranges. The intra- and interday accuracy and precisions of these analytes at three different concentration levels were within the acceptable limits of <15% at all concentrations. The mean recoveries of these analytes at three concentrations were more than 60.2% and the matrix effects were in the range of 85-115%. Stability studies proved that the analytes were stable under the tested conditions. The developed method was applied to evaluating the pharmacokinetic study of 13 bioactive compounds after oral administration of Psoraleae Fructus in rat of different genders. Some active compounds in Psoraleae Fructus had sex-related pharmacokinetics.

Isopsoralen induces different subchronic toxicities and metabolomic outcomes between male and female Wistar rats.

Isopsoralen is a major active and quality-control component of Fructus Psoraleae, but lacks a full safety evaluation. We evaluated the oral toxicity of isopsoralen in Wistar rats treated for 3 months at doses of 0, 3.5, 7.0, and 14 mg/kg. Additionally, the plasma metabolomics of isopsoralen in male and female rats treated for 3 months at doses of 0 and 14 mg/kg were investigated by gas chromatography-mass spectrometry. Many abnormalities were observed in the isopsoralen-treated rats, including suppression of body weight gain, and changes in serum biochemical parameters and visceral coefficients. Histopathological changes in liver, pancreatic, and reproductive system tissues were also observed in the isopsoralen-treated rats. The metabolomic analyses showed alterations in many metabolites (19 in female rats; 28 in male rats) after isopsoralen administration. The significant changes in these metabolites revealed metabolomic alterations in the isopsoralen-treated rats, especially in amino acid metabolism regardless of sex, including phenylalanine, tyrosine, and tryptophan biosynthesis and glycine, serine, and threonine metabolism. Furthermore, fatty acid metabolism comprised the main affected pathways in female rats, while lipid metabolism and energy metabolism were the main affected pathways in male rats.

A new hypoglycemic mechanism of catalpol revealed by enhancing MyoD/MyoG-mediated myogenesis.

AIMS: Enhancing myogenesis has been identified as a possible target to improve insulin sensitivity and protect against metabolic diseases. Catalpol, an iridoid glycoside, has been shown to exert a hypoglycaemic effect by improvement of insulin sensitivity; however, the underlying mechanism remains unknown. In this study, we tested whether catalpol has the potential to improve insulin sensitivity by augmenting myogenesis. MAIN METHODS: We examined the hypoglycaemic mechanism of catalpol in db/db mice and C2C12 cells. db/db mice were treated with catalpol (200 mg/kg) for 8 consecutive weeks. Serum analysis, skeletal muscle performance and histology, and gene and protein expression were performed. In vitro glucose uptake, gene and protein expression were determined, and small interfering RNA was used to identify the underlying hypoglycaemic mechanism of catalpol. KEY FINDINGS: In this study, we tested whether catalpol has the potential to improve skeletal insulin sensitivity by augmenting myogenesis, in which we found that, catalpol treatment in db/db mice lowered blood glucose and improved insulin sensitivity via activation of phosphatidylinositol­3­Kinase (PI3K)/protein kinase B (AKT) pathway. Moreover, catalpol-treated mice exhibited enhanced myogenesis, as evidenced by increased myogenic differentiation (MyoD), myogenin (MyoG) and myosin heavy chain (MHC) expressions. The in vitro experimental results showed that both catalpol and metformin enhanced glucose uptake via activation of PI3K/AKT pathway. However, unlike metformin, the PI3K/AKT pathway activation by catalpol was dependent on enhanced MyoD/MyoG-mediated myogenesis. SIGNIFICANCE: Improvement of insulin sensitivity by enhancing MyoD/MyoG-mediated myogenesis may constitute a new therapeutic approach for treating type 2 diabetes.

Glycyrrhetic Acid Derivative TY501 Protects Against Lithocholic Acid-Induced Cholestasis.

The aim of the study is to investigate the protective effects of TY501 against LCA-induced cholestasis in mice and to explore the potential mechanisms. It was demonstrated that TY501(5, 15 or 45 mg/kg, i.g.) can markedly reduced the level of ALT, AST and ALP which increased by LCA treatment. Meanwhile, TY501 also lowered total bile acids, total bilirubin and total cholesterol levels in serum. Furthermore, TY501 can protect HepG2 cell cultures from LCA-induced cytotoxicity. RT-PCR and Western Blot analysis showed that TY501 recovered the expression of BSEP, MRP2 and NTCP which were down-regulated by LCA. Moreover, mRNA and protein of FXR was also observed in TY501 treated mice significantly accumulation in nucleus. Taken together, It can be concluded that TY501 exerted beneficial effects on LCA-induced cholestasis, possibly via activation of FXR mediated upregulation of BSEP, MRP2 and NTCP.

8-Methoxypsoralen disrupts MDR3-mediated phospholipids efflux and bile acid homeostasis and its relevance to hepatotoxicity.

Since its discovery in 1987, multidrug resistance 3 P-glycoprotein (MDR3) had recognized to play a crucial role in the translocation of phospholipids from the inner to outer leaflets of bile canalicular membranes. An increasing number of reports suggest that drug-mediated functional disruption of MDR3 is responsible for drug-induced cholestasis. 8-Methoxypsoralen (8-MOP) is used clinically to treat psoriasis, vitiligo and other skin disorders. However, psoralens safety for long-term use is a concern. In the current study, we evaluate 8-MOP's potential hepatotoxicity and effects on bile formation. Sprague Dawley (SD) rats were treated daily 200mg/kg or 400mg/kg of 8-MOP orally for 28 days. The result showed a prominent decrease in biliary phospholipids output, which associated with the down-regulation of MDR3. Elevated bile acid serum level and increased biliary bile acid outputs were observed in 8-MOP-treated groups. The disturbance of bile acid homeostasis was associated with changes in enzymes and proteins involved in bile acid synthesis, regulation and transport. Human liver cell line L02 was used to determine on the mRNA and protein levels of MDR3. Cells treated with 8-MOP reveled a decrease in fluorescent PC (phosphatidylcholine) secretion into the pseudocanaliculi (formed between adjacent cells) compared with untreated cells. Our investigation represent the first evidence that 8-MOP can induce cholestatic liver injury by disturbing MDR3-mediated phospholipids efflux and bile acid homeostasis.

Discovery of Flexible Naphthyltriazolylmethane-based Thioacetic Acids as Highly Active Uric Acid Transporter 1 (URAT1) Inhibitors for the Treatment of Hyperuricemia of Gout.

BACKGROUND: Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy. OBJECTIVE: The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor. METHODS: The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1. RESULTS: Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 µM and 0.094 µM, respectively, against human URAT1 vs 7.18 µM for lesinurad). CONCLUSION: Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane- bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the rigid naphthyltriazole skeleton.

Discovery of a Flexible Triazolylbutanoic Acid as a Highly Potent Uric Acid Transporter 1 (URAT1) Inhibitor.

In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a-1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 µM against human URAT1 for 1q vs 7.18 µM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.

[Study on hepatotoxicity of aqueous extracts of Polygonum multiflorum in rats after 28-day oral administration: cholestasis-related mechanism].

OBJECTIVE: To study the effect of aqueous extracts of Polygonum multiflorum (AEPM) on bile acid synthesis, metabolism and transfer-related molecules in rat liver and the hepatotoxicity-related mechanism of P. multiflorum. METHOD: Sprague-Dawley rats were orally administered with 30, 60 g x kg(-1) APEM once everyday for consecutively 28 days. At the end of the experiment, mRNA and protein expressions of hepatic MRP3, MRP2, BSEP, FXR and CYP7A1 were detected by Real-time PCR and Western blot RESULT: Compared with the normal group, the AEPM high dose group showed significant increases in mRNA expressions of hepatic MRP3 and BSEP of male rats (P < 0.05); AEPM high and low dose groups revealed a notable decrease in mRNA expressions of hepatic FXR (P < 0.05) and remarkable rises in mRNA expressions of hepatic MRP3, MRP2, BSEP, CYP7A1 among female rats (P < 0.05). According to the test results of western blot assay, AEPM high and low dose groups showed consistent changes in protein and mRNA expressions hepatic MRP3, MRP2, BSEP, FXR, CYP7A1. CONCLUSION: The 28 oral administration with AEPM in rats showed a certain effect on expressions of bile acid synthesis, metabolism and transfer-related proteins, as well as cholestatic or choleretic effects in the mRNA expression.

Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms.

AIM: α-Naphthylisothiocyanate (ANIT) is a well-characterized cholestatic agent for rats. The aim of this study was to examine whether resveratrol could attenuate ANIT-induced acute cholestasis and liver injury in rats. METHODS: SD rats were treated with resveratrol (15 or 30 mg/kg, ip) or a positive control drug ursodeoxycholic acid (100 mg/kg, po) for 5 consecutive days followed by a single dose of ANIT (60 mg/kg, po). Bile flow, and serum biochemical markers and bile constituents were measured 48 h after ANIT administration. Hepatic levels of oxidative repair enzymes (glutathione peroxidase, catalase and MnSOD), myeloperoxidase activity, TNF-α, IL-6 and ATP content, as well as the expression of liver transporter genes and proteins were assayed. RESULTS: ANIT exposure resulted in serious cholestasis and liver injury, as shown by marked neutrophil infiltration in liver, dramatically increased serum levels of ALT, AST, GGT, ALP, TBA, TBIL, IBIL and DBIL, and significantly decreased bile excretion and biliary output of GSH and HCO3(-). ANIT significantly increased TNF-α and IL-6 release and myeloperoxidase activity, decreased mitochondrial biogenesis in liver, but had little effect on hepatic oxidative repair enzymes and ATP content. Furthermore, ANIT significantly decreased the expression of Mrp2, FXR and Cyp7a1, markedly increased Mrp3 expression in liver. Pretreatment with resveratrol attenuated ANIT-induced acute cholestasis and liver injury, and other pathological changes. Pretreatment with ursodeoxycholic acid was less effective. CONCLUSION: Resveratrol effectively attenuates ANIT-induced acute cholestasis and liver injury in rats, possibly through suppression of neutrophil infiltration, as well as upregulation of expression of hepatic transporters and enzymes, thus decreasing accumulation of bile acids.

Potent tumor targeting drug release system comprising MMP-2 specific peptide fragment with self-assembling characteristics.

Self-assembling peptides are capable of forming a complex containing a cavity where cytotoxic agents can be wrapped in a self-assembling manner. These complexes are beneficial for improving the pharmacological properties and pharmacokinetics of cytotoxic agents, such as doxorubicin and paclitaxel. In the present study, this self-assembling feature was successfully integrated into a hexapeptide with matrix metalloproteinase (MMP)-2 specific targeting activity, producing a supramolecule possessing controlled drug release characteristics. The MMP-2 specific substrate fragment, PVGLIG, makes this supramolecule disassociate in the presence of MMP-2, and this system is considered to be a powerful tool for the treatment of tumors with high expression of MMP-2 or tumor metastasis. Our findings show that this modified self-assembling peptide with the PVGLIG fragment was able to significantly enhance specificity against HT1080 cells, a tumor cell line with high expression of MMP-2. In addition, residence time of the complex in blood was prolonged since paclitaxel was wrapped into the supramolecule. Our results suggest that the modified MMP-2 specific substrate, SAMTA7, could act as a controlled and sustained drug carrier for treatment of tumors with high expression of MMP-2 and for tumor metastasis.

Long-acting GLP-1 analogue in V-shaped conformation by terminal polylysine modifications.

Glucagon-like peptide-1 (GLP-1) possesses multiple physiological functions, which make it a potential drug candidate for the treatment of type 2 diabetes. However, its clinical application was limited severely by its short half-life in vivo. Therefore, stabilization of GLP-1 is critical for the use of this peptide in drug development. In this study, a novel GLP-1 derivative, VGLP1K6, processed a significantly prolonged half-life in vivo. Structural analysis using molecular dynamics simulations demonstrated that VGLP1K6 has a rigid V-shaped conformation resulting from the intrapeptide disulfide bond. The C-terminal polylysine residues of VGLP1K6 caused the vulnerable N-terminus of GLP-1 (HA-fragment) to reside within the pocket-like cavity of the peptide due to the intrahydrogen bonds. The structural analysis suggested that this structural alteration contributed to the remarkable prolonged half-life of VGLP1K6, which was approximately 70 h. In addition, VGLP1K6 induced better long-acting glucose tolerance and greater HbA1c reductions than GLP-1 in rodents. Our findings suggest that the GLP-1 derivative VGLP1K6 might be a possible potent antidiabetic drug for the treatment of type 2 diabetes mellitus.

Baicalin prevents Candida albicans infections via increasing its apoptosis rate.

BACKGROUND: These experiments were employed to explore the mechanisms underlying baicalin action on Candida albicans. METHODOLOGY AND PRINCIPAL FINDINGS: We detected the baicalin inhibition effects on three isotope-labeled precursors of (3)H-UdR, (3)H-TdR and (3)H-leucine incorporation into C. albicans using the isotope incorporation technology. The activities of Succinate Dehydrogenase (SDH), cytochrome oxidase (CCO) and Ca(2)(+)-Mg(2+) ATPase, cytosolic Ca(2+) concentration, the cell cycle and apoptosis, as well as the ultrastructure of C.albicans were also tested. We found that baicalin inhibited (3)H-UdR, (3)H-TdR and (3)H-leucine incorporation into C.albicans (P<0.005). The activities of the SDH and Ca(2)(+)-Mg(2+) ATPase of C.albicans in baicalin groups were lower than those in control group (P<0.05). Ca(2+) concentrations of C. albicans in baicalin groups were much higher than those in control group (P<0.05). The ratio of C.albicans at the G0/G1 stage increased in baicalin groups in dose dependent manner (P<0.01). There were a significant differences in the apoptosis rate of C.albicans between baicalin and control groups (P<0.01). After 12-48 h incubation with baicalin (1mg/ml), C. albicans shown to be markedly damaged under transmission electron micrographs. INNOVATION AND SIGNIFICANCE: Baicalin can increase the apoptosis rate of C. albicans. These effects of Baicalin may involved in its inhibiting the activities of the SDH and Ca(2)(+)-Mg(2+) ATPase, increasing cytosolic Ca(2+) content and damaging the ultrastructure of C. albicans.

[Study on hepatotoxicity of aqueous extracts of Polygonum multiforum in rats after 28-day oral administration-analysis on correlation of cholestasis].

OBJECTIVE: To observe the liver injury degree of SD rats after 28-day administration of aqueous extracts of Polygonum multiflorum (AEPM) and the correlation with cholestasis mechanism. METHOD: Adult SD rats were orally administered with 30, 60 g x kg(-1) of APEM once every day for 28 d. After 28 d, the general condition of rats such as weight were observed, liver function-related indicators were detected. Bile was collected to determine total bile acid output, flow rate and density and changes in major compositions. Their livers were weighed then sent for histopathological examination. RESULT: AEPM did not change the general conditions and weights of rats. From the results of the related indicators of liver function and cholestasis, AEPM did not change the contents of ALT and AST in serum, but high dose of AEPM can increase the contents of ALP, GGT and TBA in serum (P < 0.05, P < 0.01) and decrease the content of TBIL in serum (P < 0.05). And the contents of GGT in serum of low dose rats were increased (P < 0.05). The bile flow was not changed by AEPM, but bile compositions of high dose male rats were obviously changed (TG increase, TBIL decrease, TBA decrease). The weights of liver and ratio of liver of the high dose rats were increased but showed no statistical significance. Pathologic examination displayed that there were only small pieces of necrosis in livers of several rats, without any severe disease. CONCLUSION: AEPM can obviously injure bile duct epithelial cells, intervene liver cell functions and change bile compositions in rats, thus it is proved to induce cholestasis without severe liver injury.

Beneficial effects of colchicine on 17alpha-ethynylestradiol-induced cholestasis in rats.

Colchicine (CAS 64-86-8) is considered to have a hepatoprotective effect and play a role in biliary excretion. 17alpha-Ethynylestradiol (EE) (5 mg/kg, subcutaneously, daily, for 5 days) causes intrahepatic cholestasis by reducing both the influx and efflux of bile acid in hepatocytes, resulting in a decrease in bile flow. The objective of this study was to evaluate whether colchicine has any effect on EE-induced cholestasis. The effects of colchicine treatment on EE-induced cholestasis in rats for 5 consecutive days were evaluated. The serum components and enzymatic activity were assayed. In addition, the bile flow and biliary excretion were determined. Furthermore, western blot analysis was used to measure the expression of farnesoid X receptor (FXR), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and cholesterol 7alpha-hydroxylase (CYP7A1). Colchicine not only significantly inhibited the elevation of cholestasis-related serum components and enzyme activity but also significantly attenuated the decrease of the bile flow and biliary excretion. Colchicine also remarkably increased the hepatic expression of FXR, BSEP and MRP2, but decreased that of CYP7A1. Our data indicates that colchicine treatment attenuated EE-induced cholestasis in rats, most likely by promoting bile flow and biliary excretion, and reduced the synthesis of bile acids.

Comparative study on the anti-inflammatory and immune suppressive effect of Wilforlide A.

Tripterygium Glycosides (TG) is effective in the treatment of patients with a variety of inflammatory and autoimmune diseases, especially rheumatoid arthritis (RA) in clinical. Wilforlide A (T(1)) serves as a quality control standard of TG that be listed in Drug Standard of Ministry of Public Health of the People's Republic of China. The pharmacologic actions of T(1) remain to be unidentified. In this paper, we studied the anti-inflammatory and immune suppressive effect of T(1), and compared it with Triptolide (TP), which believed to be the major active component of TG. Carrageenan-induced rat pedal swelling, tampon-induced rat granulation, and mice ear inhibition rate of swelling trail results show that high-dose T(1) has obvious anti-inflammatory effect. Colorimetric detection contents of hemolysin, carbon elimination from plasma of mice, mice delayed hypersensitivity immune, and organ index were measured. The results show that T(1) has no significant immune suppressive activity, and there has a significant difference with TP and TG. Therefore, we think the content of TP also should be controlled as a supplement standard in order to ensure safe and effective medication.

Sex differences in subacute toxicity and hepatic microsomal metabolism of triptolide in rats.

Triptolide, a major active component of Tripterygium wilfordii Hook F (TWHF), has multiple pharmacological activities. However, its clinical use is often limited by its severe toxicity. In the present study, we evaluated the oral toxicity of triptolide in Sprague-Dawley rats for 28 days at the dosages of 0, 200 and 400microg/kg/day, respectively. Significant difference in the toxicity of triptolide at 400microg/kg was found between different sexes. The triptolide-treated female rats showed many abnormalities, including anorexia, diarrhea, leanness, suppression of weight gain and food intake, fatty liver, splenomegaly and atrophy of ovaries. In contrast, no such abnormalities were observed in male rats except for the significant reproductive toxicity. Furthermore, the metabolism of triptolide in liver microsomes from both sexes was investigated by HPLC. A greater rate of triptolide metabolism was observed in male rat hepatic microsomes, suggesting that one of the cytochrome P450s (CYPs) responsible for triptolide metabolism is male-specific or predominant at least. The inhibition experiments with CYP inhibitors showed that CYP3A and CYP2B were mainly involved in the metabolism of triptolide. In addition, since CYP3A2 is a male-predominant form in rats, significant sex difference in the metabolism of triptolide disappeared in vitro after anti-rat CYP3A2 antibody pretreatment. Results suggested that CYP3A2 made an important contribution to the sex-related metabolism of triptolide, which may result in the sex differences in triptolide toxicity.