Ginkgolide C attenuated Western diet-induced non-alcoholic fatty liver disease via increasing AMPK activation.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a metabolic dysregulation-related disorder that is generally characterized by lipid metabolism dysfunction and an excessive inflammatory response. Currently, there are no authorized pharmacological interventions specifically designed to manage NASH. It has been reported that Ginkgolide C exhibits anti-inflammatory effects and modulates lipid metabolism. However, the impact and function of Ginkgolide C in diet-induced NASH are unclear. METHODS: In this study, mice were induced by a Western Diet (WD) with different doses of Ginkgolide C with or without Compound C (adenosine 5 '-monophosphate (AMP)-activated protein kinase (AMPK) inhibitor). The effects of Ginkgolide C were evaluated by assessing liver damage, steatosis, fibrosis, and AMPK expression. RESULTS: The results showed that Ginkgolide C significantly alleviated liver damage, steatosis, and fibrosis in the WD-induced mice. In addition, Ginkgolide C markedly improved insulin resistance and attenuated hepatic inflammation. Importantly, Ginkgolide C exerted protective effects by activating the AMPK signaling pathway, which was reversed by AMPK inhibition. CONCLUSION: Ginkgolide C alleviated NASH induced by WD in mice, potentially via activating the AMPK signaling pathway.

Current research of Assisted Reproductive Technology for women with early endometrial cancer and atypical endometrial hyperplasia after conservative treatment.

As the incidence of endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) has been increasing, and has shown young trend. It is crucial to study the fertility-preserving treatment of endometrial lesions and fertility-promoting protocols. Age, obesity, and irregular ovulation are not only high-risk factors for endometrial lesions but also key factors affecting female fertility. Assisted reproductive technology (ART) can significantly improve pregnancy outcomes in patients with AEH and EC after conservative treatment. Based on the existing studies, this article reviews the progress of research on pregnancy outcomes of ART and its influencing factors in such patients. It helps physicians in providing optimal fertility guidance.

Endogenous chemicals guard health through inhibiting ferroptotic cell death.

Ferroptosis is a new form of regulated cell death caused by iron-dependent accumulation of lethal polyunsaturated phospholipids peroxidation. It has received considerable attention owing to its putative involvement in a wide range of pathophysiological processes such as organ injury, cardiac ischemia/reperfusion, degenerative disease and its prevalence in plants, invertebrates, yeasts, bacteria, and archaea. To counter ferroptosis, living organisms have evolved a myriad of intrinsic efficient defense systems, such as cyst(e)ine-glutathione-glutathione peroxidase 4 system (cyst(e)ine-GPX4 system), guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin (BH4) system (GCH1/BH4 system), ferroptosis suppressor protein 1/coenzyme Q10 system (FSP1/CoQ10 system), and so forth. Among these, GPX4 serves as the only enzymatic protection system through the reduction of lipid hydroperoxides, while other defense systems ultimately rely on small compounds to scavenge lipid radicals and prevent ferroptotic cell death. In this article, we systematically summarize the chemical biology of lipid radical trapping process by endogenous chemicals, such as coenzyme Q10 (CoQ10), BH4, hydropersulfides, vitamin K, vitamin E, 7-dehydrocholesterol, with the aim of guiding the discovery of novel ferroptosis inhibitors.

Transarterial Chemoembolization Plus Lenvatinib and PD-1 Inhibitors for Hepatocellular Carcinoma with Main Trunk Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

Purpose: In recent years, immune checkpoint inhibitors have been used in combination with tyrosine kinase inhibitors and local therapies, creating a new era in treating hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). However, the benefits of this triple therapy remain unclear. Thus, this study evaluated whether the combination of transarterial chemoembolization (TACE), lenvatinib, and programmed death-1 (PD-1) inhibitors (triple therapy) was effective and safe for unresectable HCC with main trunk portal vein tumor thrombus (Vp4). Patients and Methods: This study enrolled patients receiving triple therapy at four institutions between August 2018 and April 2022. Patient characteristics and course of treatment were extracted from patient records. Tumors and tumor thrombus response were evaluated using an HCC-specific modified RECIST. Kaplan-Meier curve analysis demonstrated overall survival (OS) and progression-free survival (PFS). Adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Results: Median follow-up duration was 18 (4.0-26.3) months. Overall, 41 patients with HCC and Vp4 receiving first-line triple therapy were enrolled. The intrahepatic tumor objective response rate was 68.3%. The median OS was 21.7 (range, 2.8-30.5) months, whereas the median PFS was 14.5 (range, 1.3-27.6) months. Twelve patients received sequential resections. Resection was independently associated with favorable OS and PFS. Fever (31.7%), hypertension (26.8%), fatigue (24.4%), abnormal liver function (63.4%) and decreased appetite (21.9%) were the AEs frequently associated with treatment. No treatment-related mortality occurred. Conclusion: TACE plus lenvatinib and PD-1 inhibition was effective and tolerable for treating unresectable HCC with Vp4, with a high tumor response rate and favorable prognosis.

Hsa_circRNA_100146 Promotes Prostate Cancer Progression by Upregulating TRIP13 via Sponging miR-615-5p.

Objective: This study was conducted for investigating the functions of circular RNA circRNA_100146 (circRNA_100146) in the development of prostate cancer (PCa) and identifying the underlying mechanisms of the circRNA_100146/miR-615-5p/TRIP13 axis. Materials and Methods: Under the support of RT-PCR, the expression of circRNA_100146 in PCa cells was examined. Cell Counting Kit-8 (CCK-8) assays and clone formation assays were applied to the assessment of cell proliferation. We then determined cell invasion and migration through transwell assays and wound healing assays. RNA pull-down assays and luciferase reporter assays were performed for the exploration of the regulatory effects of potential molecules on the expressions of the targeting genes. In addition, a nude mouse xenograft model was applied to demonstrate the oncogenic roles of circRNA_100146 in PCa. Results: CircRNA_100146 expression was distinctly upregulated in PCa cells. Silencing of circRNA_100146 suppressed PCa cells' invasion, migration, and proliferation. CircRNA_100146 sponged miR-615-5p to suppress its expressions, while miR-615-5p targeted the 3'-UTR of TRIP13 to repress the expression of TRIP13. In addition, we observed that knockdown of miR-615-5p reversed the suppression of circRNA_100146 silence on the proliferation and invasion of PCa cells. In addition, the tumor growth was also suppressed by silencing circRNA_100146 in vivo. Conclusion: CircRNA_100146 is a tumor promoter in PCa, which promoted progression by mediating the miR-615-5p/TRIP13. CircRNA_100146 can be a potential candidate for targeted therapy of PCa.

Theoretical Insights into the Cotransport Mechanism of GSH with Anticancer Drugs by MRP1.

The multidrug resistance protein MRP1 is an ATP binding cassette (ABC) transporter that confers resistance to many anticancer drugs and regulates redox homeostasis, inflammation, and hormone secretion. MRP1 actively transports compounds across cell membranes, and the presence of glutathione (GSH) is required in many cases. However, the process of MRP1-mediated substrate transportation has been poorly understood. With extensive molecular dynamics simulations, we have found a sandwich-like structure which is generated by GSH, a transmembrane α-helices 11 (TM11)-TM17 axis, and anticancer drugs. This structure is crucial in MRP1 transportation. It triggers the motion of TM11 and TM17, followed by the movement of nucleotide-binding domains 1 (NBD1) and 2 (NBD2), and finally an occluded structure is formed. Trp1246, Lys332, and Phe594 were identified as the main contributors in the formation of the sandwich-like structure. Our findings clearly explain the synergy of GSH with an anticancer drug in MRP1 transportation and have significant meanings for the rational design of novel inhibitors against MRP1.

Anticancer effects of Mahanimbine alkaloid on the human bladder cancer cells are due to the induction of G0/G1 cell cycle arrest, apoptosis and autophagy.

PURPOSE: The main purpose of the current research work was to investigate the anticancer effects of Mahanimbine alkaloid in human bladder cancer cells along with examining its effects on cellular apoptosis, cell cycle phase distribution, and cell autophagy. METHODS: Cell viability was examined by WST-1 cell viability assay. Mahanimbine-induced apoptosis was examined by fluorescent microscopy using acridine orange (AO)/ethidium bromide (EB) staining as well as using flow cytometry in combination with annexin-v/propidium iodide (PI) staining. Further, western blot assay was used to study the effects of Mahanimbine on apoptosis-related protein expressions including Bax and Bcl-2. Autophagy induction was evaluated by transmission electron microscopy (TEM) and western blot. Flow cytometry was used to study the effects on cell cycle. RESULTS: The results showed that Mahanimbine decreased the viability of the human bladder cancer cells and exhibited an IC50 of 32.5 µM. The test molecule also caused remarkable changes in the morphology of human bladder cancer cells and inhibited their colony forming potential. The AO/EB staining assay showed that Mahanimbine inhibits the viability of cancer cells via induction of apoptotic cell death which was associated with increase in Bax and decrease in Bcl-2 levels. The apoptotic cells increased from 5.2% in control to around 75% at 100 µM concentration. Mahanimbine also led to dose-dependent G0/G1 cell cycle arrest. Autophagic vacuoles appeared in the treated cells indicating autophagic induction by the test molecule. The Mahanimbine-triggered autophagy was also linked with increase in the expression of LC3II and decrease in p62 expression. However, no apparent effects were observed on the LC3 I expression. CONCLUSION: Taken together, the results of this study indicate that Mahanimbine natural product has the potential to be developed as a promising anticancer agent against human bladder carcinoma but further studies are needed to this direction.

The increase of osteopontin and ß-carboxy-terminal cross-linking telopeptide of type I collagen enhances the risk of hip fracture in the elderly.

BACKGROUND: Hip fracture in the elderly is a health burden worldwide due to its high mortality rate. This study was conducted to determine the possible mechanisms of osteopontin (OPN) and ß-carboxy-terminal cross-linking telopeptide of type I collagen (ß-CTX) in hip fracture in the elderly. MATERIALS AND METHODS: In the study, we recruited 108 elderly patients with hip fracture diagnosed from May 2012 to May 2015 at the Third Hospital of Xiamen and 86 healthy individuals without a history of hip fracture were taken as controls. Serum levels of OPN and ß-CTX were then determined. The T and Z values for bone mineral density (BMD) were also measured. Moreover, logistic regression analysis was performed to assess the risk and protective factors for hip fracture in the elderly. RESULTS: Serum levels of both OPN and ß-CTX were increased in elderly patients with hip fracture. OPN was positively correlated with ß-CTX. In addition, the levels of OPN and ß-CTX shared a positive association with the age, and a negative association with the BMD, in terms of T and Z values of the hip. In addition, increased BMD and outdoor sports might be protective factors for hip fracture, and an increase in levels of OPN and ß-CTX might be associated with a higher risk of hip fracture in the elderly population. DISCUSSION: Collectively, increased serum levels of OPN and ß-CTX might be correlated with a higher risk of a hip fracture and have predictive values in the occurrence of hip fracture in the elderly.

Theoretical insight into the multiple interactions of quinazoline inhibitors with breast cancer resistance protein (BCRP/ABCG2).

Communicated by Ramaswamy H. Sarma.

Reactions of the Lipid Hydroperoxides With Aminic Antioxidants: The Influence of Stereoelectronic and Resonance Effects on Hydrogen Atom Transfer.

Aminic radical-trapping antioxidants (RTAs), as one of the most important antioxidants, have not received sufficient attention yet. But, an increasing number of aminic RTAs have been identified as ferroptosis inhibitors in recent years, which can potentially mediate many pathological states including inflammation, cancer, neurodegenerative disease, as well as ocular and kidney degeneration. This highlights the importance of aminic RTAs in the field of medicine. Herein, we systematically explored the radical scavenging mechanism of aminic RTAs with a quantum chemical method, particularly emphasizing the role of stereoelectronic factors and resonance factors on the transfer of H-atom and the stability to one-electron oxidation. These theoretical results elucidate the diversity of free radical scavenging mechanisms for aminic RTAs, and has significant implications for the rational design of new aminic RTAs.

Inhibition of endogenous hydrogen sulfide production exacerbates the inflammatory response during urine-derived sepsis-induced kidney injury.

The aim of the present study was to investigate the effects of endogenous H2S on the inflammatory response in kidneys following urine-derived sepsis-induced injury. A rabbit model of urine-derived sepsis was established by injecting Escherichia coli into the ligated ureter. Rabbits were randomly divided into the, control, sham, sepsis and DL-propargylglycine (PAG)-treated sepsis groups. The same surgical procedure except for the bacteria injection was performed for the sham group, while the control group was fed on normal diet without any additional treatments. The monitoring of vital signs, routine blood examinations and kidney function tests were performed prior to surgery and at 12, 24, 36 and 48 h following surgery. The serum H2S concentration and kidney cystathionine-γ-lyase (CSE) activity were determined following surgery. Pathological alterations were assessed by hematoxylin and eosin (H&E) staining, and the expression levels of inflammation-associated cytokines were detected by western blot analysis. The results demonstrated that rabbits in the sepsis and PAG groups exhibited a significant increase in rectal temperature, heart rate and respiratory rate following surgery when compared with the sham group; with the PAG group demonstrating the greatest increase. In addition, white cell counts and creatinine and urea nitrogen levels were significantly elevated following surgery in the sepsis and PAG groups when compared with the sham group. The serum H2S concentration and kidney CSE activity were significantly reduced in the sepsis group compared with the sham group, and a significant decrease in the levels of these factors were observed in the PAG group compared with the sepsis group. H&E staining indicated obvious structural abnormalities in kidney tissues in the sepsis group, which were exacerbated by PAG treatment. In addition, PAG treatment significantly increased the expression levels of nuclear factor-κB and interleukin-6, and decreased transforming growth factor-ß1 expression when compared with the sepsis group. In conclusion, PAG significantly exacerbated urine-derived sepsis-induced kidney injury potentially via altering the expression of inflammation-associated cytokines.

Correction: Chiral ruthenium polypyridyl complexes as mitochondria-targeted apoptosis inducers.

[This corrects the article DOI: 10.1039/C0MD00060D.].

O-Phenylenediamine: a privileged pharmacophore of ferrostatins for radical-trapping reactivity in blocking ferroptosis.

Ferroptosis is a non-apoptotic, iron dependent form of regulated cell death that is characterized by the accumulation of lipid hydroperoxides. It has drawn considerable attention owing to its putative involvement in diverse neurodegenerative diseases. Ferrostatins are the first identified inhibitors of ferroptosis and they inhibit ferroptosis by efficiently scavenging free radicals in lipid bilayers. However, their further medicinal application has been limited due to the deficient knowledge of the lipid peroxyl radical-trapping mechanism. In this study, experimental and theoretical methods were performed to illustrate the possible lipid hydroperoxide inhibition mechanism of ferrostatins. The results show that an ortho-amine (-NH) moiety from ferrostatins can simultaneously interact with lipid radicals, and then form a planar seven-membered ring in the transition state, and finally present greater reactivity. NBO analysis shows that the formed planar seven-membered ring forces ortho-amines into better alignment with the aromatic π-system. It significantly increases the magnitudes of amine conjugation and improves spin delocalization in the transition state. Additionally, a classical H-bond type interaction was discovered between a radical and an o-NH group as another transition state stabilizing effect. This type of radical-trapping mechanism is novel and has not been found in diphenylamine or traditional polyphenol antioxidants. It can be said that o-phenylenediamine is a privileged pharmacophore for the design and development of ferroptosis inhibitors.

Deacetyl-mycoepoxydiene, isolated from plant endophytic fungi Phomosis sp. demonstrates anti-microtubule activity in MCF-7 cells.

Deacetyl-mycoepoxydiene (DM), a novel secondary metabolite produced by the plant endophytic fungi Phomosis sp., induced the reorganization of cytoskeleton in actively growing MCF-7 cells by promoting polymerization of tubulin. DM could induce cell cycle arrest at G2/M in MCF-7 cells. Additionally, DM-induced apoptosis was characterized with up-regulating caspase-3, Bax, caspase-9, parp, and p21 while down-regulating Bcl-2 activation. DM conferred dose- and time-dependent inhibitory effects upon cell proliferation of MCF-7 cells both in cultured cells and nude mice with human breast carcinoma xenografts. The results obtained from these in vitro and in vivo models provide new data revealing the potential for DM as a novel microtubule inhibitor.

Hydrogen sulfide reduces kidney injury due to urinary-derived sepsis by inhibiting NF-κB expression, decreasing TNF-α levels and increasing IL-10 levels.

The present study aimed to investigate the effect of hydrogen sulfide (H2S) on kidney injury induced by urinary-derived sepsis. Rabbits were randomly divided into control, sham, sepsis, NaHS 2.8 µmol/kg and NaHS 8.4 µmol/kg groups, with six rabbits in each group. Upper urinary tract obstruction and acute infection was induced to establish the sepsis model. Blood was collected to carry out a white blood cell (WBC) count, and creatinine (Cr) and blood urea nitrogen (BUN) analysis. Morphological changes were observed by hematoxylin and eosin (H&E) staining and transmission electron microscopy. Immunohistochemical staining was used to detect the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-10 and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB). Cystathionine-γ-lyase (CSE) activity was measured by the spectrophotometric methylene blue method and the blood H2S concentration was measured by deproteinization. WBC, Cr and BUN levels were significantly elevated in the sepsis group compared with those in the control group (P<0.05). Following treatment with NaHS, the WBC, Cr and BUN levels were significantly decreased in the NaHS groups compared with those in the sepsis group (P<0.05). The pathological features of kidney injury were also alleviated by NaHS. In the sepsis group, the levels of TNF-α, IL-10 and NF-κB were significantly increased compared with those in the control group (P<0.05). In the NaHS groups, the TNF-α and NF-κB levels were significantly reduced whereas the IL-10 level was significantly increased compared with the respective levels in the sepsis group (P<0.05). The H2S concentration was significantly decreased in the sepsis group and this reduction was attenuated in the NaHS groups (P<0.05). Furthermore, the NaHS 8.4 µmol/kg dose revealed a more potent effect than the NaHS 2.8 µmol/kg dose. Thus, exogenous H2S reduced kidney injury from urinary-derived sepsis by decreasing the levels of NF-κB and TNF-α, and increasing the level of IL-10.

Ulinastatin reduces urinary sepsis­related inflammation by upregulating IL­10 and downregulating TNF­α levels.

The aim of the present study was to determine the efficacy of ulinastatin (UTI) for the treatment of sepsis and to investigate the associated molecular mechanisms. Twenty­four male rabbits were randomly divided into 4 groups, the normal, sham, sepsis model and UTI groups, each containing 6 rabbits. Serum levels of interleukin (IL)­10 and tumor necrosis factor­α (TNF­α) were measured by enzyme­linked immunosorbent assay (ELISA). Liver, kidney and lung tissues were stained with hematoxylin and eosin (H&E) 36 h after sacrifice and morphological changes were observed under an optical microscope. The expression levels of IL­10 and TNF­α proteins in rabbit kidney tissue in each group were determined by immunohistochemical detection and western blot analysis. ELISA results indicated that, compared with the sepsis model, IL­10 levels were significantly higher in the UTI treatment group (183.91±11.521 pg/ml) at 36 h (P=0.000), while serum TNF­α concentration decreased significantly in the UTI treatment group (31.637±2.770 pg/ml; P=0.000). Results of western blot analysis were consistent with the immunohistochemistry, indicating that UTI upregulates IL­10 and downregulates TNF­α levels. In the current study, UTI was demonstrated to effectively treat urinary sepsis and alleviate the inflammatory response in tissues. These effects were mediated by the upregulation of IL­10 and downregulation of TNF­α levels.

ß-elemene acts as an antitumor factor and downregulates the expression of survivin, Bcl-xL and Mta-1.

ß-elemene, a non-cellular antineoplastic agent, may be used to effectively inhibit the growth and proliferation of various types of tumor cells by inhibiting the nucleic acid synthesis or inducing their apoptosis and differentiation. The aim of this study was to investigate the expression, as well as the effects, of Mta-1, survivin and Bcl-xL in T24 bladder cancer cells following ß-elemene treatment. The expression of the three proteins in T24 cells following ß-elemene treatment was analyzed by immunocytochemistry staining and western blot analysis. The survival rate and apoptosis of T24 cells following ß-elemene treatment was detected by MTT assay and TUNEL staining. We analyzed the internal corelations between apoptosis-associated genes, tumor metastasis-associated genes (cancer genes) and cell apoptosis, and investigated the mechanism of action by which ß-elemene induces the apoptosis of T24 cells at a molecular level. These results provide scientific evidence for further study on the anticancer effect of ß-elemene in carcinoma of the urinary bladder. In this study, it is shown that ß-elemene downregulates the expression of survivin, Bcl-xL and Mta-1 in tumor cells. The apoptosis of T24 cells is dependent on the dosage and length of incubation time of ß-elemene.

Baicalin attenuates focal cerebral ischemic reperfusion injury through inhibition of nuclear factor κB p65 activation.

Baicalin is a flavonoid compound purified from plant Scutellaria baicalensis Georgi. We aimed to evaluate the neuroprotective effects of baicalin against cerebral ischemic reperfusion injury. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. Baicalin at doses of 50, 100 and 200 mg/kg was intravenously injected after ischemia onset. Twenty-four hours after reperfusion, the neurological deficit was scored and infarct volume was measured. Hematoxylin and eosin (HE) staining was performed to analyze the histopathological changes of cortex and hippocampus neurons. We examined the levels of NF-κB p65 in ischemic cortexes by Western blot analysis and RT-PCR assay. The results showed that the neurological deficit scores were significantly decreased from 2.0 ± 0.7 to 1.2 ± 0.4 and the volume of infarction was reduced by 25% after baicalin injection. Histopathological examination showed that the increase of neurons with pycnotic shape and condensed nuclear in cortex and hippocampus were not observed in baicalin treated animals. Further examination showed that NF-κB p65 in cortex was increased after ischemia reperfusion injury, indicating the molecular mechanism of ischemia reperfusion injury. The level of NF-κB p65 was decreased by 73% after baicalin treatment. These results suggest that baicalin might be useful as a potential neuroprotective agent in stroke therapy. The neuroprotective effects of baicalin may relate to inhibition of NF-κB p65.

Anti-proliferative effects of recombinant iron superoxide dismutase on HepG2 cells via a redox-dependent PI3k/Akt pathway.

The coding sequence for an iron superoxide dismutase (fe-sod) was amplified from the Nostoc commune genome. Recombinant Fe-SOD was overexpressed in Escherichia coli, accounting for approximately 76% of total bacterial protein. Fe-SOD was purified from bacterial lysate by Ni-NTA column chromatography and used to generate an anti-SOD antibody. The purified Fe-SOD was encapsulated in liposomes and delivered to HepG2 liver tumor cells to eliminate cellular superoxide anions. The SOD-loaded cells exhibited lower reactive oxygen species (ROS) levels and higher reduced glutathione (GSH) levels. In Fe-SOD-treated cells, the cell cycle was delayed in the G(1) phase, and HepG2 cell growth slowed in association with dephosphorylation of the serine-threonine kinase Akt. Low-dose H(2)O(2) stimulated Akt phosphorylation, implying that Akt activation in HepG2 cells is redox-sensitive. Akt phosphorylation was abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitors, suggesting that PI3K is an upstream mediator of Akt activation in HepG2 cells. This study provides insight into recombinant Fe-SOD-induced signaling mechanisms in liver tumor cells and suggests the feasibility of using Fe-SOD as an antitumor agent.