Pharmacokinetic and Safety Study of Bismuth Potassium Citrate Formulations in Healthy Subjects.

BACKGROUND: Potassium bismuth citrate is a gastric mucosal protector and a key drug for treating peptic ulcers. OBJECTIVE: To evaluate the pharmacokinetic characteristics and safety of 120-mg bismuth potassium citrate formulations administered orally under fasting conditions in healthy Chinese subjects. METHOD: A single-center open two-cycle trial was conducted on 12 healthy subjects who received a single oral dose of 120 mg of bismuth potassium citrate. The plasma concentration of bismuth was determined using a validated inductively coupled plasma mass spectrometry (ICP‒MS) method. The pharmacokinetic parameters, including maximum serum concentration (Cmax) and area under the curve concentration-time curve (AUC0-t and AUC0-∞), and safety were evaluated via noncompartment analysis. RESULTS: The ratios of the least square geometric mean ratio between the test (T) and reference (R) formulations for Cmax, AUC0-t, and AUC0-∞ were 44.8%, 55.5%, and 64.4%, respectively; the bilateral 95% confidence intervals (Cis) for these parameters were 20.2-99.6%, 24.1-127.5%, and 23.7-175.0%, respectively, and the non-inferior limits for these parameters were 169.4%, 198.8%, and 200.5%, respectively. The upper limits of the one-sided 97.5% confidence interval for the least squares geometric mean ratio (T/R) were lower than the non-inferior limits. No serious adverse reactions or adverse reactions leading to detachment were observed among the subjects. CONCLUSION: The concentration of bismuth in the blood of healthy subjects in the T formulation was not greater than that in the R formulation. Similarly, the safety of oral administration of 120 mg of bismuth potassium citrate formulations to healthy subjects was good. The trial registration number (TRN) was [2018] 013, 6 December 2018.

Widely targeted metabolomics analysis reveals the formation of nonvolatile flavor qualities during oolong tea manufacturing: a case study of Jinguanyin.

Background: The manufacturing processes of oolong tea significantly impact its nonvolatile components, leading to the emergence of distinct flavor attributes. Understanding the dynamic changes in nonvolatile components during the manufacturing stages of the Jinguanyin (JGY) cultivar is crucial for unraveling the potential mechanism behind flavor formation. Methods: Comprehensive metabolomics and sensomics analyses were conducted to investigate the dynamic changes in nonvolatile components throughout various phases of oolong tea processing, focusing on the JGY cultivar. Results: A total of 1,005 nonvolatile metabolites were detected, with 562 recognized as significant differential metabolites during various phases of oolong tea processing. Notably, the third turning-over, third setting, and high-temperature treatments exhibited the most significant effects on the nonvolatile metabolites of oolong tea. JGY finished tea demonstrated a characteristic flavor profile, marked by mellowness, sweetness in aftertaste, and a significant Yin rhyme. This flavor profile was collectively promoted by the accumulation of amino acids and organic acids, the decrease in flavonols (3-O-glycosides) and sugar substances, the alteration of phenolic acids, and the stabilization of caffeine. Conclusion: This study contribute to the understanding of the formation of oolong tea flavor qualities. The dynamic changes observed in various types of nonvolatile compounds during oolong tea processing shed light on the intricate interplay of metabolites and their influence on the final flavor characteristics.

Association between the NEP rs701109 polymorphism and the clinical efficacy and safety of sacubitril/valsartan in Chinese patients with heart failure.

OBJECTIVE: Sacubitril/valsartan is a commonly used medicine for treating heart failure (HF) patients, but the treatment effects significantly vary. Neprilysin (NEP) and carboxylesterase 1 (CES1) play an important role in the efficacy of sacubitril/valsartan. The purpose of this study was to explore the relationship between NEP and CES1 gene polymorphisms and the efficacy and safety of sacubitril/valsartan treatment in HF patients. METHODS: Genotyping of 10 single nucleotide polymorphisms (SNPs) of the NEP and CES1 genes in 116 HF patients was performed by the Sequenom MassARRAY method, and logistic regression and haplotype analysis were used to evaluate the associations between SNPs and the clinical efficacy and safety of sacubitril/valsartan in HF patients. RESULTS: A total of 116 Chinese patients with HF completed the whole trial, and T variations in rs701109 in NEP gene were an independent risk factor (P = 0.013, OR = 3.292, 95% CI:1.287-8.422) for the clinical efficacy of sacubitril/valsartan. Furthermore, haplotype analysis of 6 NEP SNPs (including rs701109) was performed and showed that the CGTACC and TGTACC haplotypes were significantly associated with clinical efficacy (OR = 0.095, 95%CI: 0.012-0.723, P = 0.003; OR = 5.586, 95% CI: 1.621-19.248, P = 0.005). Moreover, no association was found between SNPs of other selected genes in terms of efficacy in HF patients, and no association was observed between SNPs and symptomatic hypotension. CONCLUSION: Our results suggest an association between rs701109 and sacubitril/valsartan response in HF patients. Symptomatic hypotension is not associated with the presence of NEP polymorphisms.

Pharmacokinetics, safety, and bioequivalence of apixaban tablets in healthy Chinese subjects under fasting and fed conditions.

OBJECTIVE: To evaluate the pharmacokinetics (PK), safety, and bioequivalence of two formulations of apixaban in healthy Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS: A single-center, randomized, open, single-dose, two-period crossover PK study was carried out under fasting and fed conditions in 64 healthy subjects enrolled in either the fasting (36 subjects) or the fed (28 subjects) arms of the study. Subjects received a single oral dose of 2.5 mg apixaban tablets as test (T) or reference (R) formulation. The primary PK parameters determined were the area under the plasma concentration-time curve from zero to t and ∞ (AUC0-t and AUC0-∞) and the maximal plasma concentration (Cmax). Safety was assessed mainly from the occurrence of adverse events (AEs). RESULTS: A single drop-out in the fed arm of the trial was excluded from the statistical evaluation. The 90% confidence intervals (CIs) for the geometric mean ratio (GMR) for T/R using AUC0-t were 95.4 - 100.9% and 97.8 - 103.8%, and for AUC0-∞ were 95.3 - 100.6% and 98.3 - 104.3% under fasting (36 subjects) and fed (27 subjects) conditions, respectively. Similarly, the 90% CIs for Cmax were 94.6 - 103.1% and 88.8 - 102.0% under fasting (36 subjects) and the fed (27 subjects) conditions, respectively. Therefore, the 90% CIs for the T/R AUC and Cmax ratios were within the standard range for bioequivalence (80.0 - 125.0%). There were no serious adverse events (SAEs). CONCLUSION: The test and reference 2.5 mg apixaban tablets were bioequivalent and both showed good tolerability and safety.

Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes.

Neuroinflammation and the NACHT, LRR, and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury (TBI). Maraviroc, a C-C chemokine receptor type 5 antagonist, has been viewed as a new therapeutic strategy for many neuroinflammatory diseases. We studied the effect of maraviroc on TBI-induced neuroinflammation. A moderate-TBI mouse model was subjected to a controlled cortical impact device. Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days. Western blot, immunohistochemistry, and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI. Our results suggest that maraviroc administration reduced NACHT, LRR, and PYD domains-containing protein 3 inflammasome activation, modulated microglial polarization from M1 to M2, decreased neutrophil and macrophage infiltration, and inhibited the release of inflammatory factors after TBI. Moreover, maraviroc treatment decreased the activation of neurotoxic reactive astrocytes, which, in turn, exacerbated neuronal cell death. Additionally, we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score, rotarod test, Morris water maze test, and lesion volume measurements. In summary, our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI, and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.

Pharmacokinetics, Bioequivalence, and Safety of 2 Formulations of Hydroxychloroquine Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

The purpose of this trial was to evaluate the pharmacokinetics (PK), bioequivalence (BE), and safety of 2 preparations of hydroxychloroquine (200-mg tablet) under fasting and fed conditions. A total of 180 subjects (fasting condition: n = 80; fed condition: n = 100) were randomly enrolled in this randomized, open, single-dose, single-cycle parallel phase Ⅰ clinical study. Under the 2 conditions, the subjects were randomly administered the test (T) or reference (R) tablet, both at a dose of 200 mg (1 tablet). Liquid chromatography-tandem mass spectrometry was used to determine the concentration of hydroxychloroquine in healthy subjects after oral administration of the T or R preparation to evaluate the PK characteristics. In this trial, the T and R preparations of hydroxychloroquine were bioequivalent under both conditions within the range of 80%-125%. No serious adverse events (SAEs) were found in the safety assessments for either condition, and all adverse events (AEs) were mild, except for 2 moderate AEs in the fed condition, indicating good safety.

Relationship between miRNA and ferroptosis in tumors.

Malignant tumor is a major killer that seriously endangers human health. At present, the methods of treating tumors include surgical resection, chemotherapy, radiotherapy and immunotherapy. However, the survival rate of patients is still very low due to the complicated mechanism of tumor occurrence and development and high recurrence rate. Individualized treatment will be the main direction of tumor treatment in the future. Because only by understanding the molecular mechanism of tumor development and differentially expressed genes can we carry out accurate treatment and improve the therapeutic effect. MicroRNA (miRNA) is a kind of small non coding RNA, which regulates gene expression at mRNA level and plays a key role in tumor regulation. Ferroptosis is a kind of programmed death caused by iron dependent lipid peroxidation, which is different from apoptosis, necrosis and other cell death modes. Now it has been found that ferroptosis plays an important role in the occurrence and development of tumors and drug resistance. More and more studies have found that miRNAs can regulate tumor development and drug resistance through ferroptosis. Therefore, in this review, the mechanism of ferroptosis is briefly outlined, and the relationship between miRNAs and ferroptosis in tumors is reviewed.

Pharmacokinetics, Bioequivalence and Safety of Cloperastine in Chinese Healthy Subjects Under Fasting and Postprandial Conditions.

BACKGROUND: Cloperastine is a pivotal antibechic widely prescribed to treat cough caused by respiratory diseases. The present trial evaluated the pharmacokinetics (PK), bioequivalence (BE) and safety effects of the generic test (T) tablet of cloperastine after single-dose administration of cloperastine, compared with the original reference (R) tablet of cloperastine. OBJECTIVE: The purpose of this trial was to compare the PK, BE and safety of a test 10 mg versus the reference 10 mg formulation of cloperastine under fasting and postprandial conditions in healthy Chinese volunteers. METHODS: A single-centre, randomised, open, double-cycle, self-crossover, single oral administration Phase I trial was performed in healthy Chinese volunteers. A total of 60 subjects were enrolled in either the fasting (28 subjects) or the postprandial condition (32 subjects). Subjects randomly received a single dose of the T or R preparation (10 mg dose). Plasma concentrations of cloperastine were analysed by a validated LC-MS/MS method. The primary endpoints of the PK parameters were the area under the plasma concentration-time curve from zero to 72 h (AUC0-72h), under the plasma concentration-time curve from zero to infinity (AUC0-∞) and the maximal plasma concentration (Cmax). The equivalence standard range (80.0-125.0%) was used to evaluate the BE of the two preparations. The safety parameter as secondary endpoint was mainly evaluated by the occurrence of adverse events (AEs). RESULTS: A total of 25 and 30 subjects in the fasting and postprandial conditions completed this clinical trial, respectively. The geometric mean ratio (GMR) of the T/R for the Cmax, AUC0-72h and AUC0-∞ were 102.1%, 103.8% and 104.0% in the fasting condition, respectively. In the postprandial condition, the GMR of the T/R for the Cmax, AUC0-72h and AUC0-∞ were 94.2%, 98.8% and 99.0%, respectively. All the values fell within the range (80.0-125.0%). The Cmax and AUC0-72h values of the T and R preparations in fasting and postprandial conditions were not statistically significant (P > 0.05). Furthermore, no serious adverse events (SAEs) occurred during the whole trial. CONCLUSIONS: The T and R preparations were bioequivalent under both conditions. Food has no significant effect on the absorption of cloperastine. Moreover, T and R preparations were well tolerated. The trial registration number (TRN) and date of registrations were CTR20212515, 13 October 2021.

System Xc -/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy.

The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis is an iron-mediated form of cell death caused by the accumulation of lipid peroxides. The intracellular imbalance between oxidant and antioxidant due to the abnormal expression of multiple redox active enzymes will promote the produce of reactive oxygen species (ROS). So far, a few pathways and regulators have been discovered to regulate ferroptosis. In particular, the cystine/glutamate antiporter (System Xc -), glutathione peroxidase 4 (GPX4) and glutathione (GSH) (System Xc -/GSH/GPX4 axis) plays a key role in preventing lipid peroxidation-mediated ferroptosis, because of which could be inhibited by blocking System Xc -/GSH/GPX4 axis. This review aims to present the current understanding of the mechanism of ferroptosis based on the System Xc -/GSH/GPX4 axis in the treatment of drug-resistant solid tumors.

Arabinogalactan enhances Mycobacterium marinum virulence by suppressing host innate immune responses.

Arabinogalactan (AG) participates in forming the cell wall core of mycobacteria, a structure known as the mAGP complex. Few studies have reported the virulence of inartificial AG or its interaction with the host immune system. Using clustered regularly interspaced short palindromic repeats interference gene editing technology, conditional Mycobacterium marinum mutants were constructed with a low expression of embA or glfT2 (EmbA_KD or GlfT2_KD), which are separately involved in the biosynthesis of AG arabinose and galactose domains. High-performance gel permeation chromatography and high-performance liquid chromatography assays confirmed that the EmbA_KD strain showed a remarkable decrease in AG content with fragmentary arabinose chains, and the GlfT2_KD strain displayed less reduction in content with cut-down galactose chains. Based on transmission and scanning electron microscopy observations, the cell walls of the two mutants were found to be dramatically thickened, and the boundaries of different layers were more distinct. Phenotypes including the over-secretion of extracellular substances and enhanced spreading motility with a concomitant decreased resistance to ethambutol appeared in the EmbA_KD strain. The EmbA_KD and GlfT2_KD strains displayed limited intracellular proliferation after infecting murine J774A.1 macrophages. The disease progression infected with the EmbA_KD or GlfT2_KD strain significantly slowed down in zebrafish/murine tail infection models as well. Through transcriptome profiling, macrophages infected by EmbA_KD/GlfT2_KD strains showed enhanced oxidative metabolism. The cell survival measured using the CCK8 assay of macrophages exposed to the EmbA_KD strain was upregulated and consistent with the pathway enrichment analysis of differentially expressed genes in terms of cell cycle/apoptosis. The overexpression of C/EBPß and the increasing secretion of proinflammatory cytokines were validated in the macrophages infected by the EmbA_KD mutant. In conclusion, the AG of Mycobacterium appears to restrain the host innate immune responses to enhance intracellular proliferation by interfering with oxidative metabolism and causing macrophage death. The arabinose chains of AG influence the Mycobacterium virulence and pathogenicity to a greater extent.

[Analysis of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Hematological Malignancies: A Single-center Study].

OBJECTIVE: To analyze the survival, prognostic factors, and prevention of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hematological malignancies, and explore the relationship between immune reconstruction, loss of human leukocyte antigen (HLA-loss) and relapse after transplantation. METHODS: From July 2012 to June 2020, 47 patients with hematological malignancies who relapsed after allo-HSCT were retrospectively analyzed, including 20 cases undergoing matched-sibling donor transplantation (MSD), 26 cases undergoing haploidentical transplantation (HID), and 1 case undergoing matched-unrelated donor transplantation (MUD). Multivariate analysis was used to analyze the risk factors related to post-relapse overall survival (PROS). RESULTS: All the 47 patients were implanted successfully. The cumulative incidence of grade Ⅱ-Ⅳ, Ⅲ/Ⅳ acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 40.4%, 10.6%, and 31.9%, respectively. The incidence of grade Ⅱ-Ⅳ and Ⅲ/Ⅳ aGVHD in HID group was 42.3% and 11.5%, while in MD group was 38.1% and 9.5% (P=0.579, P=1.000), and the incidence of cGVHD in the two groups was 34.6% and 28.6% (P=0.659). The PROS of patients with NK cell absolute count > 190 cells/µl 30 days after transplantation was higher than that of patients with NK cell absolute count ≤190 cells/µl (P=0.021). The 1-year and 3-year PROS of all the patients was 68.1% and 28.4%, respectively, while in the HID group was 78.9% and 40.3%, in the MD group was 54.4% and 14% (P=0.048). Multivariate analysis showed that grade Ⅱ-Ⅳ aGVHD and time of relapse < 3 months were independent risk factors of PROS (P<0.05). CONCLUSION: The therapeutic effect of haploidentical transplantation in patients with relapsed hematological malignancies after allo-HSCT is better than that of matched donor transplantation. The high absolute count of NK cells 30 days after transplantation can increase PROS. Grade Ⅱ-Ⅳ aGVHD and time of relapse < 3 months have prognostic significance for long-term survival of patients with relapsed hematological malignancies after transplantation.

Clinical outcomes of doxycycline, azithromycin and chloramphenicol for the treatment of patients with severe scrub typhus.

BACKGROUND: Previous studies have evaluated treatment efficacy of various antibiotics for patients with mild-to-moderate scrub typhus (ST). However, the efficacy of different antibiotics for treating severe ST remains uncertain. METHODS: A retrospective study of patients with severe ST was undertaken in China. The treatment efficacy rates of doxycycline, azithromycin and chloramphenicol were compared, using treatment failure and time to defervescence as primary outcomes. RESULTS: In total, 876 patients with severe ST who initially received doxycycline, azithromycin or chloramphenicol were recruited. The treatment failure rate did not differ significantly between patients receiving doxycycline and patients receiving azithromycin (6.0% vs 11.4%; P=0.109). However, a higher treatment failure rate was observed for chloramphenicol compared with doxycycline (14.6% vs 6.0%; P=0.004). No significant difference in time to defervescence was observed between patients receiving doxycycline, azithromycin or chloramphenicol. Further subgroup analysis revealed a higher risk of treatment failure for chloramphenicol compared with doxycycline in patients with acute kidney injury, pneumonia and shock; and a higher risk of treatment failure for azithromycin compared with doxycycline in patients with meningitis. Significant correlation was found between azithromycin resistance and meningitis (P=0.009), and between chloramphenicol resistance and acute respiratory distress syndrome (ARDS) (P<0.001) using Cramer's V correlation coefficient. Multi-variate Cox regression analysis revealed significant associations between time to defervescence and presence of ARDS, shock, myocarditis, meningitis and acute kidney injury. CONCLUSION: Azithromycin and doxycycline were found to have significant therapeutic effects in patients with severe ST. In contast, chloramphenicol was less efficacious for the treatment of these patients.

The Role of Microglia in Alzheimer's Disease From the Perspective of Immune Inflammation and Iron Metabolism.

Alzheimer's disease (AD), the most common type of senile dementia, includes the complex pathogenesis of abnormal deposition of amyloid beta-protein (Aß), phosphorylated tau (p-tau) and neuroimmune inflammatory. The neurodegenerative process of AD triggers microglial activation, and the overactivation of microglia produces a large number of neuroimmune inflammatory factors. Microglia dysfunction can lead to disturbances in iron metabolism and enhance iron-induced neuronal degeneration in AD, while elevated iron levels in brain areas affect microglia phenotype and function. In this manuscript, we firstly discuss the role of microglia in AD and then introduce the role of microglia in the immune-inflammatory pathology of AD. Their role in AD iron homeostasis is emphasized. Recent studies on microglia and ferroptosis in AD are also reviewed. It will help readers better understand the role of microglia in iron metabolism in AD, and provides a basis for better regulation of iron metabolism disorders in AD and the discovery of new potential therapeutic targets for AD.

The Dynamic Change in Fatty Acids during the Postharvest Process of Oolong Tea Production.

As important factors to oolong tea quality, the accumulation and dynamic change in aroma substances attracts great attention. The volatile composition of oolong tea is closely related to the precursor contents. Fatty acids (FAs) and their derivatives are basic components of oolong tea fragrance during the postharvest process. However, information about the precursors of FAs during the postharvest process of oolong tea production is rare. To investigate the transformation of fatty acids during the process of oolong tea production, gas chromatograph−flame ionization detection (GC-FID) was conducted to analyze the composition of FAs. The results show that the content of total polyunsaturated FAs initially increased and then decreased. Specifically, the contents of α-linolenic acid, linoleic acid and other representative substances decreased after the turn-over process of oolong tea production. The results of partial least squares discrimination analysis (PLS-DA) showed that five types of FAs were obviously impacted by the processing methods of oolong tea (VIP > 1.0). LOX (Lipoxygenase, EC 1.13.11.12) is considered one of the key rate-limiting enzymes of long-chain unsaturated FAs in the LOX-HPL (hydroperoxide lyase) pathway, and the mechanical wounding occurring during the postharvest process of oolong tea production greatly elevated the activity of LOX.

Therapeutic Effects of Natural Products on Cervical Cancer: Based on Inflammatory Pathways.

Inflammation is a protective response of the body to an irritant. When an inflammatory response occurs, immune cells are recruited to the injury, eliminating the irritation. The excessive inflammatory response can cause harm to the organism. Inflammation has been found to contribute to cervical cancer if there is a problem with the regulation of inflammatory response. Cervical cancer is one of the most common malignant tumors globally, and the incidence tends to be younger. The harm of cervical cancer cannot be ignored. The standard treatments for cervical cancer include surgery, radiotherapy and chemotherapy. However, the prognosis for this treatment is poor, so it is urgent to find a safer and more effective treatment. Natural products are considered excellent candidates for the treatment of cervical cancer. In this review, we first describe the mechanisms by which inflammation induces cervical cancer. Subsequently, we highlight natural products that can treat cervical cancer through inflammatory pathways. We also introduce natural products for the treatment of cervical cancer in clinical trials. Finally, methods to improve the anticancer properties of natural products were added, and the development status of natural products was discussed.

Clinical characteristics and risk factors for severe scrub typhus in pediatric and elderly patients.

BACKGROUND: Scrub typhus (ST) is a life-threatening infectious disease if appropriate treatment is unavailable. Large discrepancy of clinical severity of ST patients was reported among age groups, and the underlying risk factors for severe disease are unclear. METHODS: Clinical and epidemiological data of ST patients were collected in 55 surveillance hospitals located in Guangzhou City, China, from 2012 to 2018. Severe prognosis and related factors were determined and compared between pediatric and elderly patients. RESULTS: A total of 2,074 ST patients including 209 pediatric patients and 1,865 elderly patients were included, with a comparable disease severity rate of 11.0% (95% CI 7.1%-16.1%) and 10.3% (95% CI 9.0%-11.8%). Different frequencies of clinical characteristics including lymphadenopathy, skin rash, enlarged tonsils, etc. were observed between pediatric and elderly patients. Presence of peripheral edema and decreased hemoglobin were the most important predictors of severe illness in pediatric patients with adjusted ORs by 38.99 (9.96-152.67, p<0.001) and 13.22 (1.54-113.50, p = 0.019), respectively, while presence of dyspnea and increased total bilirubin were the potential determinants of severe disease in elderly patients with adjusted ORs by 11.69 (7.33-18.64, p<0.001) and 3.17 (1.97-5.11, p<0.001), respectively. Compared with pediatric patients, elderly patients were more likely to receive doxycycline (64.8% v.s 9.9%, p<0.001), while less likely to receive azithromycin therapy (5.0% v.s 41.1%, p<0.001). CONCLUSION: The disease severity rate is comparable between pediatric and elderly ST patients, while different clinical features and laboratory indicators were associated with development of severe complications for pediatric and elderly patients, which is helpful for diagnosis and progress assessment of disease for ST patients.

The key roles of organelles and ferroptosis in Alzheimer's disease.

Alzheimer's disease (AD), an age-related neurodegenerative disease, is a striking global health problem. Ferroptosis is a newly discovered form of cell death characterized by iron-dependent lipid peroxidation products and the accumulation of lethal reactive oxygen species. Strict regulation of iron metabolism is essential to ensure neuronal homeostasis. Excess and deficiency of iron are both associated with neurodegeneration. Studies have shown that oxidative stress caused by cerebral iron metabolism disorders in the body is involved in the process of AD, ferroptosis may play an important role in the pathogenesis of AD, and regulating ferroptosis is expected to be a new direction for the treatment of AD. Various organelles are closely related to ferroptosis: mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosome are involved in the regulation of ferroptosis from the aspects of iron metabolism and redox imbalance. In this review, the relationship between AD and the dysfunction of organelles (including mitochondria, endoplasmic reticulum, lysosome, and Golgi apparatus) and the role of organelles in ferroptosis of AD were reviewed to provide insights for understanding the relationship between organelles and ferroptosis in AD and the treatment of AD.

Isoliensinine induces cervical cancer cell cycle arrest and apoptosis by inhibiting the AKT/GSK3α pathway.

Isoliensinine is a bis-benzylisoquinoline alkaloid that can be isolated from the lotus Nelumbo nucifera Gaertn. It has been reported to exert a variety of anti-cancer properties. In the present study, the potential effects of isoliensinine on cervical cancer Siha, HeLa, Caski and C33A cell lines were investigated by using Cell Counting Kit-8 (CCK-8), flow cytometry, western blotting and reverse transcription-PCR (RT-PCR) to measure cell proliferation, the cell cycle and apoptosis, in addition to elucidating the underlying molecular mechanism. Protein levels of p21, CDK2, Cyclin E, Mcl-1, cleaved Caspase-9, AKT, phosphorylated-AKT, glycogen synthase kinase (Gsk)3α, PTEN, and mRNA levels of p21, p15, p27, CDK2, CDK4, Cyclin E, Cyclin D, Gsk3α, Gsk3ß and PTEN were measured. Molecular docking assays were used to calculate the strength of binding of isoliensinine to AKT using AutoDock 4.0. Isoliensinine was found to induce cell cycle arrest at the G0/G1 phase by upregulating p21 expression and downregulating CDK2 and cyclin E in breast cancer cells. In addition, in previous research, isoliensinine promoted cell apoptosis by downregulating myeloid-cell leukemia 1 expression and activating caspase-9. Upstream, isoliensinine significantly downregulated AKT (S473) phosphorylation and GSK3α expression in a dose- and time-dependent manner. The AKT inhibitor AKTi-1/2 enhanced the function of isoliensinine on cell cycle arrest and apoptosis through the AKT/GSK3α pathway. AutoDock analysis showed that isoliensinine can bind to the AKT protein. These findings suggest that isoliensinine can induce cervical cancer cell cycle arrest and apoptosis by inhibiting the AKT/GSK3α pathway, which represents a novel strategy for the treatment of cervical cancer.

From Microbiome to Inflammation: The Key Drivers of Cervical Cancer.

Cervical cancer is the third leading cause of cancer-related death worldwide. Microbes and hosts form a mutually beneficial symbiosis relationship, and various parts of the host body are microbial habitats. Microbes can trigger inflammation in certain parts of the host body, contributing to cervical cancer development. This article reviews the relationship between cervicovaginal microbes, inflammation and cervical cancer, and discusses the effect of some key cervical microbes on cervical cancer. Finally, probiotic therapy and immunotherapy are summarized.

Metabolic Flow of C6 Volatile Compounds From LOX-HPL Pathway Based on Airflow During the Post-harvest Process of Oolong Tea.

Aroma is an essential quality indicator of oolong tea, a tea derived from the Camellia sinensis L. plant. Carboxylic 6 (C6) acids and their derivative esters are important components of fatty acid (FA)-derived volatiles in oolong tea. However, the formation and regulation mechanism of C6 acid during postharvest processing of oolong tea remains unclear. To gain better insight into the molecular and biochemical mechanisms of C6 compounds in oolong tea, a combined analysis of alcohol dehydrogenase (ADH) activity, CsADH2 key gene expression, and the FA-derived metabolome during postharvest processing of oolong tea was performed for the first time, complemented by CsHIP (hypoxia-induced protein conserved region) gene expression analysis. Volatile fatty acid derivative (VFAD)-targeted metabolomics analysis using headspace solid-phase microextraction-gas chromatography time-of-flight mass spectrometry (HS-SPEM-GC-TOF-MS) showed that the (Z)-3-hexen-1-ol content increased after each turnover, while the hexanoic acid content showed the opposite trend. The results further showed that both the ADH activity and CsADH gene expression level in oxygen-deficit-turnover tea leaves (ODT) were higher than those of oxygen-turnover tea leaves (OT). The C6-alcohol-derived ester content of OT was significantly higher than that of ODT, while C6-acid-derived ester content showed the opposite trend. Furthermore, the HIP gene family was screened and analyzed, showing that ODT treatment significantly promoted the upregulation of CsHIG4 and CsHIG6 gene expression. These results showed that the formation mechanism of oolong tea aroma quality is mediated by airflow in the lipoxygenase-hydroperoxide lyase (LOX-HPL) pathway, which provided a theoretical reference for future quality control in the postharvest processing of oolong tea.