Therapeutic evolution in HR+/HER2- breast cancer: from targeted therapy to endocrine therapy.

Breast cancer, a complex and varied disease, has four distinct subtypes based on estrogen receptor and human epidermal growth factor receptor 2 (HER2) levels, among which a significant subtype known as HR+/HER2-breast cancer that has spurred numerous research. The prevalence of breast cancer and breast cancer-related death are the most serious threats to women's health worldwide. Current progress in treatment strategies for HR+/HER2-breast cancer encompasses targeted therapy, endocrine therapy, genomic immunotherapy, and supplementing traditional methods like surgical resection and radiotherapy. This review article summarizes the current epidemiology of HR+/HER2-breast cancer, introduces the classification of HR+/HER2-breast cancer and the commonly used treatment methods. The mechanisms of action of various drugs, including targeted therapy drugs and endocrine hormone therapy drugs, and their potential synergistic effects are deeply discussed. In addition, clinical trials of these drugs that have been completed or are still in progress are included.

Combating antimicrobial resistance: the silent war.

Once hailed as miraculous solutions, antibiotics no longer hold that status. The excessive use of antibiotics across human healthcare, agriculture, and animal husbandry has given rise to a broad array of multidrug-resistant (MDR) pathogens, posing formidable treatment challenges. Antimicrobial resistance (AMR) has evolved into a pressing global health crisis, linked to elevated mortality rates in the modern medical era. Additionally, the absence of effective antibiotics introduces substantial risks to medical and surgical procedures. The dwindling interest of pharmaceutical industries in developing new antibiotics against MDR pathogens has aggravated the scarcity issue, resulting in an exceedingly limited pipeline of new antibiotics. Given these circumstances, the imperative to devise novel strategies to combat perilous MDR pathogens has become paramount. Contemporary research has unveiled several promising avenues for addressing this challenge. The article provides a comprehensive overview of these innovative therapeutic approaches, highlighting their mechanisms of action, benefits, and drawbacks.

A novel CNTs/QCS/BiOBr composite membrane with electron-ion transfer channel for Br- recovery in ESIX process.

Based on the superior selectivity of bismuth oxybromide (BiOBr) for Br-, the excellent electrical conductivity of carbon nanotubes (CNTs), and the ion exchange capacity of quaternized chitosan (QCS), a three-dimensional network composite membrane electrode CNTs/QCS/BiOBr was constructed, in which BiOBr served as the storage space for Br-, CNTs provided the electron transfer pathway, and QCS cross-linked by glutaraldehyde (GA) was used for ion transfer. The CNTs/QCS/BiOBr composite membrane exhibits superior conductivity after the introduction of the polymer electrolyte, which is seven orders of magnitude higher than that of conventional ion-exchange membranes. Furthermore, the addition of the electroactive material BiOBr improved the adsorption capacity for Br- by a factor of 2.7 in electrochemically switched ion exchange (ESIX) system. Meanwhile, the CNTs/QCS/BiOBr composite membrane displays excellent Br- selectivity in mixed solutions of Br-, Cl-, SO42- and NO3-. Therein, the covalent bond cross-linking within the CNTs/QCS/BiOBr composite membrane endows it great electrochemical stability. The synergistic adsorption mechanism of the CNTs/QCS/BiOBr composite membrane provides a new direction for achieving more efficient ion separation.

Aldehyde Dehydrogenase Isoform 1 Predicts a Poor Prognosis of Acute Cerebral Infarction.

To investigate the prognostic potential of serum aldehyde dehydrogenase isoform 1 (ALDH1) level in acute cerebral infarction, and the molecular mechanism in mediating neurological deficits, a total of 120 acute cerebral infarction cases within 72 h of onset were retrospectively analyzed. Serum ALDH1 level in them was detected by qRT-PCR. Receiver operating characteristic (ROC) and Kaplan-Meier curves were depicted for assessing the diagnostic and prognostic potentials of ALDH1 in acute cerebral infarction, respectively. An in vivo acute cerebral infarction model in rats was established by performing MCAO, followed by evaluation of neurological deficits using mNSS and detection of relative levels of ALDH1, Smad2, Smad4, and p21 in rat brain tissues. Pearson's correlation test was carried out to verify the correlation between ALDH1 and mNSS and relative levels of Smad2, Smad4, and p21. Serum ALDH1 level increased in acute cerebral infarction patients. A high level of ALDH1 predicted a poor prognosis of acute cerebral infarction patients. In addition, ALDH1 was sensitive and specific in distinguishing acute cerebral infarction cases, presenting a certain diagnostic potential. mNSS was remarkably higher in acute cerebral infarction rats than that of controls. Compared with sham operation group, relative levels of ALDH1, Smad2, and Smad4 were higher in brain tissues of modeling rats, whilst p21 level was lower. ALDH1 level in brain tissues of modeling rats was positively correlated to mNSS, and mRNA levels of Smad2 and Smad4, but negatively correlated to p21 level. Serum ALDH1 level is a promising prognostic and diagnostic factor of acute cerebral infarction, which is correlated to 90-day mortality. Increased level of ALDH1 in the brain of cerebral infarction rats is closely linked to neurological function, which is associated with the small mothers against decapentaplegic (Smad) signaling and p21.

Green solvents-based molecular weight controllable fractionation process for industrial alkali lignin at room temperature.

The molecular weight is one of the most important factors influencing the utilization of industrial lignin obtained from chemical pulping process. In this paper, a facile operative green solvent system was successfully developed for molecular weight-controllable fractionation of industrial alkali lignin (IAL) at room temperature. The results showed that through adjusting the ratio of water, ethanol and γ-Valerolactone (GVL), the industrial lignin was fractionated into six levels with molecular weight stepwise controllable from low to high. The fractionation is a physical process according to FTIR and 2D-HSQC NMR analysis, and the chemical structure of lignin has not changed. Additionally, the polydispersity of fractionated lignin with higher molecular weight tends to be narrower. The content of hydroxyl and carboxyl group is higher for the fractionated lignin with lower molecular weight, which would be beneficial for the chemical reactivity in the down-stream application.

Gut microbiota promotes cholesterol gallstone formation by modulating bile acid composition and biliary cholesterol secretion.

Cholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, H2S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism.

A Novel Prognostic Prediction Model Based on Pyroptosis-Related Clusters for Breast Cancer.

Breast cancer (BC) is the most common cancer affecting women and the leading cause of cancer-related deaths worldwide. Compelling evidence indicates that pyroptosis is inextricably involved in the development of cancer and may activate tumor-specific immunity and/or enhance the effectiveness of existing therapies. We constructed a novel prognostic prediction model for BC, based on pyroptosis-related clusters, according to RNA-seq and clinical data downloaded from TCGA. The proportions of tumor-infiltrating immune cells differed significantly in the two pyroptosis clusters, which were determined according to 38 pyroptosis-related genes, and the immune-related pathways were activated according to GO and KEGG enrichment analysis. A 56-gene signature, constructed using univariate and multivariate Cox regression, was significantly associated with progression-free interval (PFI), disease-specific survival (DSS), and overall survival (OS) of patients with BC. Cox analysis revealed that the signature was significantly associated with the PFI and DSS of patients with BC. The signature could efficiently distinguish high- and low-risk patients and exhibited high sensitivity and specificity when predicting the prognosis of patients using KM and ROC analysis. Combined with clinical risk, patients in both the gene and clinical low-risk subgroup who received adjuvant chemotherapy had a significantly lower incidence of the clinical event than those who did not. This study presents a novel 56-gene prognostic signature significantly associated with PFI, DSS, and OS in patients with BC, which, combined with the TNM stage, might be a potential therapeutic strategy for individualized clinical decision-making.

Corrigendum: Potential Mechanisms of Action of Chinese Patent Medicines for COVID-19: A Review.

[This corrects the article DOI: 10.3389/fphar.2021.668407.].

Potential Mechanisms of Action of Chinese Patent Medicines for COVID-19: A Review.

Coronavirus disease 2019 (COVID-19) is an emergent infectious pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is highly contagious and pathogenic. COVID-19 has rapidly swept across the world since it was first discovered in December 2019 and has drawn significant attention worldwide. During the early stages of the outbreak in China, traditional Chinese medicines (TCMs) were involved in the whole treatment process. As an indispensable part of TCM, Chinese patent medicines (CPMs) played an irreplaceable role in the prevention and treatment of this epidemic. Their use has achieved remarkable therapeutic efficacy during the period of medical observation and clinical treatment of mild, moderate, severe, and critical cases and during convalescence. In order to better propagate and make full use of the benefits of TCM in the treatment of COVID-19, this review will summarize the potential target of SARS-CoV-2 as well as the theoretical basis and clinical efficacy of recommended 22 CPMs by the National Health Commission and the Administration of TCM and local provinces or cities in the treatment of COVID-19. Additionally, the study will further analyze the drug composition, potential active ingredients, potential targets, regulated signaling pathways, and possible mechanisms for COVID-19 through anti-inflammatory and immunoregulation, antiviral, improve lung injury, antipyretic and organ protection to provide meaningful information about the clinical application of CPMs.

2­Hydroxypropyl­ß­cyclodextrin blocks autophagy flux and triggers caspase­8­mediated apoptotic cascades in HepG2 cells.

The cyclodextrin derivative, 2­Hydroxypropyl-ß­cyclodextrin (HPßCD), from the cyclodextrin family is widely used as a drug carrier and offers promising strategies for treating neurodegenerative diseases and atherosclerosis regression. However, its side effects are not fully understood. Therefore, the aim of the present study was to investigate the possible adverse effects of relatively high concentrations of HPßCD on hepatocytes. It was found that a high dose (20 mM) of HPßCD treatment significantly inhibited the AKT/mTOR pathway and disrupted infusion of autophagosomes and lysosomes, which rapidly led to massive autophagosome accumulation in HepG2 cells. The autophagosomal membrane serves as a platform for caspase­8 oligomerization, which is considered as the key step for its self­activation. Using flow cytometry and TUNEL assay, increased apoptosis of HepG2 cells treated with a high dose HPßCD (20 mM) for 48 h was observed. In addition, western blotting results demonstrated that the expression of cleaved­caspase­8 was positively associated with microtubule­associated protein 1 light chain 3 BII expression, which is an indicator of autophagosome level in the cytoplasm. Therefore, the present study provided novel evidence that HPßCD might be a potential risk contributing to the pathophysiological process of hepatic diseases, especially in an autophagy­deficient state.

FMO3 and its metabolite TMAO contribute to the formation of gallstones.

Trimethylamine-N-oxide (TMAO) is a metabolite derived from trimethylamine (TMA), which is first produced by gut microbiota and then oxidized by flavin-containing monooxygenase 3 (FMO3) in the liver. TMAO may contribute to the development of diseases such as atherosclerosis because of its role in regulating lipid metabolism. In this study, we found that high plasma TMAO levels were positively associated with the presence of gallstone disease in humans. We further found increased hepatic FMO3 expression and elevated plasma TMAO level in a gallstone-susceptible strain of mice C57BL/6J fed a lithogenic diet (LD), but not in a gallstone-resistant strain of mice AKR/J. Dietary supplementation of TMAO or its precursor choline increased hepatic FMO3 expression and plasma TMAO levels and induced hepatic canalicular cholesterol transporters ATP binding cassette (Abc) g5 and g8 expression in mice. Up-regulation of ABCG5 and ABCG8 expression was observed in hepatocytes incubated with TMAO in vitro. Additionally, in AKR/J mice fed a LD supplemented with 0.3% TMAO, the incidence of gallstones rose up to 70% compared with 0% in AKR/J mice fed only a LD. This was associated with increased hepatic Abcg5 and g8 expression induced by TMAO. Our study demonstrated TMAO could be associated with increased hepatic Abcg5/g8 expression, biliary cholesterol hypersecretion and gallstone formation.

Advance in Close-Edged Graphene Nanoribbon: Property Investigation and Structure Fabrication.

The absence of dangling bonds in close-edged graphene nanoribbons (CEGNRs) confers upon them a series of fascinating properties, especially when compared with cylindrical carbon nanotubes and open-edged GNRs. Here, the configuration of CEGNRs is described, followed by the structure-related properties, including mechanical, thermal, electrical, optical, and magnetic properties. Based on the unique structures and extraordinary properties, their potential applications in a variety of fields, such as field-effect transistors, energy suppliers, nanoactuators, and fibers, are discussed. Remarkably, the strategies applied for generating CEGNRs, mainly from the collapse of carbon nanotubes and graphene tubes, are depicted in detail. Finally, the prospects in the research area of CEGNRs are proposed.

Berberine ameliorates blockade of autophagic flux in the liver by regulating cholesterol metabolism and inhibiting COX2-prostaglandin synthesis.

Excessive cholesterol contributes to the development of cardiovascular diseases. Berberine (BBR) has been reported to regulate cholesterol homeostasis. Here, we found that BBR could ameliorate the hepatic autophagic flux blockade caused by cholesterol overloading. The underlying mechanism included lowering hepatic cholesterol level, modulating the cholesterol distribution targeting the plasma membrane by decreasing sterol carrier protein 2 expression and inhibiting cyclooxygenase 2-mediated production of prostaglandin metabolites, which decreased the phosphorylation of Akt/mTOR. Our study provides evidences that BBR could be a therapeutic agent for protecting liver under cholesterol overloading via the regulation of autophagic flux.

Exposure to 2,4-dichlorophenoxyacetic acid induced PPARß-dependent disruption of glucose metabolism in HepG2 cells.

2,4-Dichlorophenoxyacetic acid is one of the most widely used herbicides. Its impact on health is increasingly attracting great attentions. This study aimed to investigate the effect of 2,4-dichlorophenoxyacetic acid on glucose metabolism in HepG2 cells and the underlying mechanism. After 24 h exposure to 2,4-dichlorophenoxyacetic acid, glycogen was measured by PAS staining and glucose by ELISA in HepG2 cells. The expression of genes involved in glucose metabolism was measured by real-time PCR, Western blotting, and immunofluorescence. HepG2 cells presented more extracellular glucose consumption and glycogen content after exposed to 2,4-dichlorophenoxyacetic acid. Expression of gluconeogenesis-related genes, FoxO1, and CREB is significantly elevated. Moreover, PPARß was up-regulated dose-dependently. SiRNA knockdown of PPARß completely rescued the increase of glycogen accumulation and glucose uptake, and the up-regulation of FOXO1 and CREB expression. Our findings propose novel mechanisms that 2,4-dichlorophenoxyacetic acid causes glucose metabolism dysfunction through PPARß in HepG2 cells.

Alteration of gut microbiota in association with cholesterol gallstone formation in mice.

BACKGROUND: The gut microbiome exerts extensive roles in metabolism of nutrients, pharmaceuticals, organic chemicals. Little has been known for the role of gut microbiota in regulating cholesterol and bile acids in association with gallstone formation. This study investigated the changes in the composition of gut microbiota in mice fed with lithogenic diet (LD). METHODS: Adult male C57BL/6 J mice were fed with either lithogenic diet (1.25% cholesterol and 0.5% cholic acid) or chow diet as control for 56 days. The fecal microbiota were determined by 16S rRNA gene sequencing. RESULTS: LD led to formation of cholesterol gallstone in mice. The richness and alpha diversity of gut microbial reduced in mice fed with LD. Firmicutes was significantly decreased from 59.71% under chow diet to 31.45% under LD, P < 0.01, as well as the ratio of Firmicutes to Bacteroidetes. Differences in gut microbiota composition were also observed at phylum, family and genus levels between the two groups. CONCLUSION: Our results suggested that gut microbiota dysbiosis might play an important role in the pathogenesis of cholesterol gallstone formation in mice.

Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice.

Organochlorine pesticides (OCPs) can persistently accumulate in body and threaten human health. Bile acids and intestinal microbial metabolism have emerged as important signaling molecules in the host. However, knowledge on which intestinal microbiota and bile acids are modified by OCPs remains unclear. In this study, adult male C57BL/6 mice were exposed to p, p'-dichlorodiphenyldichloroethylene (p, p'-DDE) and ß-hexachlorocyclohexane (ß-HCH) for 8 weeks. The relative abundance and composition of various bacterial species were analyzed by 16S rRNA gene sequencing. Bile acid composition was analyzed by metabolomic analysis using UPLC-MS. The expression of genes involved in hepatic and enteric bile acids metabolism was measured by real-time PCR. Expression of genes in bile acids synthesis and transportation were measured in HepG2 cells incubated with p, p'-DDE and ß-HCH. Our findings showed OCPs changed relative abundance and composition of intestinal microbiota, especially in enhanced Lactobacillus with bile salt hydrolase (BSH) activity. OCPs affected bile acid composition, enhanced hydrophobicity, decreased expression of genes on bile acid reabsorption in the terminal ileum and compensatory increased expression of genes on synthesis of bile acids in the liver. We demonstrated that chronic exposure of OCPs could impair intestinal microbiota; as a result, hepatic and enteric bile acid profiles and metabolism were influenced. The findings in this study draw our attention to the hazards of chronic OCPs exposure in modulating bile acid metabolism that might cause metabolic disorders and their potential to cause related diseases in human.

Organochloride pesticides induced hepatic ABCG5/G8 expression and lipogenesis in Chinese patients with gallstone disease.

BACKGROUND: Organochlorine pesticides (OCPs) are one kind of persistent organic pollutants. Although they are reported to be associated with metabolic disorders, the underlying mechanism is unclear. We explored the association of OCPs with gallstone disease and its influence on hepatic lipid metabolism. MATERIALS AND METHODS: OCPs levels in omentum adipose tissues from patients with and without gallstone disease between 2008 and 2011 were measured by GC-MS. Differences of gene expression involved in hepatic lipid metabolism and hepatic lipids content were compared in liver biopsies between groups with high and low level of OCPs. Using HepG2 cell lines, the influence on hepatic lipid metabolism by individual OCP was evaluated in vitro. RESULTS: In all patients who were from non-occupational population, there were high levels of ß-hexachlorocyclohexane (ß-HCH) and p',p'-dichloroethylene (p',p'-DDE) accumulated in adipose tissues. Both ß-HCH and p', p'-DDE levels were significantly higher in adipose tissues from patients with gallstone disease (294.3± 313.5 and 2222± 2279 ng/g of lipid) than gallstone-free controls (282.7± 449.0 and 2025±2664 ng/g of lipid, P< 0.01) and they were strongly related with gallstone disease (P for trend = 0.0004 and 0.0138). Furthermore, higher OCPs in adipose tissue led to increase in the expression of hepatic cholesterol transporters ABCG5 and G8 (+34% and +27%, P< 0.01) and higher cholesterol saturation index in gallbladder bile, and induced hepatic fatty acids synthesis, which was further confirmed in HepG2 cells. CONCLUSIONS: OCPs might enhance hepatic secretion of cholesterol into bile via ABCG5/G8 which promoting gallstone disease as well as lipogenesis.

[Influence of different copper and zinc supply on their concentrations in blood serum, liver and hair of dairy cows]. / Einfluss unterschiedlicher Kupfer- und Zinkversorgung auf deren Konzentrationen in Blutserum, Leber und Deckhaar bei Milchkühen.

In a feeding trial at the Institute of Animal Nutrition of the Federal Research Institute of Animal Health (FLI) over 12 weeks with 20 cows of the German Holstein Breed the influence of different copper and zinc contents in the ration on their concentration in blood serum, liver and hair was tested. All animals received a diet based on maize- and grass silage ad libitum. The animals were divided in two groups with 10 cows each; group A received a concentrate according to their milk yield with a copper and zinc content as recommended (GfE 2001), whereas group B was offered a concentrate with roughly the double amount of copper and zinc. At the beginning and at the end of the trial a sample of blood, pigmented hair and a liver bioptate was taken from all animals to evaluate the incorporation of copper and zinc in these tissues. In serum and pigmented hair the copper concentrations did not differ between the two groups [13.4 for Group A and 12.5 micromol/L for Group B in serum respectively 6.8 (Group A) and 7.4 mg/kg DM (Group B) in pigmented hair]. Only the copper concentration in the liver was influenced by the different feeding. The higher copper content for group B resulted in a significantly higher copper concentration in the liver (506 mg/kg DM compared to 383 mg/kg DM). The liver is the best indicator organ for a sufficient copper supply. An increase in the zinc content in the ration resulted neither in higher zinc concentrations in serum (15.1 in Group B in comparison to 13.4 micromol/L for Group A) nor in higher zinc concentrations in liver (140 for Group B and 112 mg/kg DM for Group A) and pigmented hair (130 in Group A and 123 mg/kg DM in Group B). There is a significant correlation between copper intake and copper concentration in the liver (r = 0.46), whereas the correlation between zinc intake and zinc concentration in the liver is only tendencially (r = 0.23). The three tested samples serum, liver and cow hair are not qualified to reflect exactly a sufficient zinc supply.