Latest ArticlesTo explore the mechanism of theaflavin improving the inflammatory response of intestinal epithelial cells in ulcerative colitis (UC) through regulating NOD-like receptor thermal protein domain associated protein 3 (NLRP3) / Caspase-1 signaling pathway mediated by astrocyte elevated gene 1 (AEG-1).
NCM460 cells were divided into control group (conventional culture of NCM460 cells without any intervention treatment, model group (treated with 1 mg·L-1 lipopolysaccharide in NCM460 cells for 24 hours), experimental group (treated with 64 μmol·L-1 theaflavin and 1 mg·L-1 lipopolysaccharide in NCM460 cells for 24 h), pcDNA3.1-NC group (after NCM460 cells were transfected with the pcDNA3.1-NC plasmid, treated with 64 μmol·L-1 theaflavin and 1 mg·L-1 lipopolysaccharide for 24 h) and pcDNA3.1-AEG-1 group (after NCM460 cells were transfected with the pcDNA3.1-AEG-1 plasmid, treated with 64 μmol·L-1 theaflavin and 1 mg·L-1 lipopolysaccharide for 24 h). Cell viability was detected by cell counting kit-8 method, cell invasion ability was detected by Transwell assay, cell migration ability was detected by cell scratch assay, and mRNA levels of AEG-1 and barrier damage-related proteins were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction. Western blotting was used to detect the expressions of AEG-1, apoptosis, barrier injury and NLRP3/Caspase-1 signaling pathway-related proteins and enzyme-linked immunosorbent assay was used to detect the contents of inflammatory factors.
The cell migration rate of the control group, model group, experimental group were (78.85±13.47)%, (19.32±3.15)% and (54.97±9.03)%, respectively. The levels of interleukin-6 (IL-6) in the control group, model group, experimental group, pcDNA3.1-NC group and pcDNA3.1-AEG-1 group were (0.49±0.07), (1.36±0.21), (0.64±0.09), (0.68±0.10) and (1.21±0.18) pg·L-1, respectively; the apoptosis rates were (8.26±1.47)%, (27.09±4.62)%, (14.51±2.18)%, (16.75±2.83)% and (22.68±3.56)%, respectively; the relative expression levels of B-cell lymphoma-2 (Bcl-2) protein were 1.00±0.16, 0.39±0.07, 0.71±0.12, 0.67±0.09 and 0.54±0.08, respectively; the relative expression levels of Bcl-2-associated X (Bax) protein were 1.00±0.19, 6.45±1.12, 3.90±0.64, 3.79±0.58 and 6.07±0.96, respectively; the mRNA levels of AEG-1 were 1.00±0.13, 4.35±0.76, 1.92±0.33, 2.08±0.32 and 3.26±0.57, respectively; the relative expression levels of AEG-1 protein were 1.00±0.17, 4.82±0.79, 2.07±0.34, 2.25±0.36 and 3.94±0.71, respectively; the mRNA levels of Zonula Occludens-1 (ZO-1) were 1.00±0.15, 0.37±0.06, 0.76±0.13, 0.79±0.14 and 0.51±0.09, respectively, while the mRNA levels of Occludin were 1.00±0.16, 0.29±0.05, 0.58±0.10, 0.52±0.09 and 0.37±0.06, respectively; the relative protein expression levels of NLRP3 were 1.00±0.19, 6.58±1.06, 2.71±0.43, 2.59±0.42 and 5.16±0.94, respectively; the relative protein expression levels of cleaved caspase-1 were 1.00±0.16, 5.26±0.93, 3.42±0.59, 3.65±0.64 and 5.09±0.87, respectively. When comparing the model group with the control group and the experimental group, and the pcDNA3.1-NC group with the pcDNA3.1-AEG-1 group, the differences in the above indicators were all statistically significant (P<0.01, P<0.001).
Theaflavin can improve the inflammatory response of LPS-induced UC intestinal epithelial cells and inhibit cell apoptosis, and has a protective effect on epithelial barrier function. The mechanism may be related to the down-regulation of AEG-1 expression and the inhibition of the NLRP3/Caspase-1 signaling pathway.
To investigate the inhibitory effect of curcumol on the growth of hepatocellular carcinoma(HCC)cells through sialic acid-binding immunoglobulin-like lectin 15(Siglec-15)and its underlying mechanism.
Bel-7402 and HepG2 cells were randomly divided into control group(normal culture), low-dose experimental group (treated with 50 μmol·L-1 curcumol for 48 hours), and a high-dose experimental group (treated with 100 μmol·L-1 curcumol for 48 hours). The proliferative, invasive, and migratory capacities of cells were evaluated through a combination of functional assays, including the methyl thiazolyl tetrazolium (MTT) method for cell viability, Transwell and wound healing assays for migration and invasion, and flow cytometry for additional cellular characteristics. The expression levels of Siglec-15, along with key molecules involved in the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling cascade, were examined at both the messenger RNA(mRNA) and protein levels. For this purpose, real-time quantitative polymerase chain reaction (RT-qPCR) was employed to assess transcript abundance, while Western blotting was used to determine protein expression.
The cell viability rates in the control, low-dose, and high-dose experimental groups of Bel-7402 cells and HepG2 cells were (100.00±0)%, (72.09±1.07)%, (55.65±2.99)% and (100.00±0)%, (57.38±6.97)%, (44.63±6.04)%, respectively; the apoptosis rates in the corresponding groups of Bel-7402 cells and HepG2 cells were (1.87±0.05)%, (2.77±0.08)%, (4.19±0.11)% and (3.52±0.17)%, (5.46±0.11)%, (6.63±0.16)%, respectively; the wound healing rates (horizontal migration rates) in the corresponding groups of Bel-7402 cells and HepG2 cells were (39.06±0.81)%, (19.20±0.59)%, (8.34±0.89)% and (52.25±1.43)%, (21.10±1.95)%, (15.31±0.80)%, respectively; the vertical migration rates in the corresponding groups of Bel-7402 cells and HepG2 cells were (100.00±0)%, (72.40±4.34)%, (62.47±3.08)% and (100.00±0)%, (60.51±2.62)%, (40.47±2.76)%, respectively. In the control group, low-dose experimental group, and high-dose experimental group of Bel-7402 cells and HepG2 cells, the relative mRNA expression levels of Siglec-15 were 1.00±0.18, 0.89±0.01, 0.69±0.07 and 1.00±0.09, 0.90±0.04, 0.88±0.03, respectively; the relative mRNA expression levels of PI3K were 1.00±0.16, 0.80±0.12, 0.75±0.11 and 1.00±0.16, 0.93±0.08, 0.93±0.04, respectively; the relative mRNA expression levels of AKT were 1.00±0.15, 0.73±0.17, 0.52±0.11 and 1.00±0.21, 0.69±0.06, 0.27±0.05, respectively; the relative protein expression levels of Siglec-15 were 1.05±0.07, 0.91±0.09,0.84±0.07 and 0.99±0.05, 0.80±0.02, 0.64±0.04, respectively; the relative protein expression levels of PI3K were 0.96±0.09, 0.49±0.10, 0.17±0.10 and 1.01±0.03, 0.73±0.03, 0.49±0.03, respectively. The relative protein expression levels of AKT were 0.98±0.04, 0.88±0.08, 0.63±0.04 and 1.06±0.04, 0.92±0.02, 0.67±0.03, respectively. In both cell lines, compared with the control group, the differences in the above indicators between each experimental group and the control group were all statistically significant (all P<0.001).
Curcumol exerts anti-hepatocellular carcinoma effects by downregulating Siglec-15 expression and inhibiting the proliferation and migration of Bel-7402 and HepG2 hepatoma cells.
To investigate the effects of ginsenoside Rb1 on hypoxia/reoxygenation (H/R)-induced injury in human pulmonary endothelial cells (HPECs) and its underlying mechanism.
HPECs were randomly divided into control group(normal culture), model group(subjected to 3 h of hypoxia followed by 7 h of reoxygenation), and experimental group(pretreated with 0.1 μmol·L-1, 1.0 μmol·L-1, 10.0 μmol·L-1 and 100.0 μmol·L-1 ginsenoside Rb1 for 1 h prior to H/R). Cell viability was assessed using the CCK-8 assay. The levels of inflammatory factors including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). The intracellular adenosine triphosphate(ATP) content and the activities of mitochondrial respiratory chain complex Ⅰ (complex Ⅰ) and ATP synthase were detected by ELISA . The protein relative expression levels of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), zonula occludens-1 (ZO-1), vascular endothelial cadherin (VE-cadherin) and ATP synthase F1 subunit delta (ATP5D) were measured by Western blot.
The cell viability of the control group, model group and experimental group(0.1, 1.0, 10.0 and 100.0 μmol·L-1)were 1.07±0.04, 0.61±0.06, 0.68±0.07, 0.80±0.06, 0.96±0.08 and 0.95±0.09, respectively, among which 10.0 μmol·L-1 showed the optimal protective effect and this concentration was therefore used for subsequent experimental group. The levels of IL-1β in the control group, model group and experimental group were (136.25±3.61), (200.12±8.56) and (149.50±9.20) ng·L-1, respectively; the levels of IL-6 were (4.95±0.26), (8.96±0.60) and (6.23±0.34)ng·L-1, respectively; the levels of TNF-α were (328.66±19.14), (461.54±26.39) and (391.77±17.22) ng·L-1, respectively; the relative expression levels of GRP78 were 0.84±0.15, 1.45±0.13 and 0.82±0.15, respectively; the relative expression levels of CHOP were 0.66±0.11, 1.20±0.41 and 0.76±0.14, respectively; the relative expression levels of ZO-1 were 0.81±0.11, 0.25±0.07 and 0.84±0.13, respectively; the relative expression levels of VE-cadherin were 0.75±0.12, 0.32±0.09 and 0.73±0.14, respectively; the relative expression levels of ATP5D were 0.88±0.16, 0.26±0.08 and 0.83±0.17, respectively; the activities of mitochondrial respiratory chain complex Ⅰ were 2.12±0.26, 1.40±0.17 and 1.82±0.15, respectively; the activities of ATP synthase were 2.14±0.25, 1.32±0.17 and 1.81±0.18, respectively; the contents of ATP were (86.32±8.50), (52.21±5.62) and (91.12±6.10) μmol·ug-1 protein, respectively; there were statistically significant differences in the above indicators between the model group and the control group, between the experimental group and the model group (all P<0.05).
Ginsenoside Rb1 may alleviate H/R-induced HPECs injury, inflammatory response, and endoplasmic reticulum stress by improving mitochondrial function and increasing intracellular ATP content, thereby restoring normal cellular function.
To investigate the potential mechanism of lycopene mediating iron autophagy in improving the inflammatory response in endometriosis (EMs).
Fifty rats were randomly divided into sham group, model group (EMs model was constructed), experiment-L group (10.0 mg·kg-1 lycopene after modeled), experiment-H group (20.0 mg·kg-1 lycopene after modeled) and positive group (1.05 mg·kg-1 mifepristone after modeled), with 10 rats in each group. At the end of drug treatment, the volume of ectopic endometrial tissue were detected, and detected free iron content with a corresponding detection kit. The expressions of vascular endothelial growth factor A (VEGFA), interleukin (IL) -8, nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein 1 light chain 3B (LC3B) were detected by immunofluorescence, or Western blot.
The volumes of ectopic endometrial lesion tissues in the sham group, the model group, the experiment-L group, the experiment-H group and the positive group of rats were (0.00±0.00), (130.92±12.45), (97.55±10.56), (71.96±6.46), and (54.22±2.72) mm3, respectively; the levels of free iron were (262.89±23.51), (636.97±58.75), (523.63±46.13), (383.30±38.92) and (603.15±69.98) μmol·kg-1, respectively; the immunofluorescence intensities of VEGFA were (1 034.45±102.39), (3 628.16±104.65), (3 100.73±231.67), (2 193.07±293.16) and (3 418.68±377.98) a.u., respectively; the relative expression levels of IL-8 protein were 0.22±0.05, 0.79±0.10, 0.62±0.10, 0.49±0.06 and 0.71±0.07, respectively; the relative expression levels of NCOA4 protein were 0.33±0.04, 1.12±0.13, 0.85±0.10, 0.61±0.09 and 1.05±0.08, respectively; the relative expression levels of LC3Ⅱ/Ⅰ protein were 0.36±0.04, 1.02±0.12, 0.78±0.08, 0.51±0.05 and 0.94±0.07, respectively. Compared the sham operation group with the model group, compared experiment-L and experiment-H groups with the model group, the differences of above indicators were all statistically significant (all P<0.05).
Lycopene significantly inhibits inflammation and angiogenesis in EMs rats, thereby reducing the volume of ectopic lesions, which may be related to the inhibition of iron autophagy signaling.
To investigate the effects of curcumin on ferroptosis and neurological deficit in mice with intracerebral hemorrhage (ICH) and to clarify its potential molecular mechanism.
A total of 40 mice were divided into sham group, model group, experimental group and inhibitor group, with 10 mice in each group. Intracerebral hemorrhage model in mice was established by tail vein autologous blood injection. The sham group was injected with the same amount of normal saline; in the model group, the model group was established and injected with the same amount of normal saline; the experimental group was intragastrically administered with 200 mg·kg-1 curcumin, and the inhibitor group was intraperitoneally injected with 5 mg·kg-1 secretory phosphoprotein 1 (SPP1) inhibitor solution on the basis of 200 mg·kg-1 curcumin. At the end of the treatment, Longa score was used to evaluate the neurological deficit; the serum levels of Fe2+, malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by enzyme-linked immunosorbent assay (ELISA); the relative fluorescence intensity of reactive oxygen species (ROS) in brain tissue was detected by immunofluorescence method; the relative expression levels of B-cell lymphoma 2 (BCL-2), BCL-2-associated X protein (Bax), nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase (GPX4) were detected by Western blot; the relative positive level of SPP1 in brain tissue was detected by immunohistochemistry.
The neurological deficit scores of sham group, model group, experimental group and inhibitor group were (0±0), (3.20±0.42), (1.40±0.52) and (2.10±0.57) scores, respectively; the serum Fe2+levels were (220.35±26.17), (432.40±65.28), (276.52±33.20) and (329.15±45.71) μmol·kg-1, respectively; the serum MDA levels were (53.75±7.62), (120.36±18.22), (72.68±11.23) and (89.44±13.16) nmol·mg-1, respectively; the serum SOD levels were (63.78±9.80), (20.86±3.41), (51.18±7.30) and (37.35±5.08) U·mg-1, respectively; the relative fluorescence intensities of ROS were 1.00±0.09, 3.87±0.56, 1.52±0.22 and 2.43±0.38, respectively; the relative expression levels of Bax in brain tissue were 1.00±0.11, 2.95±0.33, 1.58±0.26 and 2.37±0.29, respectively; the relative expression levels of Bcl-2 were 1.00±0.15, 0.20±0.04, 0.65±0.12 and 0.43±0.07, respectively; the relative expression levels of Nrf2 were 1.00±0.13, 0.33±0.05, 0.65±0.10 and 0.54±0.09, respectively; the relative expression levels of GPX4 were 1.00±0.14, 0.21±0.04, 0.58±0.09 and 0.45±0.06, respectively; the relative positive levels of SPP1 were 1.00±0.13, 0.30±0.05, 0.76±0.12 and 0.43±0.07, respectively. There were statistically significant differences in the above indicators between the model group and the sham operation group, between the experimental group and the model group, and between the inhibitor group and the experimental group (P<0.05, P<0.01, P<0.001).
Curcumin can alleviate neuronal apoptosis and ferroptosis after ICH, and improve neurological function injury in mice. The underlying mechanism may be associated with the up-regulation of SPP1 expression, which in turn activates the Nrf2/GPX4 signaling pathway.
To assess the tablet effect of a high-fat diet on the pharmacokinetics of oral FM888 tablet in healthy Chinese participants. FM888 tablet is a novel highly selective adenylyl cyclase 1 (AC1) antagonist potentially involved in chronic pain treatment by modulation of central plasticity.
A single-center, open-label, randomized, single-dose, two-period crossover trial was conducted. Subjects were randomized 1∶1 to receive 400 mg FM888 tablet under fasting or high-fat meal conditions, then crossed over after a 7-day washout. Plasma FM888 concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and analyzed by non-compartmental methods using Phoenix WinNonlin 8.3.1.
The Cmax of FM888 tablet in the fasting state and after a highfat meal were (175.57±89.51) and (63.74±38.74) ng·mL-1, respectively; AUC0-last were (645.84±355.50) and (416.28±245.83) h·ng·mL-1, respectively; AUC0-∞ were (698.22±373.46) and (455.36±290.66) h·ng·mL-1, respectively. Exposure to FM888 tablet was lower under fed conditions than under fasting conditions, with Cmax and AUC0-last reduced to approximately 36.00% and 65.00% of the fasting values, respectively. The geometric mean ratios (fed/fasting) for Cmax、AUC0-last and AUC0-∞ were 36.86% [90% confidence interval (CI): 28.94%-46.95%], 66.01% (90% CI: 55.72%-78.20%), and 67.39% (90% CI: 55.70%-81.53%), respectively. Mixed-effects modeling confirmed a significant effect of feeding status on key parameters (P<0.05). FM888 tablet was well tolerated; all adverse events were grade 1, with no serious events.
A high-fat meal significantly reduced FM888 bioavailability, indicating a marked food effect. Despite lower exposure, FM888 tablet demonstrated favorable safety and tolerability.
To study the bioequivalence of test preparation and reference preparation of pregabalin capsule in Chinese healthy subjects under fasting and fed conditions.
Using a single center, randomized, open, two cycle crossover design, 52 healthy subjects were divided into fasting group and fed group, with 26 cases in each group. The test or reference preparation of pregabalin capsules was orally administered 150 mg once. The blood concentration was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and pharmacokinetic (PK) parameters were calculated to evaluate the bioequivalence.
The main PK parameters Cmax of pregabalin capsule test preparation and reference preparation in the fasting group were (6 722.00±1 390.00) and (6 065.00±1 218.00) ng·mL-1, respectively; AUC0-t were (32 570.52±3 877.48) and (32 721.93±4 270.54) ng·h·mL-1, respectively; AUC0-∞ were (32 941.98±4 040.07) and (33 097.11±4 428.89) ng·h·mL-1, respectively; tmax was 0.75 (0.50, 1.75) and 1.00 (0.50, 1.75) h, respectively; the t1/2 were (5.58±0.74) and (5.55±0.80) h, respectively. The main PK parameters Cmax of the test preparation and reference preparation of pregabalin capsules in the fed group were (3 786.00±513.90) and (3 786.00±437.50) ng·ml-1, respectively; AUC0-t were (32 760.51±4 250.79) and (31 923.83±3 842.92) ng·h·mL-1, respectively; AUC0-∞ were (33 371.21±4 406.02) and (32 519.87±4 050.39) ng·h·mL-1, respec tively; tmax was 3.50 (2.50, 4.50) and 3.00 (2.50, 4.51) h, respectively; the t1/2 was (5.95±0.79) and (5.89±0.91) h, respectively. Under fasting or fed conditions, the 90% confidence intervals of the main PK parameters of the test preparation and the reference preparation were both 80.00%-125.00%.
The test preparation and reference preparation of pregabalin capsules are bioequivalent under fasting and fed conditions.
Polycystic ovary syndrome (PCOS), a prevalent endocrine-metabolic disorder, is characterized by hyperandrogenemia, ovulatory dysfunction, and polycystic ovarian morphology. The nucleotide-binding leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) inflammasome, an intracellular complex composed of active-NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and pro-cysteine aspartate specific proteinase 1 (Pro-Caspase-1), is activated by stimuli such as pathogen invasion, oxidative stress, and metabolic disorders, regulating the release of pro-inflammatory cytokines including interleukin-1β (IL-1β) and IL-18 to mediate inflammatory responses. PCOS is intricately linked to NLRP3 inflammasome activation: it triggers NLRP3 via mechanisms including ion imbalance, mitochondrial dysfunction, and metabolic product accumulation, leading to the release of pro-inflammatory factors that exacerbate ovarian inflammatory microenvironment, inhibit follicular development, and induce granulosa cell apoptosis. Concurrently, NLRP3 inflammasome activation exacerbates metabolic disorders and reproductive endocrine abnormalities by disrupting insulin signaling and promoting androgen synthesis, forming a "metabolism-inflammation-reproduction" vicious cycle. This paper systematically reviews the basic research progress of traditional Chinese medicine (TCM) in regulating NLRP3 inflammasome and deeply explores the synergistic mechanisms of TCM in anti-inflammatory and metabolic regulation within PCOS models, aiming to provide novel therapeutic strategies for PCOS.
Pharmacological treatment of bladder cancer (BC), including intravesical chemotherapy, systemic chemotherapy, chemoradiotherapy, and immunotherapy, still faces major challenges such as high recurrence rates, drug resistance, and treatment-related toxicities. As an important adaptive response under therapeutic stress, autophagy exerts a dual role in BC; it may cooperate with apoptosis and other pathways to mediate tumor cell death, or function as protective autophagy to promote cell survival and drive drug resistance. Therefore, strategies aimed at inducing lethal autophagy or inhibiting therapy-induced protective autophagy/autophagic flux blockade have emerged as potential approaches to optimize treatment response. Active components and compound formulas of traditional Chinese medicine can modulate autophagy through signaling pathways such as AMP-activated protein kinase/mechanistic target of rapamycin (AMPK/mTOR), and have shown potential to suppress tumor growth, enhance therapeutic sensitivity, and reduce toxicity. However, current evidence is still largely limited to in vitro and animal studies, criteria for autophagic flux evaluation remain inconsistent, and systematic studies on pharmacokinetics/pharmacodynamics (PK/PD), drug-drug interactions, and safety are lacking. Based on a systematic review of previous basic and preclinical studies, this article focuses on the representative molecular mechanisms by which active components and compound formulas of traditional Chinese medicine regulate autophagy, as well as their potential benefits and major limitations in the pharmacological treatment of BC, and further proposes possible directions for subsequent combination therapy and optimization of therapeutic strategies from the perspective of clinical pharmacology.
Ursodeoxycholic acid (UDCA) is an endogenous substance. After oral administration of UDCA preparations, conjugated UDCA is formed, and its metabolism in the body is more complex than that of exogenous substances. This article based on the pharmacokinetic (PK) characteristics of UDCA, summarized the technical key points in the current bioequivalence (BE) studies of UDCA preparations. It analyzed from various aspects, including trial design, methodological validation, biological sample analysis, and bioequivalence result evaluation. This provides a certain reference for the bioequivalence studies of endogenous drugs such as ursodeoxycholic acid preparations.
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