Rat Hepatocytes Protect against Lead-Cadmium-Triggered Apoptosis Based on Autophagy Activation.

Lead and cadmium are foodborne contaminants that threaten human and animal health. It is well known that lead and cadmium produce hepatotoxicity; however, defense mechanisms against the co-toxic effects of lead and cadmium remain unknown. We investigated the mechanism of autophagy (defense mechanism) against the co-induced toxicity of lead and cadmium in rat hepatocytes (BRL-3A cells). Cultured rat liver BRL-3A cell lines were co-cultured with 10, 20, 40 µM lead and 2.5, 5, 10 µM cadmium alone and in co-culture for 12 h and exposed to 5 mM 3-Methyladenine (3-MA), 10 µM rapamycin (Rapa), and 50 nM Beclin1 siRNA to induce cellular autophagy. Our results show that treatment of BRL-3A cells with lead and cadmium significantly decreased the cell viability, increased intracellular reactive oxygen species levels, decreased mitochondrial membrane potential levels, and induced apoptosis, which are factors leading to liver injury, and cell damage was exacerbated by co-exposure to lead-cadmium. In addition, the results showed that lead and cadmium co-treatment induced autophagy. We further observed that the suppression of autophagy with 3-MA or Beclin1 siRNA promoted lead-cadmium-induced apoptosis, whereas enhancement of autophagy with Rapa suppressed lead-cadmium-induced apoptosis. These results demonstrated that co-treatment with lead and cadmium induces apoptosis in BRL-3A cells. Interestingly, the activation of autophagy provides cells with a self-protective mechanism against induced apoptosis. This study provides insights into the role of autophagy in lead-cadmium-induced apoptosis, which may be beneficial for the treatment of lead-cadmium-induced liver injury.

Application Value of CYFRA21-1 Combined with NSE, CEA, and SCC-Ag in Lung Cancer.

BACKGROUND: This study aims to investigate the application value of serum cytokeratin 19 fragment (CYFRA21-1) combined with nerve-specific enolase (NSE), carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCC-Ag) in the diagnosis of lung cancer (LC). METHODS: A total of 831 cases of LC, 360 cases of benign lung disease (BLD) and 102 healthy controls, were enrolled. The data were processed using SPSS, GraphPad Prism, and MedCalc software. RESULTS: The tumor marker (TM) levels in the LC and BLD groups were significantly higher than those in the control group; the CYFRA21-1, NSE, and CEA levels in the patients with LC were higher than in those with BLD. In particular, the increase was predominantly observed for the levels of CEA and CYFRA21-1 in adenocarcinoma (LUAD), CYFRA21-1 and SCC-Ag in squamous cell carcinoma (LUSC), and NSE in small cell carcinoma (SCLC). The CYFRA21-1, NSE, and CEA levels were significantly higher in stage IV than in other stages in LC. Univariate binary logistic analysis showed that increased levels of all four TMs were risk factors for BLD and LC. The area under the curve (AUC) of CYFRA21-1 was most effective in distinguishing patients with BLD or LC from the controls and in distinguishing patients with BLD and LC. The AUCs of combined CYFRA21-1, NSE, and CEA were increased to 0.755, 0.922, and 0.783, respectively, with no significant difference with the AUC of the four combined tests. In the histological classification, the best predictors were CEA, for LUAD, CYFRA21-1 for LUSC, and NSE for SCLC. Moreover, the expression levels of CYFRA21-1, NSE, and CEA significantly decreased after each treatment course. CONCLUSIONS: The combined assay of CYFRA21-1, NSE, and CEA addresses the aspects of accuracy, sensitivity, specificity, and economic cost and should be considered as a potential diagnostic test in LC.

Ultrasonic-assisted extraction of polysaccharide from Paeoniae Radix alba: Extraction optimization, structural characterization and antioxidant mechanism in vitro.

Paeoniae Radix alba is used in Traditional Chinese Medicine for the treatment of gastrointestinal disorders, immunomodulatory, cancer, and other diseases. In the current study, the yield of Paeoniae Radix alba polysaccharide (PRP) was significantly increased with optimal ultrasound-assisted extraction compared to hot water extraction. Further, an acidic polysaccharide (PRP-AP) was isolated from PRP after chromatographic separation and was characterized as a typical pectic polysaccharide with side chains of arabinogalactans types I and II. Moreover, it showed antioxidant effects on LPS-induced damage on IPEC-J2 cells determined by qRT-PCR and ELISA, including decreasing the pro-inflammatory factors' expressions and increasing the antioxidant enzymes activities, which was shown to be related to the Nrf2/Keap1 pathway modulated by PRP-AP. The metabolites change (such as itaconate, cholesterol sulfate, etc.) detected by untargeted metabolomic analysis in cells was also shown to be modulated by PRP-AP, and these metabolites were further utilized and protected cells damaged by LPS. These results revealed the cellular active mechanism of the macromolecular PRP-AP on protecting cells, and supported the hypothesis that PRP-AP has strong benefits as an alternative dietary supplement for the prevention of intestinal oxidative stress by modulating cellular metabolism.

Onosma glomeratum Y. L. Liu polysaccharide alleviates LPS-induced pulmonary inflammation via NF-κB signal pathway.

As a traditional Chinese medicinal and edible homologous plant, Onosma glomeratum Y. L. Liu has been used for treating lung diseases in Tibet. In this study, a pectin polysaccharide, OGY-LLPA, with a molecular weight of 62,184 Da, was isolated and characterized by GC-MS and NMR analysis. It mainly consists of galacturonic acid (GalA), galactose (Gal), rhamnose (Rha), and arabinose (Ara), with a linear main chain of galacturonic acid (homogalacturonan, HG) inserted by part of rhamnose galacturonic acid (rhamnogalacturonan, RG), attaching with arabinogalactan (AG) branches at RG-I. Both in the LPS-induced A549 cell model and LPS-induced pneumonia mouse model, OGY-LLPA demonstrated strong anti-inflammatory effects, even comparable to DEX, indicating its potential as an anti-pneumonia candidate agent. Moreover, low-dose OGY-LLPA alleviated LPS-induced pulmonary inflammation by inhibiting the NF-κB signaling pathway. Overall, these findings could not only contribute to the utilization of Onosma glomeratum Y. L. Liu., but also provides a theoretical basis for the treatment of inflammation-related diseases.

Precision targeting of CuET overload to disrupt mitochondrial unfolded protein response by integrated liposome.

Mitochondria in breast cancer play a critical role in survival and adaptation to dynamic environments. Thus, targeting mitochondria emerges as a promising therapeutic strategy for breast cancer. However, the adaptive unfolded protein response in mitochondria (UPRmt) due to mitochondrial unspecific distribution might contribute to diminished therapeutic outcomes. Herein, mitochondrial targeting liposome agents (CTPP-Lipid) are constructed and adopted for delivering the copper ion (CuET-DSF), which is especially sensitive for mitochondria-abundant breast tumors. In brief, the CTPP-Lipid@CuET achieves the goal of Cu2+ overloading by mitochondria targeting delivery. This rapidly increases ROS production, disrupts mitochondrial structure, and avoids the adaptive UPRmt formation, finally leading to apoptosis of breast cancer cells. In general, the Cu2+ overloading at mitochondria by CTPP-Lipid@CuET is a potential strategy for antitumor therapy, providing new insights into breast tumor therapy.

Protective effects of an alcoholic extract of Kaempferia galanga L. rhizome on ethanol-induced gastric ulcer in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Kaempferia galanga L., a medicinal and edible Plant, was widely distributed in many Asian and African counties. It has been traditionally used to treat gastroenteritis, hypertension, rheumatism and asthma. However, there is a lack of modern pharmacology studies regarding its anti-gastric ulcer activity. AIM OF THE STUDY: The objective of this study is to investigate the protective effects of an extract from K. galanga L. rhizome (Kge) and its active components kaempferol and luteolin on ethanol-induced gastric ulcer. MATERIALS AND METHODS: The kge was prepared by ultrasonic-assisted extraction, and the contents of kaempferol and luteolin were determined by HPLC. The mice were randomly divided into seven groups: blank control (0.5 % CMC-Na; 0.1 mL/10 g), untreatment (0.5 % CMC-Na; 0.1 mL/10 g), Kge (100, 200 and 400 mg/kg), kaempferol (100 mg/kg) and luteolin (100 mg/kg) groups. The mice were treated intragastrically once daily for 7 days. At 1 h post the last administration, the mice in all groups except the blank control group were intragastrically administrated with anhydrous alcohol (0.1 mL/10 g) once to induce gastric ulcer. Then, fasting was continued for 1 h, followed by sample collection for evaluation by enzyme-linked immunosorbent assay and real-time reverse transcription polymerase chain reaction assay. RESULTS: The contents of kaempferol and luteolin in Kge were determined as 3713 µg/g and 2510 µg/g, respectively. Alcohol induced severely damages with edema, inflammatory cell infiltration and bleeding, and the ulcer index was 17.63 %. After pre-treatment with Kge (100, 200 and 400 mg/kg), kaempferol and luteolin, the pathological lesions were obviously alleviated and ulcer indices were reduced to 13.42 %, 11.65 %, 6.54 %, 3.58 % and 3.85 %, respectively. In untreated group, the contents of Ca2+, myeloperoxidase, malondialdehyde, NO, cyclic adenosine monophosphate and histamine were significantly increased, while the contents of hexosamine, superoxide dismutase, glutathione peroxidase, and prostaglandin E2 were significantly decreased; the transcriptional levels of IL-1α, IL-1ß, IL-6, calcitonin gene related peptide, substance P, M3 muscarinic acetylcholine receptor, histamine H2 receptor, cholecystokinin 2 receptor and H+/K+ ATPase were significantly increased when compared with the blank control group. After pre-treatment, all of these changes were alleviated, even returned to normal levels. Kge exhibited anti-gastric ulcer activity and the high dose of Kge (400 mg/kg) exhibited comparable activity to that of kaempferol and luteolin. CONCLUSION: The study showed that K. galanga L., kaempferol, and luteolin have protective effects against ethanol-induced gastric ulcers. This is achieved by regulating the mucosal barrier, oxidative stress, and gastric regulatory mediators, as well as inhibiting the TRPV1 signaling pathway and gastric acid secretion, ultimately reducing the gastric ulcer index.

An "all-in-one" treatment and imaging nanoplatform for breast cancer with photothermal nanoparticles.

Drug delivery systems based on nanoparticles still face challenges of low efficacy and an inability to track treatment effects in tumor therapy due to biological barriers. This limitation hinders clinicians' ability to determine treatment effects and proper drug dosages, thus, ultimately impeding the further application and transformation of nanoplatforms. To address this challenge, an all-in-one nanoplatform for therapy and imaging is proposed. The nanoplatform is constructed by using nanoparticles through the co-encapsulation of the photothermal therapeutic agent IR780, the passively targeted drug OA@Fe3O4, and the chemotherapeutic drug paclitaxel. Under the guidance of magnetic navigation, the nanoparticles can enhance local enrichment of the drug, while the luminescence properties of IR780 enable drug tracking at the same time. Remarkably, the nanoparticles exhibit improved photothermal-chemotherapy synergy under magnetic targeting guidance, demonstrating antitumor effects in both in vitro and in vivo experiments. It is demonstrated that the use of these polymeric nanoparticles has significant potential for future biomedical applications and clinical decisions.

Bioactive polysaccharides in different plant parts of Aconitum carmichaelii.

BACKGROUND: Aconitum carmichaelii is an industrially cultivated medicinal plant in China and its lateral and mother roots are used in traditional Chinese medicine due to the presence of alkaloids. However, the rootlets and aerial parts are discarded after collection of the roots, and the non-toxic polysaccharides in this plant have attracted less attention than the alkaloids and poisonous features. In this study, five neutral and 14 acidic polysaccharide fractions were isolated systematically from different plant parts of A. carmichaelii, and their structural features and bioactivity were studied and compared. RESULTS: The neutral fraction isolated from the rootlets differed from those isolated from the lateral and mother roots. It consisted of less starch and more possible mannans, galactans, and/or xyloglucans, being similar to those of the aerial parts. Pectic polysaccharides containing homogalacturonan and branched type-I rhamnogalacturonan (RG-I) were present in all plant parts of A. carmichaelii. However, more arabinogalactan (AG)-II side chains in the RG-I backbone were present in the aerial parts of the plants, while more amounts of arabinans were found in the roots. Various immunomodulatory effects were observed, determined by complement fixation activity and anti-inflammatory effects on the intestinal epithelial cells of all polysaccharide fractions. CONCLUSION: This study highlighted the diversity of polysaccharides present in A. carmichaelii, especially in the unutilized plant parts, and showed their potential medicinal value. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

A Pectic Polysaccharide from Codonopsis pilosula Alleviates Inflammatory Response and Oxidative Stress of Aging Mice via Modulating Intestinal Microbiota-Related Gut-Liver Axis.

Aging is a biological process that leads to the progressive deterioration and loss of physiological functions in the human body and results in an increase in morbidity and mortality, and aging-related disease is a major global problem that poses a serious threat to public health. Polysaccharides have been shown to delay aging by reducing oxidative damage, suppressing inflammatory responses, and modulating intestinal microbiota. Our previous studies have shown that polysaccharide CPP-1 extracted from the root of Codonopsis pilosula possesses noticeable anti-oxidant activity in vitro. Thus, in our study, we tested the anti-aging effect of CPP-1 in naturally aging mice (in vivo). Eighteen C57/BL mice (48-week-old, male) were divided into a control group, high-dose CPP-1 group (20 mg/mL), and low-dose CPP-1 group (10 mg/mL). We discovered that CPP-1 can exert a reparative effect on aging stress in the intestine and liver, including alleviating inflammation and oxidative damage. We revealed that CPP-1 supplementation improved the intestinal microbiota composition and repaired the intestinal barrier in the gut. Furthermore, CPP-1 was proved to modulate lipid metabolism and repair hepatocyte injury in the liver by influencing the enterohepatic axis associated with the intestinal microbiota. Therefore, we concluded that CPP-1 prevents and alleviates oxidative stress and inflammatory responses in the intestine and liver of aging mice by modulating the intestinal microbiota-related gut-liver axis to delay aging.

Polysaccharides and Bioactive Phenolics from Aconitum septentrionale Roots.

Aconitum septentrionale is known to contain toxic diterpene alkaloids, while other bioactive compounds in the plant remain unclear. The aim of this study was to explore the phenolic compounds and polysaccharides from the water extract of A. septentrionale roots. Fifteen phenolic compounds were isolated and identified by NMR and MS, including fourteen known and one new dianthramide glucoside (2-[[2-(ß-D-glucopyranosyloxy)-5-hydroxybenzoyl]amino]-4,5-dihydroxybenzoic acid methyl ester, 14). One neutral (complex of glucans with minor amounts of mannans) and two acidic polysaccharide fractions (complexes of pectic polysaccharides and glucans) were also obtained. Hydroxytyrosol (1), hydroxytyrosol-1-O-ß-glucoside (2) and bracteanolide A (7) inhibited the release of nitric oxide by dendritic cells. Magnoflorine (8) and 2-[[2-(ß-D-glucopyranosyloxy)-5-hydroxybenzoyl]amino]-5-hydroxybenzoic acid methyl ester (12) inhibited 15-lipoxygenase, and bracteanolide A (7) was a moderate inhibitor of xanthine oxidase. This study is the first to describe the diversity of phenolics and polysaccharides from A. septentrionale and their anti-inflammatory and anti-oxidant activities.

Polysaccharide from aerial part of Chuanminshen violaceum alleviates oxidative stress and inflammatory response in aging mice through modulating intestinal microbiota.

Aging is a biological process of progressive deterioration of physiological functions, which poses a serious threat to individual health and a heavy burden on public health systems. As population aging continues, research into anti-aging drugs that prolong life and improve health is of particular importance. In this study, the polysaccharide from stems and leaves of Chuanminshen violaceum was obtained with water extraction and alcohol precipitation, and then separated and purified with DEAE anion exchange chromatography and gel filtration to obtain CVP-AP-I. We gavaged natural aging mice with CVP-AP-I and performed serum biochemical analysis, histological staining, quantitative real-time PCR (qRT-PCR) and ELISA kit assays to analyze inflammation and oxidative stress-related gene and protein expression in tissues, and 16SrRNA to analyze intestinal flora. We found that CVP-AP-I significantly improved oxidative stress and inflammatory responses of the intestine and liver, restored the intestinal immune barrier, and balanced the dysbiosis of intestinal flora. In addition, we revealed the potential mechanism behind CVP-AP-I to improve intestinal and liver function by regulating intestinal flora balance and repairing the intestinal immune barrier to regulate the intestinal-liver axis. Our results indicated that C. violaceum polysaccharides possessed favorable antioxidant, anti-inflammatory and potentially anti-aging effects in vivo.

Angelica sinensis aboveground part polysaccharide and its metabolite 5-MT ameliorate colitis via modulating gut microbiota and TLR4/MyD88/NF-κB pathway.

The roots of Angelica sinensis have been used in Traditional Chinese Medicine for thousands of years. However, tons of aerial parts of this herb (aboveground part) are commonly discarded during the process of root preparations. A polysaccharide (ASP-Ag-AP) in the aboveground parts of A. sinensis was isolated and preliminarily characterized as typical plant pectin. ASP-Ag-AP exhibited noticeable protective effects against dextran sodium sulfate (DSS)-induced colitis, including reduction of colonic inflammation, modulation of barrier function, and alteration of gut microbiota and serum metabolite profile. Anti-inflammatory effects of ASP-Ag-AP were observed by inhibiting TLR4/MyD88/NF-κB signaling pathway in vitro and in vivo. Additionally, the level of serum metabolite 5-methyl-dl-tryptophan (5-MT) was reduced by DSS and restored by ASP-Ag-AP, which also negatively correlated with Bacteroides, Alistipes, Staphylococcus and pro-inflammatory factors. The protection from inflammatory stress on intestinal porcine enterocytes cells (IPEC-J2) of 5-MT was observed through the inhibition of TLR4/MyD88/NF-κB pathway. Besides, 5-MT also exhibited robust anti-inflammatory effect in colitis mice with improving colitis symptoms, barrier function and gut microbiota, which was the same as presented by ASP-Ag-AP. Therefore, ASP-Ag-AP could be a promising agent for colitis prevention and 5-MT could be the signal metabolite of ASP-Ag-AP on defending against intestinal inflammatory stress.

Salvia miltiorrhiza polysaccharide and its related metabolite 5-methoxyindole-3-carboxaldehyde ameliorate experimental colitis by regulating Nrf2/Keap1 signaling pathway.

The roots of Salvia miltiorrhiza have been used in Traditional Chinese Medicine for thousands of years. However, tons of aerial parts of this plant are usually discarded in the production of roots preparation. To make better use of these plant resources, the polysaccharide isolated from the aerial part of S. miltiorrhiza was investigated for its potential protection against intestinal diseases. A pectic polysaccharide (SMAP-1) was isolated and characterized being composed of homogalacturonan as the main chain and rhamnogalacturonan type I as ramified region, with side chains including arabinans and possible arabinogalactan type I and II. SMAP-1 exhibited robust protective effects against dextran sodium sulfate (DSS)-induced colitis and restored colitis symptoms, colonic inflammation, and barrier functions. Anti-oxidative effects were also observed by up-regulating Nrf2/Keap1 signaling pathway. Additionally, the level of serum 5-methoxyindole-3-carboxaldehyde (5-MC) was restored by SMAP-1 identified in metabolomic analysis, being correlated with the aforementioned effects. Protection against oxidative stress on intestinal porcine enterocyte cells (IPEC-J2) by 5-MC was observed through the activation of Nrf2/Keap1 system, as also shown by SMAP-1. In conclusion, SMAP-1 could be a promising candidate for colitis prevention, and 5-MC could be the signal metabolite of SMAP-1 in protecting against oxidative stress in the intestine.

Stabilization of IGF2BP1 by USP10 promotes breast cancer metastasis via CPT1A in an m6A-dependent manner.

Metastasis leads to the vast majority of breast cancer mortality. Increasing evidence has shown that N6-methyladenosine (m6A) modification and its associated regulators play a pivotal role in breast cancer metastasis. Here, we showed that overexpression of the m6A reader IGF2BP1 was clinically correlated with metastasis in breast cancer patients. Moreover, IGF2BP1 promoted distant metastasis in vitro and in vivo. Mechanistically, we first identified USP10 as the IGF2BP1 deubiquitinase. USP10 can bind to, deubiquitinate, and stabilize IGF2BP1, resulting in its higher expression level in breast cancer. Furthermore, by MeRIP-seq and experimental verification, we found that IGF2BP1 directly recognized and bound to the m6A sites on CPT1A mRNA and enhanced its stability, which ultimately mediated IGF2BP1-induced breast cancer metastasis. In clinical samples, USP10 levels correlated with IGF2BP1 and CPT1A levels, and breast cancer patients with high levels of USP10, IGF2BP1, and CPT1A had the worst outcome. Therefore, these findings suggest that the USP10/IGF2BP1/CPT1A axis facilitates breast cancer metastasis, and this axis may be a promising prognostic biomarker and therapeutic target for breast cancer.

Melatonin increases susceptibility to atrial fibrillation in obesity via Akt signaling impairment in response to lipid overload.

Melatonin has been proven to have antiarrhythmic potential; however, several studies have recently challenged this view. Herein, using a mouse model of obesity-induced atrial fibrillation (AF), we tentatively explored whether exogenous melatonin supplementation could increase AF susceptibility in the context of obesity. We observed that an 8-week drinking administration of melatonin (60 µg/ml in water) induced a greater susceptibility to AF in obese mice, although obesity-induced structural remodeling was alleviated. An investigation of systemic insulin sensitivity showed that melatonin treatment improved insulin sensitivity in obese mice, whereas it inhibited glucose-stimulated insulin secretion. Notably, melatonin treatment inhibited protein kinase B (Akt) signaling in the atria of obese mice and palmitate-treated neonatal rat cardiomyocytes, thereby providing an AF substrate. Melatonin increased lipid stress in obesity, as evidenced by elevated lipid accumulation and lipolysis-related gene expression, thus contributing to the impairment in atrial Akt signaling. Taken together, our results demonstrated that melatonin could increase AF susceptibility in obesity, probably due to increased lipid stress and resultant impairment of atrial Akt signaling. Our findings suggest that special precautions should be taken when administering melatonin to obese subjects.

Intermittent fasting attenuates obesity-related atrial fibrillation via SIRT3-mediated insulin resistance mitigation.

OBJECTIVE: Atrial fibrillation (AF) is the most common tachyarrhythmia in urgent need of therapeutic optimization. Obesity engenders AF, and its pathogenesis is closely intertwined with insulin resistance (IR), but mechanism-based management is still underinvestigated. Intermittent fasting (IF) is a novel lifestyle intervention that mitigates IR, a potential AF driver, yet whether IF can prevent obesity-related AF remains elusive. Here, we aimed to evaluate the impacts of short-term IF on AF and to uncover the underlying mechanism. METHODS: We subjected obese mice (high-fat diet for 8-week) to IF (alternative-day fasting for another 5-week) for AF vulnerability and substrate formation assessment, and similarly treated neonatal atrial cardiomyocytes (NRCMs) and fibroblasts (NRCFs) (palmitate, 200 µM) with IF (alternative-day short-term starvation for 8-day) for mechanism investigation. RESULTS: Obese mice were prone to AF and atrial remodeling. IF reduced AF inducibility, duration, and reversed atrial remodeling including channel disturbance, left atrial dilation, cardiac hypertrophy and fibrosis in obese mice independent of weight loss. Mechanistically, IF up-regulated the SIRT3 protein level both in vivo and in vitro, and pharmacologic inhibition (3-(1H-1,2,3-Triazol-4-yl) pyridine, 50 µM) and genetic suppression of SIRT3 could attenuate the IF-mediated benefits against hypertrophy and fibrosis. Furthermore, IF activated AMPK and Akt signaling, two positive downstream targets of SIRT3, and inactivated HIF1α signaling, a negative downstream target of SIRT3 in both obese mice atria and palmitate-treated cells, while inhibition of SIRT3 reversed these effects. CONCLUSION: IF prevents obesity-related AF via SIRT3-mediated IR mitigation, thus representing a feasible lifestyle intervention to improve AF management.

Brevicidine acts as an effective sensitizer of outer membrane-impermeable conventional antibiotics for Acinetobacter baumannii treatment.

The antibiotic resistance of Acinetobacter baumannii poses a significant threat to global public health, especially those strains that are resistant to carbapenems. Therefore, novel strategies are desperately needed for the treatment of infections caused by antibiotic-resistant A. baumannii. In this study, we report that brevicidine, a bacterial non-ribosomally produced cyclic lipopeptide, shows synergistic effects with multiple outer membrane-impermeable conventional antibiotics against A. baumannii. In particular, brevicidine, at a concentration of 1 µM, lowered the minimum inhibitory concentration of erythromycin, azithromycin, and rifampicin against A. baumannii strains by 32-128-fold. Furthermore, mechanistic studies were performed by employing erythromycin as an example of an outer membrane-impermeable conventional antibiotic, which showed the best synergistic effects with brevicidine against the tested A. baumannii strains in the present study. The results demonstrate that brevicidine disrupted the outer membrane of A. baumannii at a concentration range of 0.125-4 µM in a dose-dependent manner. This capacity of brevicidine could help the tested outer membrane-impermeable antibiotics enter A. baumannii cells and thereafter exert their antimicrobial activity. In addition, the results show that brevicidine-erythromycin combination exerted strong A. baumannii killing capacity by the enhanced inhibition of adenosine triphosphate biosynthesis and accumulation of reactive oxygen species, which are the main mechanisms causing the death of bacteria. Interestingly, brevicidine and erythromycin combination showed good therapeutic effects on A. baumannii-induced mouse peritonitis-sepsis models. These findings demonstrate that brevicidine is a promising sensitizer candidate of outer membrane-impermeable conventional antibiotics for treating A. baumannii infections in the post-antibiotic age.

Left bundle branch area pacing: A promising modality for cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) is recognized as the first-line management for patients with heart failure (HF) and conduction disorders. As a conventional mode for delivering CRT, biventricular pacing (BVP) improves cardiac function and reduces HF hospitalizations and mortality, but there are still limitations given the high incidence of a lack of response rates. Alternative pacing methods are needed either for primary or rescue therapy. In recent years, conduction system pacing (CSP) has emerged as a more physiological pacing modality for simultaneous stimulation of the ventricles, including His bundle pacing (HBP) and left bundle branch pacing (LBBP). CSP activates the His-Purkinje system, allowing normal ventricular stimulation. However, HBP is technically challenging with a relatively low success rate, high pacing threshold, and failure to correct distal conduction abnormalities. Therefore, LBBP stands out as a novel ideal physiological pacing modality for CRT. Several non-randomized studies compared the feasibility and safety of LBBP with BVP and concluded that LBBP is superior to BVP for delivering CRT with a narrower QRS and greater improvements in left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) functional class. Concurrently, some studies showed lower and stable pacing thresholds and greater improvement of B-type natriuretic peptide (BNP) levels, as well as better mechanical synchronization and efficiency. LBBP ensures better ventricular electromechanical resynchronization than BVP. In this review, we discuss current knowledge of LBBP, compare LBBP with BVP, and explore the potential of LBBP to serve as an alternative primary therapy to realize cardiac resynchronization.

Pectic polysaccharides from Aconitum carmichaelii leaves protects against DSS-induced ulcerative colitis in mice through modulations of metabolism and microbiota composition.

The industrial processing of Aconitum carmichaelii roots for use in Traditional Chinese Medicine generates a high amount of waste material, especially leaves. An acidic polysaccharide fraction isolated from these unutilized leaves, AL-I, was in our previous work shown to contain pectic polysaccharides. This study aimed to investigate the protective effect of AL-I on ulcerative colitis for the possible application of A. carmichaelii leaves in the treatment of intestinal inflammatory diseases. AL-I was found to alleviate symptoms and colonic pathological injury in colitis mice, and ameliorate the levels of inflammatory indices in serum and colon. The production of short- and branched-chain fatty acids was also restored by AL-I. The observed protective effect could be due to the inhibition of NOD1 and TLR4 activation, the promotion of gene transcription of tight-junction proteins, and the modulation of gut microbiota composition like Bacteroides, Dubosiella, Alistipes and Prevotella,. A regulation of serum metabolomic profiles being relevant to the bacterial change, such as D-mannose 6-phosphate, D-erythrose 4-phosphate and uric acid, was also observed.

Polysaccharides from Aconitum carmichaelii leaves: Structure, immunomodulatory and anti-inflammatory activities.

Roots of Aconitum carmichaelii are used in Asian countries due to its content of bioactive alkaloids. In the production of root preparations, tons of leaves are usually discarded, leading to a huge waste of herbal material. The aim of this study is to investigate the polysaccharides in these unutilized leaves. A neutral polysaccharide (AL-N) appeared to be a mixture of heteromannans, and two purified acidic polysaccharides (AL-I-I and AL-I-II) were shown to be pectins containing a homogalacturonan backbone substituted with terminal ß-Xylp-units. AL-I-I consisted of a type-I rhamnogalacturonan core, with arabinan and type-II arabinogalactan domains while AL-I-II was less branched. AL-N and AL-I-I were able to modulate the complement system, while AL-I-II was inactive. Interestingly, AL-N, AL-I-I and AL-I-II were shown to exert anti-inflammatory effects on porcine enterocyte IPEC-J2 cells. AL-I-I and AL-I-II were able to down-regulate the expression of toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 1 (NOD1).