Overcoming Cancer Persister Cells by Stabilizing the ATF4 Promoter G-quadruplex.

Persister cells (PS) selected for anticancer therapy have been recognized as a significant contributor to the development of treatment-resistant malignancies. It is found that imposing glutamine restriction induces the generation of PS, which paradoxically bestows heightened resistance to glutamine restriction treatment by activating the integrated stress response and initiating the general control nonderepressible 2-activating transcription factor 4-alanine, serine, cysteine-preferring transporter 2 (GCN2-ATF4-ASCT2) axis. Central to this phenomenon is the stress-induced ATF4 translational reprogramming. Unfortunately, directly targeting ATF4 protein has proven to be a formidable challenge because of its flat surface. Nonetheless, a G-quadruplex structure located within the promoter region of ATF4 (ATF4-G4) is uncovered and resolved, which functions as a transcriptional regulator and can be targeted by small molecules. The investigation identifies the natural compound coptisine (COP) as a potent binder that interacts with and stabilizes ATF4-G4. For the first time, the high-resolution structure of the COP-ATF4-G4 complex is determined. The formation of this stable complex disrupts the interaction between transcription factor AP-2 alpha (TFAP2A) and ATF4-G4, resulting in a substantial reduction in intracellular ATF4 levels and the eventual death of cancer cells. These seminal findings underscore the potential of targeting the ATF4-G4 structure to yield significant therapeutic advantages within the realm of persister cancer cells induced by glutamine-restricted therapy.

Evaluation of the adjuvant effect of imiquimod and CpG ODN 1826 in chimeric DNA vaccine against Japanese encephalitis.

Vaccines represent a significant milestone in the history of human medical science and serve as the primary means for controlling infectious diseases. In recent years, the geographical distribution of Japanese encephalitis viruses (JEV) of various genotypes has become increasingly complex, which provides a rationale for the development of safer and more effective vaccines. The advent of subunit and nucleic acid vaccines, especially propelled by advancements in genetic engineering since the 1980s, has accelerated the application of novel adjuvants. These novel vaccine adjuvants have diversified into toll-like receptor (TLR) agonists, complex adjuvants, nanoparticles and so on. However, the efficacy of adjuvant combinations can vary depending on the host system, disease model, or vaccine formulation, sometimes resulting in competitive or counteractive effects. In our previous study, we constructed a pJME-LC3 chimeric DNA vaccine aimed at inducing an immune response through autophagy induction. Building on this, we investigated the impact of the TLR7/8 agonist imiquimod (IMQ) and the TLR9 agonist CpG ODN 1826 as adjuvants on the immunogenicity of the Japanese encephalitis chimeric DNA vaccine. Our findings indicate that the combination of the pJME-LC3 vaccine with IMQ and CpG ODN 1826 adjuvants enhanced the innate immune response, promoting the maturation and activation of antigen-presenting cells in the early immune response. Furthermore, it played a regulatory and optimizing role in subsequent antigen-specific immune responses, resulting in effective cellular and humoral immunity and providing prolonged immune protection. The synergistic effect of IMQ and CpG ODN 1826 as adjuvants offers a novel approach for the development of Japanese encephalitis nucleic acid vaccines.

Enrichment methods of N-linked glycopeptides from human serum or plasma: A mini-review.

Human diseases often correlate with changes in protein glycosylation, which can be observed in serum or plasma samples. N-glycosylation, the most common form, can provide potential biomarkers for disease prognosis and diagnosis. However, glycoproteins constitute a relatively small proportion of the total proteins in human serum and plasma compared to the non-glycosylated protein albumin, which constitutes the majority. The detection of microheterogeneity and low glycan abundance presents a challenge. Mass spectrometry facilitates glycoproteomics research, yet it faces challenges due to interference from abundant plasma proteins. Therefore, methods have emerged to enrich N-glycans and N-linked glycopeptides using glycan affinity, chemical properties, stationary phase chemical coupling, bioorthogonal techniques, and other alternatives. This review focuses on N-glycans and N-glycopeptides enrichment in human serum or plasma, emphasizing methods and applications. Although not exhaustive, it aims to elucidate principles and showcase the utility and limitations of glycoproteome characterization.

Native mitral valve fungal endocarditis caused by Aspergillus fumigatus: A case report.

INTRODUCTION: Aspergillus endocarditis is a rare fungal infection associated with a poor prognosis. Most cases of Aspergillus endocarditis involve prosthetic valves, with native valve involvement being rarely reported. CASE PRESENTATION: A 53-year-old asian female patient presented with fever, chills, dyspnea, generalized fatigue, and significant weight loss one month after undergoing left lower lobectomy for a pulmonary abscess. Echocardiogram showed a large mobile vegetation with a broad base on the anterior leaflet of the mitral valve, resembling atrial myxoma. Despite negative blood cultures, circulating DNA of Aspergillus fumigatus was detected by metagenome Next Generation Sequencing, prompting the initiation of empiric antifungal therapy with voriconazole. Emergency surgery, involving thorough debridement and mitral valve replacement, was successfully performed. Indefinite fungal suppression therapy with oral voriconazole is continued to mitigate the risk of recurrence. The patient survived with no signs of Aspergillus disease recurrence for four years. CLINICAL DISCUSSION: Diagnosis of Aspergillus endocarditis requires a high index of suspicion and is often delayed due to consistently negative results from blood cultures. Non-culture-based methods, particularly metagenome Next-Generation Sequencing, play a crucial role in early diagnosis and therapeutic decision-making. Surgical debridement and valve replacement are imperative for survival in cases of Aspergillus endocarditis. Voriconazole should be considered the primary fungicidal agent for its treatment. Moreover, lifelong fungal suppression therapy is strongly recommended for all survivors to ensure long-term survival and minimize the risk of recurrence. CONCLUSION: Despite grim prognosis associated with Aspergillus endocarditis, patients can attain long-term survival through meticulous surgical debridement and lifelong antifungal therapy.

Conserved Enzymatic Cascade for Bacterial Azoxy Biosynthesis.

Azoxy compounds exhibit a wide array of biological activities and possess distinctive chemical properties. Although there has been considerable interest in the biosynthetic mechanisms of azoxy metabolites, the enzymatic basis responsible for azoxy bond formation has remained largely enigmatic. In this study, we unveil the enzyme cascade that constructs the azoxy bond in valanimycin biosynthesis. Our research demonstrates that a pair of metalloenzymes, comprising a membrane-bound hydrazine synthase and a nonheme diiron azoxy synthase, collaborate to convert an unstable pathway intermediate to an azoxy product through a hydrazine-azo-azoxy pathway. Additionally, by characterizing homologues of this enzyme pair from other azoxy metabolite pathways, we propose that this two-enzyme cascade could represent a conserved enzymatic strategy for azoxy bond formation in bacteria. These findings provide significant mechanistic insights into biological N-N bond formation and should facilitate the targeted isolation of bioactive azoxy compounds through genome mining.

Identification of the Microbial Transformation Products of Secoisolariciresinol Using an Untargeted Metabolomics Approach and Evaluation of the Osteogenic Activities of the Metabolites.

Secoisolariciresinol (SECO) is one of the major lignans occurring in various grains, seeds, fruits, and vegetables. The gut microbiota plays an important role in the biotransformation of dietary lignans into enterolignans, which might exhibit more potent bioactivities than the precursor lignans. This study aimed to identify, synthesize, and evaluate the microbial metabolites of SECO and to develop efficient lead compounds from the metabolites for the treatment of osteoporosis. SECO was fermented with human gut microbiota in anaerobic or micro-aerobic environments at different time points. Samples derived from microbial transformation were analyzed using an untargeted metabolomics approach for metabolite identification. Nine metabolites were identified and synthesized. Their effects on cell viability, osteoblastic differentiation, and gene expression were examined. The results showed that five of the microbial metabolites exerted potential osteogenic effects similar to those of SECO or better. The results suggested that the enterolignans might account for the osteoporotic effects of SECO in vivo. Thus, the presence of the gut microbiota could offer a good way to form diverse enterolignans with bone-protective effects. The current study improves our understanding of the microbial transformation products of SECO and provides new approaches for new candidate identification in the treatment of osteoporosis.

Sanguinarine induces apoptosis in osteosarcoma by attenuating the binding of STAT3 to the single-stranded DNA-binding protein 1 (SSBP1) promoter region.

BACKGROUND AND PURPOSE: Osteosarcoma, a primary malignant bone tumour prevalent among adolescents and young adults, remains a considerable challenge despite protracted progress made in enhancing patient survival rates over the last 40 years. Consequently, the development of novel therapeutic approaches for osteosarcoma is imperative. Sanguinarine (SNG), a compound with demonstrated potent anticancer properties against various malignancies, presents a promising avenue for exploration. Nevertheless, the intricate molecular mechanisms underpinning SNG's actions in osteosarcoma remain elusive, necessitating further elucidation. EXPERIMENTAL APPROACH: Single-stranded DNA-binding protein 1 (SSBP1) was screened out by differential proteomic analysis. Apoptosis, cell cycle, reactive oxygen species (ROS) and mitochondrial changes were assessed via flow cytometry. Western blotting and quantitative real-time reverse transcription PCR (qRT-PCR) were used to determine protein and gene levels. The antitumour mechanism of SNG was explored at a molecular level using chromatin immunoprecipitation (ChIP) and dual luciferase reporter plasmids. KEY RESULTS: Our investigation revealed that SNG exerted an up-regulated effect on SSBP1, disrupting mitochondrial function and inducing apoptosis. In-depth analysis uncovered a mechanism whereby SNG hindered the JAK/signal transducer and activator of transcription 3 (STAT3) signalling pathway, relieved the inhibitory effect of STAT3 on SSBP1 transcription, and inhibited the downstream PI3K/Akt/mTOR signalling axis, ultimately activating apoptosis. CONCLUSIONS AND IMPLICATIONS: The study delved further into elucidating the anticancer mechanism of SNG in osteosarcoma. Notably, we unravelled the previously undisclosed apoptotic potential of SSBP1 in osteosarcoma cells. This finding holds substantial promise in advancing the development of novel anticancer drugs and identification of therapeutic targets.

Del-Nido cardioplegia in cardiac surgery for elderly patients: a propensity score-matched analysis.

OBJECTIVES: To compare the safety and efficacy of del-Nido cardioplegia (DNC) with traditional 4:1 cold blood cardioplegia (CBC) in coronary artery bypass grafting and/or valve surgeries in elderly patients. METHODS: The present study is a retrospective case-series study that included 302 consecutive patients aged 70 years and over who underwent on-pump valve surgery and/or coronary artery bypass graft (CABG). DNC was administered to 90 patients and CBC to 212 patients. After propensity-score matching, 89 pairs were compared. The safety and efficacy were analyzed between the two groups. RESULTS: The DNC group had a similar mortality (3.4% vs. 5.6%, OR = 0.79, P = 0.720) and extracorporeal membrane oxygenation (ECMO) implantation rate (1.1% vs. 2.2%, OR = 0.75, P = 1.000) to the CBC group, a lower incidence of postoperative intra-aortic balloon pump (IABP) implantation (1.1% vs. 9.0%, OR = 0.54, P = 0.034) and a higher left ventricular ejection fraction (LVEF) at discharge (60 (56-64) % vs. 57 (51-62)%, P = 0.007). The estimated glomerular filtration rate (eGFR) in the DNC group was higher when the patient was transferred to the intensive care unit (79.4 (65.0-94.3) ml/min/1.73m2 vs. 77.2 (59.8-88.7) ml/min/1.73m2, P = 0.014), but no significant differences were identified after 24 h. The serum lactate values of the DNC group were significantly lower than those of the CBC group (0 h: 2.7 (2.0-3.2) vs. 3.2 (2.4-4.4), P = 0.001; 3 h: 3.2 (2.0-4.8) vs. 4.8 (2.8-6.6), P < 0.001; 6 h: 3.5 (2.2-5.4) vs. 5.8 (3.4-8.4), P < 0.001; 9 h: 3.4 (2.0-7.0) vs. 5.5 (2.9-8.3), P = 0.005). There were no differences between the two groups in respect of lactate levels at 12 h and thereafter. Postoperative creatinine kinase-MB concentrations were similar between the two groups. CONCLUSIONS: Del-Nido cardioplegia is safe and effective in elderly patients undergoing CABG and/or valve surgery.

Outcomes of minimally invasive isolated tricuspid valve reoperation after left-side valve surgery: A single-center experience.

Background: Late severe tricuspid regurgitation (TR) after left-side valve surgery (LSVS) is not uncommon. However, the tricuspid valve has been deemed the forgotten valve because the isolated TR is well tolerated with medication, and reoperation has a higher rate of adverse events. With the advancement of minimally invasive techniques, isolated tricuspid valve reoperation (ITVR) via totally endoscopy or transcatheter approach brings the tricuspid valve into spotlight. Our aim is to report the safety and efficacy of minimally invasive ITVR using endoscopic and transcatheter approaches. Methods: From October 2020 to October 2021, 21 patients with LSVS history and secondary massive TR underwent minimally invasive ITVR in our institution. Baseline characteristics, surgical outcomes and follow-up results were analyzed, and data between the totally endoscopy approach and the transcatheter approach were compared. Results: Of the 21 cases, totally endoscopic isolated tricuspid valve surgery (EITVS) accounts for 16 (76.2%) cases, with 14 tricuspid valvuloplasty cases, and 2 tricuspid valve replacement cases; the remaining 5 (23.8%) cases underwent transcatheter tricuspid valve replacement (TTVR). The mean age was (60.0 ± 8.4) years, with 15 (71.4%) being female. Minimally invasive ITVR procedures were 100% successfully performed in all patients without any perioperative mortality, sternotomy conversion, or reoperation. During the median follow-up of 16.8 months (IQR, 13.0-20.6 months), New York Heart Association Class improved significantly from baseline (P = 0.004). TR severity was significantly improved during postoperative and follow-up period (both P < 0.001). Compared with the EITVS group, the TTVR group had a higher clinical risk score [8.00 (8.00, 9.00) vs. 5.00 (3.25, 5.00), P = 0.001], but a higher success rate in reducing TR to less than grade 1+ (100 vs. 43.8%, P = 0.045) at follow-up. Conclusion: In our series, minimally invasive ITVR, including EITVS and TTVR, is a safe and feasible option for severe TR after LSVS, and presents excellent early outcomes in selected patients. TTVR is a reliable alternative for patients with high surgical risk. To improve the results of ITVR, it is necessary to improve patient's preoperative status or perform reoperation before the onset of significant right heart failure. Further studies with a larger sample size and a longer follow-up period are awaited.

Toxic epidermal necrolysis in hepatitis A infection with acute-on-chronic liver failure: Case report and literature review.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are acute inflammatory skin adverse reactions characterized by epidermal exfoliation and multi-site mucositis and are considered medical emergencies. The risk factors for SJS/TEN include immune disorders, malignancy, and genetic susceptibility. In most cases, medication is considered to be the leading cause of TEN. In addition, several studies suggest that infections, such as the herpes simplex virus, human immunodeficiency virus (HIV), Mycoplasma pneumoniae, streptococcus, and meningococcus infections, can trigger the occurrence of SJS/TEN. In this rare case, we share our experience managing TEN in a hepatitis A virus infection with an acute-on-chronic liver failure patient. A 38-year-old man was infected with hepatitis A virus on the basis of liver cirrhosis and progressed to acute-on-chronic liver failure. As the infection progressed, the target-like skin lesions accompanied by mucosal involvement worsened. The condition of the patient progressively worsened with a severe generalized rash, bullae, and epidermal detachment accompanied by severe erosive mucosal lesions. His skin detachment area gradually involved 30% of the body surface area (BSA), and the disease progressed to TEN. The intravenous infusion of corticosteroids alleviated the patient's hypersensitivity, and the patient obtained lasting remission without severe adverse reactions and complications.

Heritable and Nonheritable Rumen Bacteria Are Associated with Different Characters of Lactation Performance of Dairy Cows.

Recent studies have reported that some rumen microbes are heritable. However, it is necessary to clarify the functions and specific contributions of the heritable rumen microbes to cattle phenotypes (microbiability) in comparison with those that are nonheritable. This study aimed to identify the distribution and predicted functions of heritable and nonheritable bacterial taxa at species level in the rumen of dairy cows and their respective contributions to energy-corrected milk yield, protein content and yield, and fat content and yield in milk. Thirty-two heritable and 674 nonheritable bacterial taxa were identified at species level, and the functional analysis revealed that predicted microbial functions for both groups were mainly enriched for energy, amino acid, and ribonucleotide metabolism. The mean microbiability (to reflect a single taxon's contribution) of heritable bacteria was found to range from 0.16% to 0.33% for the different milk traits, whereas the range for nonheritable bacteria was 0.03% to 0.06%. These findings suggest a strong contribution by host genetics in shaping the rumen microbiota, which contribute significantly to milk production traits. Therefore, there is an opportunity to further improve milk production traits through attention to host genetics and the interaction with the rumen microbiota. IMPORTANCE Rumen bacteria produce volatile fatty acids which exert a far-reaching influence on hepatic metabolism, mammary gland metabolism, and animal production. In the current study, 32 heritable and 674 nonheritable bacterial taxa at species level were identified, and shown to have different microbiability (overall community contribution) and mean microbiability (the average of a single taxon's contribution) for lactation performance. The predicted functions of heritable and nonheritable bacterial taxa also differed, suggesting that targeted nutritional and genetic breeding approaches could be used to manipulate them to improve dairy cow performance.

The Value of Early Positive Nucleic Acid Test and Negative Conversion Time of SARS-CoV-2 RNA in the Clinical Outcome of COVID-19 Patients.

Background: The outbreak of coronavirus disease (COVID-19) poses a great threat to global public health. At present, the number of newly confirmed COVID-19 cases and deaths is increasing worldwide. The strategy of comprehensive and scientific detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through quantitative real-time polymerase chain reaction (qRT-PCR) for special populations and environments provides great support for the prevention and control of this pandemic in China. Our study focused on determining the factors associated with the length of time from symptom onset to the first positive nucleic acid test of throat swabs in COVID-19 patients, evaluating the effect of early positive nucleic acid detection on the disease severity and its significance in prognosis, and predicting the factors associated with the time from positive SARS-CoV-2 RNA test to negative conversion (negative conversion of SARS-CoV-2 virus) in COVID-19 patients. Methods: This study included 116 hospitalized patients with COVID-19 from January 30, 2020 to March 4, 2020 in Wuhan, China. Throat swab samples were collected for qRT-PCR testing of SARS-CoV-2 RNA, and all patients included in this study were positive for this test. Results: The multivariate Cox proportional hazards model showed that disease severity (HR = 0.572; 95% CI 0.348-0.942; p = 0.028) was a protective factor for the time from symptom onset to positive nucleic acid detection. Meanwhile, the time from symptom onset to positive nucleic acid detection (HR = 1.010; 95% CI 1.005-1.020; p = 0.0282) was an independent risk factor for the delay in negative conversion time of SARS-CoV-2 virus. However, the severity of the disease (HR=1.120; 95% CI 0.771-1.640; p = 0.544) had no correlation with the negative conversion time of SARS-CoV-2 virus. Conclusions: Patients with more severe disease had a shorter time from symptom onset to a positive nucleic acid test. Prolonged time from symptom onset to positive nucleic acid test was an independent risk factor for the delay in negative conversion time of SARS-CoV-2 virus, and the severity of the disease had no correlation with negative conversion time of SARS-CoV-2 virus.

The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases.

For decades, it has been widely believed that the blood-brain barrier (BBB) provides an immune privileged environment in the central nervous system (CNS) by blocking peripheral immune cells and humoral immune factors. This view has been revised in recent years, with increasing evidence revealing that the peripheral immune system plays a critical role in regulating CNS homeostasis and disease. Neurodegenerative diseases are characterized by progressive dysfunction and the loss of neurons in the CNS. An increasing number of studies have focused on the role of the connection between the peripheral immune system and the CNS in neurodegenerative diseases. On the one hand, peripherally released cytokines can cross the BBB, cause direct neurotoxicity and contribute to the activation of microglia and astrocytes. On the other hand, peripheral immune cells can also infiltrate the brain and participate in the progression of neuroinflammatory and neurodegenerative diseases. Neurodegenerative diseases have a high morbidity and disability rate, yet there are no effective therapies to stop or reverse their progression. In recent years, neuroinflammation has received much attention as a therapeutic target for many neurodegenerative diseases. In this review, we highlight the emerging role of the peripheral and central immune systems in neurodegenerative diseases, as well as their interactions. A better understanding of the emerging role of the immune systems may improve therapeutic strategies for neurodegenerative diseases.

Separation and Enrichment of Alkaloids from Coptidis Rhizoma and Euodiae Fructus by Macroporous Resin and Evaluation of the Effect on Bile Reflux Gastritis Rats.

The Zuojin Pill consists of Coptidis Rhizoma (CR) and Euodiae Fructus (EF). It has been a classic prescription for the treatment of gastrointestinal diseases in China since ancient times. Alkaloids are considered to be its main pharmacologically active substances. The authors of the present study investigated the feasibility of preparing high purity total alkaloids (TAs) from CR and EF extracts separately and evaluated the effect for the treatment of bile reflux gastritis (BRG). Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. were used in the study. An optimized method for the enrichment and purification of TAs with macroporous resin was established. Furthermore, qualitative analysis by using ultra-high performance liquid chromatography coupled with electrospray ionization and quadrupole-time of flight mass spectrometry (UHPLC-ESI-QTOF-MS) was explored to identify the components of purified TAs. Thirty-one compounds, thirty alkaloids and one phenolic compound, were identified or tentatively assigned by comparison with reference standards or literature data. A method of ultra-high performance liquid chromatography coupled with diode array detector (UHPLC-DAD) for quantitative analysis was also developed. The contents of nine alkaloids were determined. Moreover, a rat model of BRG was used to investigate the therapeutic effect of the combination of purified TAs from CR and EF. Gastric pathologic examination suggested that the alkaloids' combination could markedly attenuate the pathological changes of gastric mucosa.

Totally endoscopic aortic valve replacement: Techniques and early results.

Objective: To demonstrate the technical details of total endoscopic aortic valve replacement using a standard prosthesis, compare the clinical effect and safety of endoscopic aortic valve replacement and traditional aortic valve replacement. Methods: From 2020 to 2021, 60 consecutive patients underwent elective isolated aortic valve replacement (AVR). They were divided into two groups: the total endoscopic AVR group (TE-AVR group, 29 patients, nine women, aged 51.65 ± 11.79 years), and the traditional full-sternotomy group (AVR group, 31 patients, 13 women, aged 54.23 ± 12.06 years). Three working ports were adopted in the TE-AVR procedure. Results: No patient died in either group. The cardiopulmonary bypass (CPB) time and aortic cross-clamp (ACC) time in the TE-AVR group were longer than those in the AVR group (CPB time: 177.6 ± 43.2 vs. 112.1 ± 18.1 min, p < 0.001; ACC time: 118.3 ± 29.7 vs. 67.0 ± 13.2 min, p < 0.001). However, the mechanical ventilation duration (14.2 ± 9.3 vs. 24.0 ± 18.9 h, p = 0.015) and postoperative hospital stay (6.0 ± 1.7 vs. 8.0 ± 4.5 days, p = 0.025) were shorter in patients of TE-AVR group than those of AVR group. Although the ICU stay (55.1 ± 26.9 vs. 61.5 ± 44.8 h, p = 0.509) and post-operative chest drainage of the first 24 h (229.8 ± 125.0 vs. 273.2 ± 103.2 ml, p = 0.146) revealed no statistical difference, there was a decreasing trend in the TE-AVR group. Among the patients of the TE-AVR group, two patients were converted to thoracotomy because of mild to moderate paravalvular leakage identified by intraoperative transesophageal echocardiography. Conclusion: Total endoscopic aortic valve replacement is safe and feasible, with less trauma and quicker recovery.

The Emerging Role of Ferroptosis in Liver Diseases.

Ferroptosis is a newly discovered type of cell death mediated by iron-dependent lipid peroxide. The disturbance of iron metabolism, imbalance of the amino acid antioxidant system, and lipid peroxide accumulation are considered distinct fingerprints of ferroptosis. The dysregulation of ferroptosis has been intensively studied in recent years due to its participation in various diseases, including cancer, kidney injury, and neurodegenerative diseases. Notably, increasing evidence indicates that ferroptosis plays different roles in a wide spectrum of liver diseases. On the one hand, inhibiting ferroptosis may counteract the pathophysiological progression of several liver diseases, such as alcoholic liver injury, nonalcoholic steatosis hepatitis and fibrosis. On the other hand, inducing ferroptosis may restrict the emergence of secondary resistance to current medicines, such as sorafenib, for hepatocellular carcinoma (HCC) therapy. Here, we summarize the biological characteristics and regulatory signalling pathways of ferroptosis involved in liver disease. The current available medical agents targeting ferroptosis, including inducers or inhibitors applied in liver diseases, are also reviewed. This work aims to provide new insight into the emerging role of pathogenesis and therapeutic approaches for liver diseases.

Non-ephedrine constituents from the herbaceous stems of Ephedra sinica.

Three new flavonoids, ephedroside A (1), ephedroside B (2), ephedroside C (3), together with fifty-four known compounds 4-57 were isolated from the EtOH extract of the herbaceous stems of Ephedra sinica. The structures of these compounds were elucidated by spectroscopic techniques, as well as by comparison with literature data. Thirty-eight of these compounds were isolated from the genus Ephedra for the first time. The antimicrobial activities of eight compounds were tested by measuring the minimum inhibitory concentrations (MIC) against bacteria (both Gram positive and Gram negative) and fungi, and were found to be in the range of 0.105-0.926 mM. Among them, compound 2 showed the best antimicrobial activity against Pseudomonas aeruginosa with MIC value of 0.105 mM.

Harzianic Acid from Trichoderma afroharzianum Is a Natural Product Inhibitor of Acetohydroxyacid Synthase.

Acetohydroxyacid synthase (AHAS) is the first enzyme in the branched-chain amino acid biosynthetic pathway and is a validated target for herbicide and fungicide development. Here we report harzianic acid (HA, 1) produced by the biocontrol fungus Trichoderma afroharzianum t-22 (Tht22) as a natural product inhibitor of AHAS. The biosynthetic pathway of HA was elucidated with heterologous reconstitution. Guided by a putative self-resistance enzyme in the genome, HA was biochemically demonstrated to be a selective inhibitor of fungal AHAS, including those from phytopathogenic fungi. In addition, HA can inhibit a common resistant variant of AHAS in which the active site proline is mutated. Structural analysis of AHAS complexed with HA revealed the molecular basis of competitive inhibition, which differs from all known commercial AHAS inhibitors. The alternative binding mode also rationalizes the selectivity of HA, as well as effectiveness toward resistant mutants. A proposed role of HA biosynthesis by Tht22 in the rhizosphere is discussed based on the data.

Clinical characteristics and peripheral immunocyte subsets alteration of 85 COVID-19 deaths.

OBJECTIVES: To retrospectively evaluate the clinical and immunological characteristics of patients who died of COVID-19 and to identify patients at high risk of death at an early stage and reduce their mortality. RESULTS: Total white blood cell count, neutrophil count and C-reactive protein were significantly higher in patients who died of COVID-19 than those who recovered from it (p < 0.05), but the total lymphocyte count, CD4 + T cells, CD8 + T cells, B cells and natural killer cells were significantly lower when compared in the same groups. Multiple logistic regression analysis showed that increased D-dimer, decreased CD4 + T cells and increased neutrophils were risk factors for mortality. Further multiple COX regression demonstrated that neutrophil ≥ 5.27 × 109/L increased the risk of death in COVID-19 patients after adjustment for age and gender. However, CD4 + T cells ≥ 260/µL appeared to reduce the risk of death. CONCLUSION: SARS-CoV-2 infection led to a significant decrease of lymphocytes, and decreased CD4 + T cell count was a risk factor for COVID-19 patients to develop severe disease and death. METHODS: This study included 190 hospitalized COVID-19 patients from January 30, 2020 to March 4, 2020 in Wuhan, China, of whom 85 died and 105 recovered. Two researchers independently collected the clinical and laboratory data from electronic medical records.