Comparative Effects of Umbilical Cord Mesenchymal Stem Cell Treatment via Different Routes on Lipopolysaccharide-Induced Acute Lung Injury.

BACKGROUND: Although umbilical cord mesenchymal stem cell (UCMSC) infusion has been proposed as a promising strategy for the treatment of acute lung injury (ALI), the parameters of UCMSC transplantation, such as infusion routes and doses, need to be further optimized. METHODS: In this study, we compared the therapeutic effects of UCMSCs transplanted via intravenous injection and intratracheal instillation on lipopolysaccharide-induced ALI using a rat model. Following transplantation, levels of inflammatory factors in serum; neutrophils, total white blood cells, and lymphocytes in bronchoalveolar lavage fluid (BALF); and lung damage levels were analyzed. RESULTS: The results indicated that UCMSCs administered via both intravenous and intratracheal routes were effective in alleviating ALI, as determined by analyses of arterial blood gas, lung histopathology, BALF contents, and levels of inflammatory factors. Comparatively, the intratracheal instillation of UCMSCs was found to result in lower levels of lymphocytes and total proteins in BALF, whereas greater reductions in the serum levels of tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) were detected in rats receiving intravenously injected stem cells. CONCLUSIONS: Our findings in this study provide convincing evidence to indicate the efficacy of UCMSC therapy in the treatment of ALI mediated via different delivery routes, thereby providing a reliable theoretical basis for further clinical studies. Moreover, these findings imply that the effects obtained using the two assessed delivery routes for UCMSC transplantation are mediated via different mechanisms, which could be attributable to different cellular or molecular targets.

Effect of ultrasonic degradation on the physicochemical characteristics, GLP-1 secretion, and antioxidant capacity of Polygonatum cyrtonema polysaccharide.

This study aimed to evaluate the influence of ultrasonic degradation on the physicochemical and biological characteristics of Polygonatum cyrtonema polysaccharide (PCP, 8.59 kDa). PCP was subjected to ultrasonic treatment for 8, 16, and 24 h and yielded the degraded fractions PCP-8, PCP-16, and PCP-24 (5.06, 4.13, and 3.69 kDa), respectively. Compared with the intact PCP, PCP-8, PCP-16 and PCP-24 had a reduced particle size (decrements of 28.03 %, 46.15 % and 62.54 %, respectively). Although ultrasonic degradation did not alter the primary structure of PCP, its triple helical and superficial structures were disrupted, with degraded fractions demonstrating reduced thermal stability and apparent viscosities compared with those of the intact PCP. Furthermore, the functional properties of the degraded fractions were different. PCP-16 most favourably affected GLP-1 secretion, while PCP-8 and PCP-24 exhibited the strongest antioxidant and enzyme inhibitory activities, respectively. Hence, controlled ultrasound irradiation is an appealing approach for partially degrading PCP and enhancing its bioactivity as a functional agent.

Enhanced diabetic wound healing with injectable hydrogel containing self-assembling nanozymes.

To build a smart system in response to the variable microenvironment in infected diabetic wounds, a multifunctional wound dressing was constructed by co-incorporating glucose oxidase (GOx) and a pH-responsive self-assembly Cu2-xSe-BSA nanozyme into a dual-dynamic bond cross-linked hydrogel (OBG). This composite hydrogel (OBG@CG) can adhere to the wound site and respond to the acidic inflammatory environment, initiating the GOx-catalyzed generation of H2O2 and the self-assembly activated peroxidase-like property of Cu2-xSe-BSA nanozymes, resulting in significant hydroxyl radical production to attack the biofilm during the acute infection period and alleviate the high-glucose microenvironment for better wound healing. During the wound recovery phase, Cu2-xSe-BSA aggregates disassembled owing to the elevated pH, terminating catalytic reactive oxygen species generation. Simultaneously, Cu2+ released from the Cu2-xSe-BSA not only promotes the production of mature collagen but also enhances the migration and proliferation of endothelial cells. RNA-seq analysis demonstrated that OBG@CG exerted its antibacterial property by damaging the integrity of the biofilm by inducing radicals and interfering with the energy supply, along with destroying the defense system by disturbing thiol metabolism and reducing transporter activities. This work proposes an innovative glucose consumption strategy for infected diabetic wound management, which may inspire new ideas in the exploration of smart wound dressing.

Advances in spatial transcriptomics and its applications in cancer research.

Malignant tumors have increasing morbidity and high mortality, and their occurrence and development is a complicate process. The development of sequencing technologies enabled us to gain a better understanding of the underlying genetic and molecular mechanisms in tumors. In recent years, the spatial transcriptomics sequencing technologies have been developed rapidly and allow the quantification and illustration of gene expression in the spatial context of tissues. Compared with the traditional transcriptomics technologies, spatial transcriptomics technologies not only detect gene expression levels in cells, but also inform the spatial location of genes within tissues, cell composition of biological tissues, and interaction between cells. Here we summarize the development of spatial transcriptomics technologies, spatial transcriptomics tools and its application in cancer research. We also discuss the limitations and challenges of current spatial transcriptomics approaches, as well as future development and prospects.

Rickettsia symbionts spread via mixed mode transmission, increasing female fecundity and sex ratio shift by host hormone modulating.

Heritable symbionts are common among animals in nature, but the molecular mechanisms underpinning symbiont invasions of host populations have been elusive. In this study, we demonstrate the spread of Rickettsia in an invasive agricultural pest, the whitefly Bemisia tabaci Mediterranean (MED), across northeastern China from 2018 to 2023. Here, we show that the beneficial symbiont Rickettsia spreads by manipulating host hormone signals. Our analyses suggest that Rickettsia have been horizontally acquired by B. tabaci MED from another invasive whitefly B. tabaci Middle East-Asia Minor 1 during periods of coexistence. Rickettsia is transmitted maternally and horizontally from female B. tabaci MED individuals. Rickettsia infection enhances fecundity and results in female bias among whiteflies. Our findings reveal that Rickettsia infection stimulates juvenile hormone (JH) synthesis, in turn enhancing fecundity, copulation events, and the female ratio of the offspring. Consequently, Rickettsia infection results in increased whitefly fecundity and female bias by modulating the JH pathway. More female progeny facilitates the transmission of Rickettsia. This study illustrates that the spread of Rickettsia among invasive whiteflies in northeastern China is propelled by host hormone regulation. Such symbiont invasions lead to rapid physiological and molecular evolution in the host, influencing the biology and ecology of an invasive species.

Effect of mineralized dentin matrix on the prognosis of bone defect and retained root after coronectomy.

OBJECTIVE: To investigate the impact of mineralized dentin matrix (MDM) on the prognosis on bone regeneration and migration of retained roots after coronectomy. MATERIALS AND METHODS: Patients were divided into three groups based on the type of bone graft after coronectomy: Group C (n = 20, collagen), Group T (n = 20, tricalcium phosphate (TCP) + collagen), and Group D (n = 20, MDM + collagen). CBCT scans, conducted immediately and 6 months after surgery, were analyzed using digital software. Primary outcomes, including changes in bone defect depth and retained root migration distance, were evaluated 6 months after surgery. RESULTS: After 6 months, both Groups D and T exhibited greater reduction of the bone defect and lesser retained root migration than Group C (p < 0.001). Group D had greater regenerated bone volume in the distal 2 mm (73 mm3 vs. 57 mm3, p = 0.011) and lesser root migration (2.18 mm vs. 2.96 mm, p < 0.001) than Group T. The proportion of completely bone embedded retained roots was also greater in Group D than in Group C (70.0% vs. 42.1%, p = 0.003). CONCLUSIONS: MDM is an appropriate graft material for improving bone defect healing and reducing retained root migration after coronectomy. CLINICAL RELEVANCE: MDM is an autogenous material prepared chairside, which can significantly improve bone healing and reduce the risk of retained root re-eruption. MDM holds promise as a routine bone substitute material after M3M coronectomy.

Environmental monobutyl phthalate exposure promotes liver cancer via reprogrammed cholesterol metabolism and activation of the IRE1α-XBP1s pathway.

Humans are widely exposed to phthalates, a major chemical plasticizer that accumulates in the liver. However, little is known about the impact of chronic phthalate exposure on liver cancer development. In this study, we applied a long-term cell culture model by treating the liver cancer cell HepG2 and normal hepatocyte L02 to environmental dosage of monobutyl phthalate (MBP), the main metabolite of phthalates. Interestingly, we found that long-term MBP exposure significantly accelerated the growth of HepG2 cells in vitro and in vivo, but barely altered the function of L02 cells. MBP exposure triggered reprogramming of lipid metabolism in HepG2 cells, where cholesterol accumulation subsequently activated the IRE1α-XBP1s axis of the unfolded protein response. As a result, the XBP1s-regulated gene sets and pathways contributed to the increased aggressiveness of HepG2 cells. In addition, we also showed that MBP-induced cholesterol accumulation fostered an immunosuppressive microenvironment by promoting tumor-associated macrophage polarization toward the M2 type. Together, these results suggest that environmental phthalates exposure may facilitate liver cancer progression, and alerts phthalates exposure to patients who already harbor liver tumors.

Analgesia efficacy of erector spinae plane block in laparoscopic Abdominal surgeries: A systemic review and meta-analysis.

BACKGROUND: Multimodal analgesia is now widely practised to minimise postoperative opioid consumption while optimising pain control. The aim of this meta-analysis was to assess the analgesic efficacy of erector spinae plane block (ESPB) in patients undergoing laparoscopic abdominal surgeries. This will be determined by perioperative opioid consumption, subjective pain scores and incidences of postoperative nausea and vomiting. METHODS: We systemically searched electronic databases for randomised controlled trials (RCTs) published up to February 2023 comparing ESPB with other adjuvant analgesic techniques in laparoscopic abdominal surgeries. Nine randomised controlled trials encompassing 666 subjects were included in our study. RESULTS: ESPB was shown to reduce postoperative opioid consumption [mean difference (MD) of -5.95mg (95% CI: -8.86 to -3.04; P< 0.0001); I2=89%], intraoperative opioid consumption [mean difference (MD) of -102.4mcg (95% CI: -145.58 to -59.21; P< 0.00001); I2=39%] and incidence of nausea [RR 0.38 (95% CI: 0.25 to 0.60; P< 0.0001); I2=0%] and vomiting [RR 0.32 (95% CI: 0.17 to 0.63; P=0.0009); I2=0%] in laparoscopic abdominal surgeries. Subgroup analysis on laparoscopic colorectal surgeries further showed reduction in postoperative pain scores [mean difference (MD) of -0.68 (95% CI: -0.94 to -0.41); P< 0.00001; I2=0%]. CONCLUSIONS: This study concludes that ESPB is a valuable technique with proven efficacy to potentially promote faster postoperative recovery through optimising pain control while minimising opioid requirements.

Dynamically changing antineutrophil cytoplasmic antibodies in granulomatosis with polyangiitis: A case report.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is one of the most prevalent forms of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. GPA is characterized histologically by necrotizing granulomatous inflammation in addition to vasculitis. The diagnosis of GPA depends on clinical presentation, serological evidence of a positive ANCA, and/or histological evidence of necrotizing vasculitis or granulomatous destructive parenchymal inflammation. Cytoplasmic ANCA (c-ANCA) is positive in 65%-75% of GPA patients, accompanied by proteinase 3 (PR3), the main target antigen of c-ANCA, another 5% of GPA patients had negative ANCA. CASE SUMMARY: The patient, a 52-year-old male, presented with unexplained nasal congestion, tinnitus, and hearing loss. After a duration of 4 months experiencing these symptoms, the patient subsequently developed fever and headache. The imaging examination revealed the presence of bilateral auricular mastoiditis and partial paranasal sinusitis, and the ANCA results were negative. The anti-infective therapy proved to be ineffective, but the patient's symptoms and fever were quickly relieved after 1 wk of treatment with methylprednisolone 40 mg once a day. However, after continuous use of methylprednisolone tablets for 3 months, the patient experienced a recurrence of fever accompanied by right-sided migraine, positive c-ANCA and PR3, and increased total protein in cerebrospinal fluid. The patient was diagnosed with GPA. After receiving a treatment regimen of intravenous methylprednisolone 40 mg/d and cyclophosphamide 0.8 g monthly, the patient experienced alleviation of fever and headache. Additionally, the ANCA levels became negative and there has been no recurrence. CONCLUSION: For GPA patients with negative ANCA, there is a potential for early missed diagnosis. The integration of histopathological results and multidisciplinary communication plays a crucial role in facilitating ANCA-negative GPA.

Progressive Ataxia due to de novo Missense Variants in the CACNA1A Gene.

The CACNA1A gene encodes the alpha-1A subunit of P/Q type voltage-gated calcium channel Cav2.1, which is associated with a broad clinical spectrum and variable symptomatology. While few patients with progressive ataxia caused by CACNA1A missense variants have been reported, here we report three unrelated Chinese patients with progressive ataxia due to de novo missense variants in the CACNA1A gene, including a novel pathogenic variant (c.4999C > G) and a previously reported pathogenic variant (c.4037G > A). Our findings and a systematic literature review show the unique phenotype of progressive ataxia caused by missense variants and enlarge the genetic and clinical spectrum of CACNA1A. This suggests that in addition to routine screening for dynamic mutations, screening for CACNA1A variants is important for clinicians facing patients with progressive ataxia.

[Effect of Partial Substitution of Chemical Fertilizers with Organic Fertilizers on N2O and NO Emissions from a Peach Orchard].

Organic fertilizer substitution has been promoted as a weight loss, efficient, and diversified fertilizer substitution technology in agricultural production. However, there is a lack of comprehensive assessment of the impact of organic fertilizers on N2O and NO emissions from orchards. In this study, N2O and NO emissions from peach orchards were observed annually using static dark box-gas chromatography to compare the effects of chemical fertilizer application alone and partial replacement of chemical fertilizer treatment on NO emissions from peach orchards. The results showed that the partial replacement of chemical fertilizers with organic fertilizers reduced the total N2O and NO emissions from peach orchards by 15.0 % and 9.4 %, respectively. The N2O and NO emission factors were reduced by 21.3 % and 21.1 %. The mineral N content of the soil in the organic fertilizer treatment was lower than that in the chemical fertilizer treatment alone. The organic fertilizer treatment increased the contribution of AOA to nitrification and decreased the contribution of AOB, thus reducing N2O and NO from nitrification. In addition, the results of the dual isotope mixing model[δ18O(N2O/H2O) vs. δ15NSP] indicated that the bacterial denitrification/nitrifying bacterial denitrification (bD/nD) process served as the primary pathway for N2O emissions in peach orchards. Partial substitution with organic fertilizers enhanced soil denitrification, resulting in larger reductions in the amounts of N2O and NO. Therefore, partial substitution of organic fertilizer is a viable measure to mitigate nitrogen oxide emissions from orchards and to achieve green and low-carbon development in agriculture.

Improved Synthesis of Hollow Fiber SSZ-13 Zeolite Membranes for High-Pressure CO2/CH4 Separation.

High-silica CHA zeolite membranes are highly desired for natural gas upgrading because of their separation performance in combination with superior mechanical and chemical stability. However, the narrow synthesis condition range significantly constrains scale-up preparation. Herein, we propose a facile interzeolite conversion approach using the FAU zeolite to prepare SSZ-13 zeolite seeds, featuring a shorter induction and a longer crystallization period of the membrane synthesis on hollow fiber substrates. The membrane thickness was constant at ~3 µm over a wide span of synthesis time (24-96 h), while the selectivity (separation efficiency) was easily improved by extending the synthesis time without compromising permeance (throughput). At 0.2 MPa feed pressure and 303 K, the membranes showed an average CO2 permeance of (5.2±0.5)×10-7 mol m-2 s-1 Pa-1 (1530 GPU), with an average CO2/CH4 mixture selectivity of 143±7. Minimal defects ensure a high selectivity of 126 with a CO2 permeation flux of 0.4 mol m-2 s-1 at 6.1 MPa feed pressure, far surpassing requirements for industrial applications. The feasibility for successful scale-up of our approach was further demonstrated by the batch synthesis of 40 cm-long hollow fiber SSZ-13 zeolite membranes exhibiting CO2/CH4 mixture selectivity up to 400 (0.2 MPa feed pressure and 303 K) without using sweep gas.

Research Note: Pharmacokinetics of bromhexine hydrochloride in broilers after single oral and intravenous administration.

The current study aimed to investigate the pharmacokinetics of bromhexine hydrochloride in broilers after single intravenous (IV) and oral (PO) administration at 2.5 mg/kg body weight (BW). The trial adopted a randomized, parallel-controlled design, where 20 twelve-wk-old broilers were randomly assigned to either the PO or IV group. Blood samples were collected at predetermined time points, and plasma was further separated for analysis. The bromhexine hydrochloride concentrations in plasma samples were determined using an ultra-performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method. Noncompartmental analysis (NCA) using Phoenix software was conducted to analyze the concentration versus time data of bromhexine hydrochloride in every chicken. Subsequently, the main pharmacokinetic parameters between the 2 groups were statistically analyzed using SPSS software. Results from NCA revealed that after oral administration at 2.5 mg/kg BW, bromhexine hydrochloride exhibited slow absorption, reaching an average peak concentration of 32.72 ng/mL at 1.78 h. However, incomplete absorption was observed, with an absolute bioavailability of only 20.06% ± 10.84%. Additionally, bromhexine hydrochloride displayed wide distribution, with a steady-state distribution volume (VSS) of 22.55 ± 13.45 L/kg, and slow elimination, with a clearance (Cl) of 1.52 ± 0.38 L/h/kg. Furthermore, gender effects were assessed on the pharmacokinetics of bromhexine hydrochloride in broilers, revealing better absorption in male broilers compared to females. This disparity may be attributed to the faster blood flow and richer blood volume typically found in male broilers.

Surveillance of Parrot Bornavirus in Taiwan Captive Psittaciformes.

Parrot bornavirus (PaBV) is an infectious disease linked with proventricular dilatation disease (PDD) with severe digestive and neurological symptoms affecting psittacine birds. Despite its detection in 2008, PaBV prevalence in Taiwan remains unexplored. Taiwan is one of the leading psittacine bird breeders; hence, understanding the distribution of PaBV aids preventive measures in controlling spread, early disease recognition, epidemiology, and transmission dynamics. Here, we aimed to detect the prevalence rate of PaBV and assess its genetic variation in Taiwan. Among 124 psittacine birds tested, fifty-seven were PaBV-positive, a prevalence rate of 45.97%. Most of the PaBV infections were adult psittacine birds, with five birds surviving the infection, resulting in a low survival rate (8.77%). A year of parrot bornavirus surveillance presented a seasonal pattern, with peak PaBV infection rates occurring in the spring season (68%) and the least in the summer season (25%), indicating the occurrence of PaBV infections linked to seasonal factors. Histopathology reveals severe meningoencephalitis in the cerebellum and dilated cardiomyopathy of the heart in psittacine birds who suffered from PDD. Three brain samples underwent X/P gene sequencing, revealing PaBV-2 and PaBV-4 viral genotypes through phylogenetic analyses. This underscores the necessity for ongoing PaBV surveillance and further investigation into its pathophysiology and transmission routes.

Differentiation and immunosuppressive function of CD19+CD24hiCD27+ regulatory B cells are regulated through the miR-29a-3p/NFAT5 pathway.

BACKGROUND: Regulatory B cells (Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs (miRNAs), miR-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and miR-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs (mBregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. METHODS: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce miR-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. RESULTS: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of mBregs in the circulating blood were significantly impaired. miR-29a-3p was found to be a regulator of mBregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5 (NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of mBregs. The inhibition of miR-29a-3p in CD19+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into mBregs. In addition, the observed enhancement of differentiation and immunosuppressive function of mBregs upon miR-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. CONCLUSIONS: miR-29a-3p was found to be a crucial regulator for mBregs differentiation and immunosuppressive function. Silencing miR-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.

Persistent differences in the immunogenicity of the two COVID-19 primary vaccines series, modulated by booster mRNA vaccination and breakthrough infection.

INTRODUCTION: The long-term impact of initial immunogenicity induced by different primary COVID-19 vaccine series remains unclear. METHODS: A prospective cohort study was conducted at 10 tertiary hospitals in Korea from March 2021 to September 2022. Immunogenicity assessments included anti-spike protein antibody (Sab), SARS-CoV-2-specific interferon-gamma releasing assay (IGRA), and multiplex cytokine assays for spike protein-stimulated plasma. Spike proteins derived from wild-type SARS-CoV-2 and alpha variant (Spike1) and beta and gamma variant (Spike2) were utilized. RESULTS: A total of 235 healthcare workers who had received a two-dose primary vaccine series of either ChAdOx1 or BNT162b2, followed by a third booster dose of BNT162b2 (166 in the ChAdOx1/ChAdOx1/BNT162b2 (CCB) group and 69 in the BNT162b2/BNT162b2/BNT162b2 (BBB) group, based on the vaccine series) were included. Following the primary vaccine series, the BBB group exhibited significantly higher increases in Sab levels, IGRA responses, and multiple cytokines (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1ß, interleukin (IL)-1ra, IFN-γ, IL-2, IL-4, and IL-10) compared to the CCB group (all P < 0.05). One month after the third BNT162b2 booster, the CCB group showed Sab levels comparable to those of the BBB group, and both groups exhibited lower levels after six months without breakthrough infections (BIs). However, among those who experienced BA.1/2 BIs after the third booster, Sab levels increased significantly more in the BBB group than in the CCB group (P < 0.001). IGRA responses to both Spike1 and Spike2 proteins were significantly stronger in the BBB group than the CCB group after the third booster, while only the Spike2 response were higher after BIs (P = 0.007). The BBB group exhibited stronger enhancement of T-cell cytokines (IL-2, IL-4, and IL-17A) after BIs than in the CCB group (P < 0.05). CONCLUSION: Differences in immunogenicity induced by the two primary vaccine series persisted, modulated by subsequent booster vaccinations and BIs.

Anti-HBV Activities of Cembranoids from the South China Sea Soft Coral Sinularia pedunculata and Their Structure Activity Relationship.

Hepatitis B Virus (HBV) infection is a global public health challenge that seriously endangers human health. Soft coral, as a major source of terpenoids, contains many structurally novel and highly bioactive compounds. In previous studies, it has been demonstrated that cembranoid-type diterpenoids showed significant anti-inflammatory and anti-colorectal cancer activities. In this study, cembranoids isolated from Sinularia pedunculata was found with anti-HBV activity for the first time. Among them, compound 6 showed significant anti-HBV activity with an IC50 value of 5.57 µM without cytotoxicity. We analysed the preliminary structure-activity relationship (SAR). Furthermore, it is demonstrated that compound 6 can accelerate the formation of capsid, inhibit HBeAg, HBV core particle DNA, HBV total RNA and pregenomic RNA in a dose dependent manner. We also confirmed the anti-HBV activity in HepG2-NTCP infection system. Finally, we find the anti-HBV mechanism of these compounds by inhibiting the ENI/Xp enhancer/promoter.

A novel bellidifolin intervention mitigates nonalcoholic fatty liver disease-like changes induced by bisphenol F.

As a potential endocrine-disrupting chemical, bisphenol F (BPF) may cause nonalcoholic fatty liver disease (NAFLD)-like changes, but the mechanisms underpinning its pathogenesis as well as the intervention strategies remain poorly understood. Using the electron microscopy technology, along with LipidTOX Deep Red neutral and Bodipy 493/503 staining assays, we observed that BPF treatment elicited a striking accumulation of lipid droplets in HepG2 cells, accompanied by an increased total level of triglycerides. At the molecular level, the lipogenesis-associated mRNAs and proteins, including acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase-1, peroxisome proliferator-activated receptor gamma, and CCAAT-enhancer-binding proteins, increased significantly via the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling regulation in both in vitro and in vivo studies. Furthermore, the immunofluorescence results also showed the robust lipogenesis induced by BPF, evident in its ability to promote the translocation of sterol regulatory element-binding protein-1c from the cytoplasm to the nuclei. To investigate the intervention strategies for BPF-induced NAFLD-like changes, we demonstrated that bellidifolin, isolated and purified from Swertia chirayita, significantly attenuated BPF-induced lipid droplet deposition in HepG2 cell and NAFLD-like changes in mice by blocking the expression of lipogenesis-associated proteins. Therefore, the present study elucidates the mechanisms underlying BPF-induced lipid accumulation in HepG2 cells, while also highlighting the potential of bellidifolin to mitigate BPF-induced NAFLD-like changes.

Three-in-One Zinc Anodes Created by a Large-scale Two-Step Method Achieving Excellent Long-Term Cyclic Reversibility and Thin Electrode Integrity.

Practical aqueous zinc-ion batteries require low-cost thin zinc anodes with long-term reversible stripping/depositing. However, thin zinc anodes encounter more severe issues than thick zinc, such as dendrites and uneven stripping, resulting in subpar performance and limited lifetimes. Here, this work proposes a three-in-one zinc anode obtained by a large-scale two-step method to address the above issues. In a three-in-one zinc anode, the copper foil as an inactive current collector solves the gradual reduction of the active area when only the pure zinc as an active current collector. This work develops an automatic electroplating device that can continuously deposit a zinc layer on a conducting foil to meet the demand for zinc-coated copper foils. The sodium carboxymethylcellulose (CMC)-zinc fluoride (ZnF2) protective layer prevents direct contact between zinc and separator, and provides a uniform and sufficient supply of zinc ions. The CMC-ZnF2-coated copper foil performs up to 3000 reversible zinc deposition/stripping cycles with a cumulative capacity of 6 Ah cm-2 and an average Coulombic efficiency of 99.94%. The Zn||ZnVO cell using the three-in-one anode achieved a high capacity retention of over 70% after 15 000 cycles. The proposed three-in-one anode and the automatic electroplating device will facilitate industrialization of practical thin zinc anodes.

Antimicrobial activity of ceftazidime-avibactam against KPC-2-producing Enterobacterales: a cross-combination and dose-escalation titration study with relebactam and vaborbactam.

With the introduction of ceftazidime-avibactam worldwide, the antimicrobial activity of new ß-lactam/ß-lactamase inhibitors (BL/BLIs) needs to be investigated. From January 2020 to June 2023, Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales were collected. With a broth microdilution test of new BL/BLIs, cross-activity test with nine combinations of BLs and new BLIs and dose-escalation titration test for non-susceptible isolates were conducted to investigate inhibitory activities of new BLIs. A total of 188 isolates was collected and most isolates (186/188, 98.9%) carried the KPC-2 gene exclusively, while two isolates (1.1%) co-harbored NDM-1. Among the 186 KPC-2-producing isolates, 184 (98.9%) were susceptible to ceftazidime-avibactam, 173 (93.0%) to imipenem-relebactam, and 184 (98.9%) to meropenem-vaborbactam. All isolates non-susceptible to imipenem-relebactam or meropenem-vaborbactam became susceptible when avibactam replaced relebactam or vaborbactam, with 7 of 11 (63.6%) imipenem-relebactam non-susceptible isolates and both (100.0%) of the meropenem-vaborbactam non-susceptible isolates. When the minimum inhibitory concentrations (MICs) of BLs were compared using log2 scales, combinations with avibactam showed statistically significant efficacy in lowering MICs compared to relebactam and vaborbactam (all P < 0.05). In the dose-escalation test of new BLIs, increasing dose of all new BLIs corresponded to increased susceptibility to BLs. Ceftazidime-avibactam exhibited excellent susceptibility against KPC-2-producing Enterobacterales unless co-harboring metallo-ß-lactamase. The cross-combination test against non-susceptible isolates suggests that the inhibitory activity of avibactam was superior to those of relebactam or vaborbactam. Increasing the dose of new BLIs produced increased susceptibility to BLs, suggesting that high-concentration regimen need to be developed. IMPORTANCE: This study investigated 188 Klebsiella pneumoniae carbapenemase (KPC)-2-producing Enterobacterales collected from January 2020 to June 2023 in a tertiary care hospital of Korea. Most isolates were susceptible to ceftazidime-avibactam (98.9%) and meropenem-vaborbactam (98.9%), while susceptibility to imipenem-relebactam was lower (93.0%). The cross-combination test using nine combinations of the individual ß-lactams (BLs) and new ß-lactamase inhibitors (BLIs) showed that the inhibitory activity of avibactam was significantly superior to relebactam or vaborbactam when the Log2 MIC of BLs were compared for each combination with BLIs (all P < 0.05). The dose-escalation test of new BLIs demonstrated that increasing doses of new BLIs corresponded to increased susceptibility to BLs. Taken together, this study illustrates the excellent activity of ceftazidime-avibactam against KPC-2-producing Enterobacterales and suggests further investigation into high-concentration regimens for potentially non-susceptible clinical isolates.