Identification of metabolic components of carotid plaque in high-risk patients utilizing liquid chromatography-tandem mass spectrometry.

OBJECTIVE: Carotid atherosclerosis is a chronic progressive vascular disease that can be complicated by stroke in severe cases. Prompt diagnosis and treatment of high-risk patients are quite difficult due to the lack of reliable clinical biomarkers. This study aimed to explore potential plaque metabolic markers of stroke-prone risk and relevant targets for pharmacological intervention. METHOD: Carotid intima and plaque sample tissues were obtained from 20 patients with cerebrovascular symptoms of carotid origin. An untargeted metabolomics approach based on liquid chromatography-tandem mass spectrometry was utilized to characterize the metabolic profiles of the tissues. Multivariate and univariate analysis tools were used. RESULTS: A total of 154 metabolites were significantly altered in carotid plaque when compared with thickened intima. Of these, 62 metabolites were upregulated, whereas 92 metabolites were downregulated. Support vector machines identified the 15 most important metabolites, such as N-(cyclopropylmethyl)-N'-phenylurea, 9(S)-HOTrE, ACar 12:2, quinoxaline-2,3-dithiol, and l-thyroxine, as biomarkers for high-risk plaques. Metabolic pathway analysis showed that abnormal purine and nucleotide metabolism, amino acid metabolism, glutathione metabolism, and vitamin metabolism may contribute to the occurrence and progression of carotid atherosclerotic plaque. CONCLUSIONS: Our study identifies the biomarkers and related metabolic mechanisms of carotid plaque, which is stroke-prone, and provides insights and ideas for the precise prevention and targeted intervention of the disease.

Melatonin inhibits the formation of chemically induced experimental encapsulating peritoneal sclerosis through modulation of T cell differentiation by suppressing of NF-κB activation in dendritic cells.

Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). Surgery is a therapeutic strategy for the treatment of complete intestinal obstruction. However, complete intestinal obstruction in long-term PD results in high mortality and morbidity rates after surgery. Immunopathogenesis participates in EPS formation: CD8, Th1, and Th17 cell numbers increased during the formation of EPS. The anti-inflammatory and immunomodulatory effects of melatonin may have beneficial effects on this EPS. In the present study, we determined that melatonin treatment significantly decreases the Th1 and Th17 cell populations in mice with EPS, decreases the production of IL-1ß, TNF-α, IL-6, and IFN-γ, and increases the production of IL-10. The suppression of Th1 and Th17 cell differentiation by melatonin occurs through the inhibition of dendritic cell (DC) activation by affecting the initiation of the NF-κB signaling pathway in DCs. Our study suggests that melatonin has preventive potential against the formation of EPS in patients with PD.

The complete chloroplast genome of Hedychium flavum Roxb., an ornamental, edible and medicinal plant.

Hedychium flavum Roxb. 1820 is a perennial herb mainly distributed in China, India, Myanmar and Thailand with ornamental, edible and medicinal value. It is extensively cultivated as a source of aromatic essential oils, ornamental plant, food flavorings and vegetables, and folk medicine. In this study, we sequence the complete chloroplast genome of H. flavum by de novo assembly. The assembled genome has a typical quadripartite circular structure with 163,909 bp in length, containing a large single-copy region (LSC, 88,589 bp), a small single-copy region (SSC, 15,762 bp), and two inverted repeat regions (IRs, 29,779 bp). The cp genome contains 133 genes, including 87 protein-coding genes, 38 tRNA genes and 8 rRNA genes. Phylogenetic analysis based on the complete cp genome shows a close affinity of H. flavum and H. neocarneum with 100% bootstrap support. This study will provide useful genetic resource for further phylogenetic analysis of the genus Hedychium and Zingiberaceae.

Methanovulcanius yangii gen. nov., sp. nov., a hydrogenotrophic methanogen, isolated from a submarine mud volcano in the offshore area of southwestern Taiwan.

A novel mesophilic, hydrogenotrophic methanogen, strain CYW5T, was isolated from a sediment sample of a piston core collected from submarine mud volcano MV5 located in the offshore area of southwestern Taiwan. Cells of strain CYW5T were irregular coccids, 0.5-1.0 µm in diameter and lysed easily by 0.01 % sodium dodecyl sulphate (SDS) treatment. Strain CYW5Tutilized formate or hydrogen plus carbon dioxide as catabolic substrates for methanogenesis. The optimal growth conditions were 37 °C, 0.043-0.085 M NaCl and pH 6.02-7.32. The genomic DNA G+C content calculated from the genome sequence of strain CYW5T was 56.2 mol%. The results of phylogenetic analysis of 16S rRNA gene sequences indicated that strain CYW5T represented a member of the family Methanomicrobiaceae in the order Methanomicrobiales, and was closely related to the members of the genus Methanogenium. The most closely related species was Methanogenium cariaci JR1T (94.9 % of 16S rRNA gene sequence identity). The average nucleotide identity and average amino acid identity values between strain CYW5T and members of the family Methanomicrobiaceae were 74.7-78.5 % and 49.1-64.9%, respectively. Although many of the morphological and physiological characteristics of strain CYW5T and the species of the genus Methanogenium were similar, they were distinguishable by the differences in genomic G+C content and temperature, NaCl and pH ranges for growth. Based on these phenotypic, phylogenetic and genomic results, we propose that strain CYW5T represents a novel species, of a novel genus, named Methanovulcanius yangii gen. nov., sp. nov. The type strain is CYW5T (=BCRC AR10048T=DSM 100756T=NBRC 111404T).

[Research of implant accuracy using a digital registration method].

PURPOSE: The aim of this study was to introduce a new method to evaluate the clinical accuracy of implant position. The results were compared to traditional cone beam CT (CBCT) method. METHODS: A total of 36 implants from 24 patients with sufficient bone volume were enrolled into the study. CBCT method and digital registration method were compared to evaluate the accuracy of implant position. The measurement parameters were defined as deviations between ideal and postsurgical implant position at occlusal point(d1), apical point(d2) and axis(α). The deviations between two methods were analyzed with SPSS 19.0 software package. RESULTS: The deviations between ideal and postsurgical implant position using CBCT were (0.88±0.64) mm for occlusal point, (1.07±0.85) mm for apical point and (4.74±2.35)° for angle. In digital registration method, the deviations were (0.86±0.67) mm for occlusal point, (1.12±0.88) mm for apical point and (4.56±2.66)° for angle. No significant difference(P＞0.05) was found between the two methods. CONCLUSIONS: There was no significant difference between the two methods in evaluating the clinical accuracy of implant position. Digital registration method could be accepted in clinical application.

Ultraviolet Photodissociation of Proteinogenic Amino Acids.

The ultraviolet photochemistry of the amino acids glycine, leucine, proline, and serine in their neutral forms was investigated using parahydrogen matrix-isolation spectroscopy. Irradiation by 213 nm light destroys the chirality of all three chiral amino acids as a result of the α-carbonyl C-C bond cleavage and hydrocarboxyl (HOCO) radical production. The temporal behavior of the Fourier-transform infrared spectra revealed that HOCO radicals rapidly reach a steady state, which occurs predominantly due to photodissociation of HOCO into CO + OH or CO2 + H. In glycine and leucine, the amine radicals generated by the α-carbonyl C-C bond cleavage rapidly undergo hydrogen elimination to yield methanimine and 3-methylbutane-1-imine, respectively. Breaking of the α-carbonyl C-C bond in proline appeared to yield 1-pyrroline, although due to its weak absorption it remains unconfirmed. In serine, additional products were formaldehyde and E/Z ethanimine. The present study shows that the direct production of HOCO previously observed in α-alanine generalizes to other amino acids of varying structure. It also revealed a tendency for amino acid photolysis to form imines rather than amine radicals. HOCO should be useful in the search for amino acids in interstellar space, particularly in combination with simple imine molecules.

Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for Treatment of Nectin-4-expressing Cancers.

Overexpression of nectin cell adhesion protein 4 correlates with cancer progression and poor prognosis in many human malignancies. Enfortumab vedotin (EV) is the first nectin-4-targeting antibody-drug conjugate (ADC) approved by the FDA for the treatment of urothelial cancer. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV. Furthermore, ocular, pulmonary, and hematologic toxic side effects are common in nectin-4-targeted therapy, which frequently results in dose reduction and/or treatment termination. Thus, we designed a second generation nectin-4-specific drug, 9MW2821, based on interchain-disulfide drug conjugate technology. This novel drug contained a site specifically conjugated humanized antibody and the cytotoxic moiety monomethyl auristatin E. The homogenous drug-antibody ratio and novel linker chemistry of 9MW2821 increased the stability of conjugate in the systemic circulation, enabling highly efficient drug delivery and avoiding off-target toxicity. In preclinical evaluation, 9MW2821 exhibited nectin-4-specific cell binding, efficient internalization, bystander killing, and equivalent or superior antitumor activity compared with EV in both cell line-derived xenograft and patient-derived xenograft (PDX) models. In addition, 9MW2821 demonstrated a favorable safety profile; the highest nonseverely toxic dose in monkey toxicologic studies was 6 mg/kg, with milder adverse events compared with EV. Overall, 9MW2821 is a nectin-4-directed, investigational ADC based on innovative technology that endowed the drug with compelling preclinical antitumor activity and a favorable therapeutic index. The 9MW2821 ADC is being investigated in a phase I/II clinical trial (NCT05216965 and NCT05773937) in patients with advanced solid tumors.

Physician-Modified Endovascular Graft for Left Subclavian Artery Fenestration during Thoracic Endovascular Aortic Repair.

BACKGROUND: This study aimed to evaluate the safety and efficacy of physician-modified endovascular graft for preservation of left subclavian artery during thoracic endovascular aortic repair. METHODS: From June 2019 to October 2022, 66 patients with a variety of thoracic aortic pathologies were treated with thoracic endovascular aortic repair using physician-modified endovascular graft left subclavian artery fenestration to achieve adequate proximal landing zone. The details of surgical techniques were described. The perioperative morbidity, mortality, and the outcomes of mid-term follow-up were analyzed. RESULTS: Of the 66 patients (men: women, 53:13; age, 55.18 [55.18 ± 10.62] years), 53 (80.30%) presented with type B aortic dissection, 10 (15.15%) with thoracic penetrating aortic ulcer, 2 (3.03%) with thoracic aortic aneurysm, and 1 (1.52%) with left subclavian artery aneurysm. All of them underwent thoracic endovascular aortic repair using physician-modified endovascular graft left subclavian artery fenestration on the sterile back table. The technique success rate was 96.97% (n = 64). Total operation time was 92 min (interquartile range, 86-118), graft modification time was 19 min (interquartile range, 17-21), fluoroscopy time was 49 min (interquartile range, 41-62), and contrast agent dosage was 165 mL (interquartile range, 155-185). 30-day perioperative morbidities were 3 (4.55%) strokes, 1 (1.52%) retrograde type A aortic dissection, 1 (1.52%) aortic intimal intussusception, 1 (1.52%) left arm ischemia, and 3 (4.55%) type Ia endoleaks. Postoperative 30-day mortality and reintervention rates were 1.52% and 4.55%, respectively. Among the 63 patients included in the follow-up of 17 months (interquartile range, 7.75-18.25), the primary patency of left subclavian artery fenestration stents was 100%. Late complications were 1 (1.59%) distal stent graft-induced new entry and 1 (1.59%) death due to retrograde type A aortic dissection during the follow-up. The stent graft-induced new entry patient was observed with stable false lumen. CONCLUSIONS: Thoracic endovascular aortic repair with physician-modified endovascular graft for left subclavian artery revascularization is a safe, feasible, and efficacious technique associated with high success rate. Further study is needed for long-term outcome investigation.

Crocetin protects cardiomyocytes against hypoxia/reoxygenation injury by attenuating Drp1-mediated mitochondrial fission via PGC-1α.

BACKGROUND: Saffron (Crocus sativus L.) has been traditionally used as food, spice, and medicine. Crocetin (CRT), as main bioactive component of saffron, has accumulated pieces of beneficial evidence on myocardial ischemia/reperfusion (I/R) injury. However, the mechanisms are poorly explored. This study aims to investigate the effects of CRT on H9c2 cells under hypoxia/reoxygenation (H/R) and elucidated the possible underlying mechanism. METHODS: H/R attack was performed on H9c2 cells. Cell counting kit-8 was used to detect the cell viability. Cell samples and culture supernatants were evaluated via commercial kits to measure the superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and cellular adenosine triphosphate (ATP) content. Various fluorescent probes were used to detect cell apoptosis, intracellular and mitochondrial reactive oxygen species (ROS) content, mitochondrial morphology, mitochondrial membrane potential (MMP), and mitochondrial permeability transition pore (mPTP) opening. Proteins were evaluated via Western Blot. RESULTS: H/R exposure severely reduced cell viability and increased LDH leakage. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) suppression and dynamin-related protein 1 (Drp1) activation were coincided with excessive mitochondrial fission, mitochondrial permeability transition pore (mPTP) opening and mitochondrial membrane potential (MMP) collapse in H9c2 cells treated with H/R. Mitochondria fragmentation under H/R injury induced ROS over-production, oxidative stress, and cell apoptosis. Notably, CRT treatment significantly prevented mitochondrial fission, mPTP opening, MMP loss, and cell apoptosis. Moreover, CRT sufficiently activated PGC-1α and inactivated Drp1. Interestingly, mitochondrial fission inhibition with mdivi-1 similarly suppressed mitochondrial dysfunction, oxidative stress and cell apoptosis. However, silencing PGC-1α with small interfering RNA (siRNA) abolished the beneficial effects of CRT on H9c2 cells under H/R injury, accompanied with increased Drp1 and p-Drp1ser616 levels. Furthermore, over-expression of PGC-1α with adenovirus transfection replicated the beneficial effects of CRT on H9c2 cells. CONCLUSIONS: Our study identified PGC-1α as a master regulator in H/R-injured H9c2 cells via Drp1-mediated mitochondrial fission. We also presented the evidence that PGC-1α might be a novel target against cardiomyocyte H/R injury. Our data revealed the role of CRT in regulating PGC-1α/Drp1/mitochondrial fission process in H9c2 cells under the burden of H/R attack, and we suggested that modulation of PGC-1α level may provide a therapeutic target for treating cardiac I/R injury.

Electroacupuncture in Treatment of Acute Gastrointestinal Injury in Patients with Severe Traumatic Brain Injury: A Multicenter Randomized Controlled Trial.

OBJECTIVE: To evaluate whether electroacupuncture (EA) would improve gastrointestinal function and clinical prognosis in patients with severe traumatic brain injury (TBI) complicocted by acute gastrointestinal injury (AGI). METHODS: This multicenter, single-blind trial included patients with TBI and AGI admitted to 5 Chinese hospitals from September 2018 to December 2019. A total of 500 patients were randomized to the control or acupuncture groups using a random number table, 250 cases in each group. Patients in the control group received conventional treatment, including mannitol, nutritional support, epilepsy and infection prevention, and maintenance of water, electrolytes, and acid-base balance. While patients in the acupuncture group received EA intervention at bilateral Zusanli (ST 36), Shangjuxu (ST 37), Xiajuxu (ST 39), Tianshu (ST 25), and Zhongwan (RN 12) acupoints in addition to the conventional treatment, 30 min per time, twice daily, for 7 d. The primary endpoint was 28-d mortality. The secondary endpoints were serum levels of D-lactic acid (D-lac), diamine oxidase (DAO), lipopolysaccharide (LPS), motilin (MTL) and gastrin (GAS), intra-abdominal pressure (IAP), bowel sounds, abdominal circumference, AGI grade, scores of gastrointestinal failure (GIF), Glasgow Coma Scale (GCS), Acute Physiology and Chronic Health Evaluation (APACHE II), Sequential Organ Failure Assessment (SOFA), and Multiple Organ Dysfunction Syndrome (MODS), mechanical ventilation time, intense care unit (ICU) stay, and the incidence of hospital-acquired pneumonia. RESULTS: The 28-d mortality in the acupuncture group was lower than that in the control group (22.80% vs. 33.20%, P<0.05). Compared with the control group, the acupuncture group at 7 d showed lower GIF, APACHE II, SOFA, MODS scores, D-lac, DAO, LPS, IAP, and abdominal circumference and higher GCS score, MTL, GAS, and bowel sound frequency (all P<0.05). In addition, the above indices showed simillar changes at 7 d compared with days 1 and 3 (all P<0.05) in the EA group. CONCLUSION: Early EA can improve gastrointestinal function and clinical prognosis in patients with severe TBI complicated by AGI. (Registration No. ChiCTR2000032276).

Electroacupuncture in Treatment of Acute Gastrointestinal Injury in Patients with Severe Traumatic Brain Injury: A Multicenter Randomized Controlled Trial / 中国结合医学杂志

OBJECTIVE@#To evaluate whether electroacupuncture (EA) would improve gastrointestinal function and clinical prognosis in patients with severe traumatic brain injury (TBI) complicocted by acute gastrointestinal injury (AGI).@*METHODS@#This multicenter, single-blind trial included patients with TBI and AGI admitted to 5 Chinese hospitals from September 2018 to December 2019. A total of 500 patients were randomized to the control or acupuncture groups using a random number table, 250 cases in each group. Patients in the control group received conventional treatment, including mannitol, nutritional support, epilepsy and infection prevention, and maintenance of water, electrolytes, and acid-base balance. While patients in the acupuncture group received EA intervention at bilateral Zusanli (ST 36), Shangjuxu (ST 37), Xiajuxu (ST 39), Tianshu (ST 25), and Zhongwan (RN 12) acupoints in addition to the conventional treatment, 30 min per time, twice daily, for 7 d. The primary endpoint was 28-d mortality. The secondary endpoints were serum levels of D-lactic acid (D-lac), diamine oxidase (DAO), lipopolysaccharide (LPS), motilin (MTL) and gastrin (GAS), intra-abdominal pressure (IAP), bowel sounds, abdominal circumference, AGI grade, scores of gastrointestinal failure (GIF), Glasgow Coma Scale (GCS), Acute Physiology and Chronic Health Evaluation (APACHE II), Sequential Organ Failure Assessment (SOFA), and Multiple Organ Dysfunction Syndrome (MODS), mechanical ventilation time, intense care unit (ICU) stay, and the incidence of hospital-acquired pneumonia.@*RESULTS@#The 28-d mortality in the acupuncture group was lower than that in the control group (22.80% vs. 33.20%, P<0.05). Compared with the control group, the acupuncture group at 7 d showed lower GIF, APACHE II, SOFA, MODS scores, D-lac, DAO, LPS, IAP, and abdominal circumference and higher GCS score, MTL, GAS, and bowel sound frequency (all P<0.05). In addition, the above indices showed simillar changes at 7 d compared with days 1 and 3 (all P<0.05) in the EA group.@*CONCLUSION@#Early EA can improve gastrointestinal function and clinical prognosis in patients with severe TBI complicated by AGI. (Registration No. ChiCTR2000032276).

Optoelectronic Properties of MAPbBr3 Perovskite Light-Emitting Diodes Using Anti-Solvent and PEDOT:PSS/PVK Double-Layer Hole Transport Layers.

Perovskite light-emitting diodes (PeLEDs) have attracted extensive attention due to their advantages such as low-temperature solution processing, high photoluminescence quantum efficiency, high color purity, tunable wavelength, and excellent carrier mobility. The hole transport layer plays an important role in the device's performance. In this paper, the effect of anti-solvent (ethyl acetate) on the performance of PeLEDs was studied in order to determine the optimal anti-solvent condition. The effect of PEDOT:PSS/PVK double-layer hole transport layers on the optoelectronic properties of MAPbBr3 PeLEDs was investigated. The device with 8 mg/mL PVK produced the best results, with a maximum luminance of 5139 cd/m2 and a maximum current efficiency of 2.77 cd/A. Compared with the control device with PEDOT:PSS HTL, the maximum luminance of the device with 8 mg/mL PVK is increased by 2.02 times, and the maximum current efficiency is increased by 188%. The experimental results show that the addition of PVK helps to reduce the size of perovskite particles, contributing to the spatial confinement of excitons, and suppress the quenching of luminescence occurring at the interface between PEDOT:PSS and MAPbBr3, thereby enhancing the optoelectronic performance of PeLEDs. The results of this paper can provide a basis for the improvement and industrialization of PeLEDs.

Hif-2α regulates lipid metabolism in alcoholic fatty liver disease through mitophagy.

BACKGROUND: Disordered lipid metabolism plays an essential role in both the initiation and progression of alcoholic fatty liver disease (AFLD), and fatty acid ß-oxidation is increasingly considered as a crucial factor for controlling lipid metabolism. Hif-2α is a member of the Hif family of nuclear receptors, which take part in regulating hepatic fatty acid ß-oxidation. However, its functional role in AFLD and the underlying mechanisms remain unclear. RESULTS: Hif-2α was upregulated in EtOH-fed mice and EtOH-treated AML-12 cells. Inhibition or silencing of Hif-2α led to increased fatty acid ß-oxidation and BNIP3-dependent mitophagy. Downregulation of Hif-2α activates the PPAR-α/PGC-1α signaling pathway, which is involved in hepatic fatty acid ß-oxidation, by mediating BNIP3-dependent mitophagy, ultimately delaying the progression of AFLD. CONCLUSIONS: Hif-2α induces liver steatosis, which promotes the progression of AFLD. Here, we have described a novel Hif-2α-BNIP3-dependent mitophagy regulatory pathway interconnected with EtOH-induced lipid accumulation, which could be a potential therapeutic target for the prevention and treatment of AFLD.

Enhanced Performance of Perovskite Light-Emitting Diodes via Phenylmethylamine Passivation.

Organic-inorganic perovskite materials are widely used in the preparation of light-emitting diodes due to their low raw material cost, solution preparation, high color purity, high fluorescence quantum yield, continuously tunable spectrum, and excellent charge transport properties. It has become a research hotspot in the field of optoelectronics today. At present, the nonradiative recombination and fluorescence quenching occurring at the interface between the device transport layer and the light-emitting layer are still important factors limiting the performance of perovskite light-emitting diodes (PeLEDs). In this work, based on CH3NH3PbBr3 perovskite, the effects of parameters such as precursor solution, anti-solvent chlorobenzene (CB), and small amine molecule phenylmethylamine (PMA) on the performance of perovskite films and devices were investigated. The research results show that adding an appropriate amount of PMA can reduce the grain size of perovskite, improve the coverage of the film, enhance the crystallinity of the film, and increase the fluorescence intensity of the perovskite film. When the PMA content is 0.050 vol.%, the maximum luminance of PeLEDs is 2098 cd/m2 and the maximum current efficiency is 1.592 cd/A, which is greatly improved by 30% and 64.8% compared with the reference device without PMA doping. These results suggest that an appropriate amount of PMA can effectively passivate the defects in perovskite films, and inhibit the non-radiative recombination caused by the traps, thereby improving the optoelectronic performance of the device.

Effectiveness of Low-Frequency Electrical Stimulation for Radical Hysterectomy Women: Systematic Review and Meta-Analysis.

INTRODUCTION: The aim of the study was to explore the effects of low-frequency electrical stimulation (LFES) in preventing urinary retention after radical hysterectomy (RH) in women with cervical cancer. METHODS: Seven electronic bibliographic databases were searched from inception to December 25, 2021. The mean difference (MD) or risk ratio (RR) with its corresponding 95% CI was selected as effect size. The meta-analysis of all data was conducted using RevMan 5.4 and the evidence was summarized according to GRADE (the grading of recommendation, assessment, development, and evaluation). RESULTS: Twelve randomized control trials consisting of 1,033 women with cervical cancer who had undergone RH were included. Compared with women in the control group, women receiving LFES had improved therapeutic effect (RR = 0.22, 95% CI: 0.16-0.29) and reduced residual urine volume (MD = -32.27, 95% CI: -34.10 to -30.43) and catheter retention time (MD = -4.46, 95% CI: -5.17 to -3.76) following treatment. Muscle strength scores of pelvic floor type I and type II muscle fibers in the LFES group were also higher than in the control group (MD = 1.07, 95% CI: 0.91-1.24). CONCLUSION: LFES may be an effective auxiliary treatment for women with cervical cancer after hysterectomy, which can help reduce the duration of indwelling urethral catheter and residual urine volume.

Rhamnazin Inhibits Hepatocellular Carcinoma Cell Aggressiveness in Vitro via Glutathione Peroxidase 4-Dependent Ferroptosis.

Ferroptosis, a newly recognized type of programmed cell death, is characterized by lipid peroxidation and implicated in multiple pathophysiological processes. Ferroptosis agonists are attracting tremendous attention for the clinical management of malignancy. We uncovered that rhamnazin exerted its anti-cancer property via reducing cell proliferation and invasion in hepatocellular carcinoma (HCC) cells. The ferroptosis inhibitor ferrostatin-1 (Fer-1) partially reversed rhamnazin-triggered cell proliferation inhibition, indicating that ferroptosis contributed to the inhibitory potency of rhamnazin. Further characterization corroborated that exposure with rhamnazin, reactive oxygen species (ROS) accumulation and lipid peroxidation, and iron content were elevated in HCC cells. Mechanistically, we demonstrated that glutathione peroxidase 4 (GPX4) was involved in rhamnazin-initiated ferroptotic cell death. Overexpression of GPX4 weakened HCC cell ferroptosis caused by rhamnazin. Collectively, these results strongly suggest that rhamnazin exerts a ferroptosis-inducing role in HCC cells by inhibiting GPX4 expression.

Bmal1 inhibits phenotypic transformation of hepatic stellate cells in liver fibrosis via IDH1/α-KG-mediated glycolysis.

Hepatic stellate cells (HSCs) play an important role in the initiation and development of liver fibrogenesis, and abnormal glucose metabolism is increasingly being considered a crucial factor controlling phenotypic transformation in HSCs. However, the role of the factors affecting glycolysis in HSCs in the experimental models of liver fibrosis has not been completely elucidated. In this study, we showed that glycolysis was significantly enhanced, while the expression of brain and muscle arnt-like protein-1 (Bmal1) was downregulated in fibrotic liver tissues of mice, primary HSCs, and transforming growth factor-ß1 (TGF-ß1)-induced LX2 cells. Overexpression of Bmal1 in TGF-ß1-induced LX2 cells blocked glycolysis and inhibited the proliferation and phenotypic transformation of activated HSCs. We further confirmed the protective effect of Bmal1 in liver fibrosis by overexpressing Bmal1 from hepatic adeno-associated virus 8 in mice. In addition, we also showed that the regulation of glycolysis by Bmal1 is mediated by the isocitrate dehydrogenase 1/α-ketoglutarate (IDH1/α-KG) pathway. Collectively, our results indicated that a novel Bmal1-IDH1/α-KG axis may be involved in regulating glycolysis of activated HSCs and might hence be used as a therapeutic target for alleviating liver fibrosis.