Molecular physiological characterization of the dynamics of persister formation in Staphylococcus aureus.

Bacteria possess the ability to enter a growth-arrested state known as persistence in order to survive antibiotic exposure. Clinically, persisters are regarded as the main causative agents for chronic and recurrent infectious diseases. To combat this antibiotic-tolerant population, a better understanding of the molecular physiology of persisters is required. In this study, we collected samples at different stages of the biphasic kill curve to reveal the dynamics of the cellular molecular changes that occur in the process of persister formation. After exposure to antibiotics with different modes of action, namely, vancomycin and enrofloxacin, similar persister levels were obtained. Both shared and distinct stress responses were enriched for the respective persister populations. However, the dynamics of the presence of proteins linked to the persister phenotype throughout the biphasic kill curve and the molecular profiles in a stable persistent population did show large differences, depending on the antibiotic used. This suggests that persisters at the molecular level are highly stress specific, emphasizing the importance of characterizing persisters generated under different stress conditions. Additionally, although generated persisters exhibited cross-tolerance toward tested antibiotics, combined therapies were demonstrated to be a promising approach to reduce persister levels. In conclusion, this investigation sheds light on the stress-specific nature of persisters, highlighting the necessity of tailored treatment approaches and the potential of combined therapy.

Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by inflammation of the synovial tissue and joint bone destruction, often leading to significant disability. The main pathological manifestation of joint deformity in RA patients is bone destruction, which occurs due to the differentiation and proliferation of osteoclasts. The transcription factor nuclear factor-activated T cell 1 (NFATc1) plays a crucial role in this process. The regulation of NFATc1 in osteoclast differentiation is influenced by three main factors. Firstly, NFATc1 is activated through the upstream nuclear factor kappa-B ligand (RANKL)/RANK signaling pathway. Secondly, the Ca2+-related co-stimulatory signaling pathway amplifies NFATc1 activity. Finally, negative regulation of NFATc1 occurs through the action of cytokines such as B-cell Lymphoma 6 (Bcl-6), interferon regulatory factor 8 (IRF8), MAF basic leucine zipper transcription factor B (MafB), and LIM homeobox 2 (Lhx2). These three phases collectively govern NFATc1 transcription and subsequently affect the expression of downstream target genes including TRAF6 and NF-κB. Ultimately, this intricate regulatory network mediates osteoclast differentiation, fusion, and the degradation of both organic and inorganic components of the bone matrix. This review provides a comprehensive summary of recent advances in understanding the mechanism of NFATc1 in the context of RA-related bone destruction and discusses potential therapeutic agents that target NFATc1, with the aim of offering valuable insights for future research in the field of RA. To assess their potential as therapeutic agents for RA, we conducted a drug-like analysis of potential drugs with precise structures.

Zero Voltage-Degradation of Li2MnO3 with Ultrathin Amorphous Li─Mn─O Coating.

Manganese-based lithium-rich layered oxides (Mn-LLOs) are promising candidate cathode materials for lithium-ion batteries, however, the severe voltage decay during cycling is the most concern for their practical applications. Herein, an Mn-based composite nanostructure constructed Li2MnO3 (LMO@Li2MnO3) is developed via an ultrathin amorphous functional oxide LixMnOy coating at the grain surface. Due to the thin and universal LMO amorphous surface layer etched from the lithiation process by the high-concentration alkaline solution, the structural and interfacial stability of Li2MnO3 are enhanced apparently, showing the significantly improved voltage maintenance, cycle stability, and energy density. In particular, the LMO@Li2MnO3 cathode exhibits zero voltage decay over 200 cycles. Combining with ex situ spectroscopic and microscopic techniques, the Mn2+/4+ coexisted behavior of the amorphous LMO is revealed, which enables the stable electrochemistry of Li2MnO3. This work provides new possible routes for suppressing the voltage decay of Mn-LLOs by modifying with the composite functional unit construction.

CD63 + tumor-associated macrophages drive the progression of hepatocellular carcinoma through the induction of epithelial-mesenchymal transition and lipid reprogramming.

BACKGROUND: Tumor-associated macrophages (TAMs) constitute a substantial part of human hepatocellular carcinoma (HCC). The present study was devised to explore TAM diversity and their roles in HCC progression. METHODS: Through the integration of multiple 10 × single-cell transcriptomic data derived from HCC samples and the use of consensus nonnegative matrix factorization (an unsupervised clustering algorithm), TAM molecular subtypes and expression programs were evaluated in detail. The roles played by these TAM subtypes in HCC were further probed through pseudotime, enrichment, and intercellular communication analyses. Lastly, vitro experiments were performed to validate the relationship between CD63, which is an inflammatory TAM expression program marker, and tumor cell lines. RESULTS: We found that the inflammatory expression program in TAMs had a more obvious interaction with HCC cells, and CD63, as a marker gene of the inflammatory expression program, was associated with poor prognosis of HCC patients. Both bulk RNA-seq and vitro experiments confirmed that higher TAM CD63 expression was associated with the growth of HCC cells as well as their epithelial-mesenchymal transition, metastasis, invasion, and the reprogramming of lipid metabolism. CONCLUSIONS: These analyses revealed that the TAM inflammatory expression program in HCC is closely associated with malignant tumor cells, with the hub gene CD63 thus representing an ideal target for therapeutic intervention in this cancer type.

Bacillus subtilis and Enterococcus faecium co-fermented feed alters antioxidant capacity, muscle fibre characteristics and lipid profiles of finishing pigs.

This study aimed to assess how Bacillus subtilis and Enterococcus faecium co-fermented feed (FF) affects the antioxidant capacity, muscle fibre types and muscle lipid profiles of finishing pigs. In this study, a total of 144 Duroc × Berkshire × Jiaxing Black finishing pigs were randomly assigned into three groups with four replicates (twelve pigs per replication). The three treatments were a basal diet (0 % FF), basal diet + 5 % FF and basal diet + 10 % FF, respectively. The experiment lasted 38 d after 4 d of acclimation. The study revealed that 10 % FF significantly increased the activity of superoxide dismutase (SOD) and catalase (CAT) compared with 0 % FF group, with mRNA levels of up-regulated antioxidant-related genes (GPX1, SOD1, SOD2 and CAT) in 10 % FF group. 10 % FF also significantly up-regulated the percentage of slow-twitch fibre and the mRNA expression of MyHC I, MyHC IIa and MyHC IIx, and slow MyHC protein expression while reducing MyHC IIb mRNA expression. Lipidomics analysis showed that 5 % FF and 10 % FF altered lipid profiles in longissimus thoracis. 10 % FF particularly led to an increase in the percentage of TAG. The Pearson correlation analysis indicated that certain molecular markers such as phosphatidic acid (PA) (49:4), Hex2Cer (d50:6), cardiolipin (CL) (72:8) and phosphatidylcholine (PC) (33:0e) could be used to indicate the characteristics of muscle fibres and were closely related to meat quality. Together, our findings suggest that 10 % FF improved antioxidant capacity, enhanced slow-twitch fibre percentage and altered muscle lipid profiles in finishing pigs.

Reconstructing the COVID-19 incidence in India using airport screening data in Japan.

BACKGROUND: A major epidemic of COVID-19 caused by the Delta variant (B.1.617.2) occurred in India from March to July 2021, resulting in 19 million documented cases. Given the limited healthcare and testing capacities, the actual number of infections is likely to have been greater than reported, and several modelling studies and excess mortality research indicate that this epidemic involved substantial morbidity and mortality. METHODS: To estimate the incidence during this epidemic, we used border entry screening data in Japan to estimate the daily incidence and cumulative incidence of COVID-19 infection in India. Analysing the results of mandatory testing among non-Japanese passengers entering Japan from India, we calculated the prevalence and then backcalculated the incidence in India from February 28 to July 3, 2021. RESULTS: The estimated number of infections ranged from 448 to 576 million people, indicating that 31.8% (95% confidence interval (CI): 26.1, 37.7) - 40.9% (95% CI: 33.5, 48.4) of the population in India had experienced COVID-19 infection from February 28 to July 3, 2021. In addition to obtaining cumulative incidence that was consistent with published estimates, we showed that the actual incidence of COVID-19 infection during the 2021 epidemic in India was approximately 30 times greater than that based on documented cases, giving a crude infection fatality risk of 0.47%. Adjusting for test-negative certificate before departure, the quality control of which was partly questionable, the cumulative incidence can potentially be up to 2.3-2.6 times greater than abovementioned estimates. CONCLUSIONS: Our estimate of approximately 32-41% cumulative infection risk from February 28 to July 3, 2021 is roughly consistent with other published estimates, and they can potentially be greater, given an exit screening before departure. The present study results suggest the potential utility of border entry screening data to backcalculate the incidence in countries with limited surveillance capacity owing to a major surge in infections.

Evaluation of the exit screening policy among travelers arriving from Asian and pacific nations.

BACKGROUND: The Japanese government has instituted border control measures against COVID-19, including entry and exit screening of people arriving from overseas. We sought to evaluate the effectiveness of the exit screening policy in Japan in reducing the risk of importing COVID-19 cases among travelers from Asian and Pacific countries. METHODS: The study period was stratified based on the timing of exit screening: (i) the control period (the pre-exit screening period from 25 October 2020 to 16 January 2021), (ii) the time period with the Alpha variant from 17 January to 10 April 2021, and (iii) the time period with the Delta variant from 2 May to 2 October 2021. Incidence data in the countries of origin were used to adjust for the risk of infection among travelers. The positivity rate of entry screening in Japan was compared among the three different study periods, adjusting for the risk of infection in the country of origin. RESULTS: The adjusted relative risk of positivity was greatly reduced and substantially below the value of 1 during the Alpha variant period compared with the control period. Although the relative risks increased when comparing the Delta variant period against control, the estimate remained below 1, except for among travelers from India and Myanmar. The relative risk reduction was greatest in high-income countries, with estimates of 100% and 96% risk reduction during the Alpha and Delta variant periods, respectively, followed by upper-middle-income countries with estimates of 90% and 76%, respectively. CONCLUSIONS: Even in the presence of the Alpha and Delta variants, exit screening clearly reduced the risk of infection among travelers arriving from Asian and Pacific nations. As the testing relies on the country of origin, the effectiveness varied greatly by the socioeconomic income status and epidemiological situation of those countries. Test standardization and quality assurance may be required in low- and middle-income countries.

Protein profiles reveal MSH6/MSH2 as a potential biomarker for hepatocellular carcinoma with microvascular invasion.

AIM: Microvascular invasion (MVI) is an independent risk factor for postoperative recurrence and metastasis in hepatocellular carcinoma (HCC). However, the specific protein expression profiles that differentiate HCC with MVI from those without MVI remain unclear. METHODS: The profiles of proteins in early-stage HCC tissues and normal liver tissues were characterized by quantitative proteomics techniques. Immunohistochemical (IHC) staining was undertaken on tissue microarrays from 80 HCC patients to assess the expression of MSH2 and MSH6. Cell counting, colony formation, migration, and invasion assays were carried out in vitro. RESULTS: We identified 5164 proteins in both HCC tissues and adjacent normal liver tissues. Compared to HCC without MVI, 148 upregulated proteins and 97 downregulated proteins were found in HCC with MVI. Particularly noteworthy was the remarkable upregulation of MSH6/MSH2 among these dysregulated proteins in HCC with MVI. Further validation through bioinformatics prediction and IHC confirmed the elevated expression of MSH6/MSH2, which correlated with aggressive disease characteristics and poor prognosis. Receiver operating characteristic curve analyses revealed a substantial area under the curve of 0.761 (specificity 71.79%, sensitivity 73.17%) for the combined use of MSH6/MSH2. Knockdown of MSH6/MSH2 significantly inhibited HCC cell proliferation and invasion in vitro. CONCLUSIONS: Our study establishes MSH6 or MSH2 as an oncogene that is prominently overexpressed during HCC progression, which provides new targets for HCC with MVI.

Efficacy of physical exercise intervention on children with acute lymphoblastic leukemia during treatment and rehabilitation: a systematic review and meta-analysis.

OBJECTIVE: To systematically evaluate the impact of physical exercise intervention on children with acute lymphoblastic leukemia (ALL) during the treatment and rehabilitation consolidation periods. METHOD: Randomized controlled trials (RCTs) were retrieved from PubMed, Scopus, Web of Science, CNKI, and Cochrane databases, with a search time range from database establishment to September 1, 2023. The quality of the included RCTs was evaluated using the Cochrane risk assessment tool, and a systematic evaluation was conducted using RevMan 5.4. The study has been registered with INPLASY (registration number: 202390100). RESULT: A total of 12 RCTs including 423 subjects was included. The meta-analysis results showed that long-term exercise intervention can effectively improve the endurance performance (SMD = 1.37, 95% CI 0.45 to 2.29, p = 0.004), functional mobility (MD = - 1.17, 95% CI - 1.85 to - 0.49, p = 0.0008), cancer-related fatigue (CRF) (MD = - 1.25, 95% CI - 1.69 to - 0.80, p < 0.00001), and quality of life (QOL) (MD = 4.93, 95% CI 1.80 to 8.05, p = 0.002) of ALL children during the treatment and rehabilitation consolidation periods. Its promoting effect on the muscle strength (SMD = 0.53, 95% CI - 0.33 to 1.39, p = 0.23) and bone mineral density (BMD) (SMD = 0.48, 95% CI 0.20 to 0.77, p = 0.05) of the subjects was not significant. Further meta-analysis showed that exercise intervention with a duration of less than 1 year (SMD = 0.91, 95% CI 0.55 to 1.28, p < 0.00001) rather than more than 1 year (SMD = - 0.16, 95% CI - 0.61 to 0.29, p = 0.49) can effectively reduce subject BMD, while in terms of strength, exercise intervention can effectively improve strength during the treatment period (SMD = 0.97, 95% CI 0.40 to 1.54, p = 0.0008) rather than the consolidation period (SMD = - 0.27, 95% CI - 1.08 to 0.53, p = 0.51). CONCLUSION: Long-term regular exercise can effectively improve the endurance, functional mobility, CRF, and QOL of children with ALL in the rehabilitation and treatment consolidation stages. Their strength and BMD may be influenced by the timing of treatment and the intervention cycle, respectively. Considering the limited number of included literature and the instability of some outcome indicators, it is necessary to design more comprehensive and rigorous high-quality RCTs in the future to test the exercise efficacy of ALL children.

Achieving deep intratumoral penetration and multimodal combined therapy for tumor through algal photosynthesis.

BACKGROUND: Elevated interstitial fluid pressure within tumors, resulting from impaired lymphatic drainage, constitutes a critical barrier to effective drug penetration and therapeutic outcomes. RESULTS: In this study, based on the photosynthetic characteristics of algae, an active drug carrier (CP@ICG) derived from Chlorella pyrenoidosa (CP) was designed and constructed. Leveraging the hypoxia tropism and phototropism exhibited by CP, we achieved targeted transport of the carrier to tumor sites. Additionally, dual near-infrared (NIR) irradiation at the tumor site facilitated photosynthesis in CP, enabling the breakdown of excessive intratumoral interstitial fluid by generating oxygen from water decomposition. This process effectively reduced the interstitial pressure, thereby promoting enhanced perfusion of blood into the tumor, significantly improving deep-seated penetration of chemotherapeutic agents, and alleviating tumor hypoxia. CONCLUSIONS: CP@ICG demonstrated a combined effect of photothermal/photodynamic/starvation therapy, exhibiting excellent in vitro/in vivo anti-tumor efficacy and favorable biocompatibility. This work provides a scientific foundation for the application of microbial-enhanced intratumoral drug delivery and tumor therapy.

GADD45A regulates subcutaneous fat deposition and lipid metabolism by interacting with Stat1.

BACKGROUND: Obesity, characterized by excessive white adipose tissue expansion, is associated with several metabolic complications. Identifying new adipogenesis regulators may lead to effective therapies for obesity-induced metabolic disorders. RESULTS: Here, we identified the growth arrest and DNA damage-inducible A (GADD45A), a stress-inducible histone-folding protein, as a novel regulator of subcutaneous adipose metabolism. We found that GADD45A expression was positively correlated with subcutaneous fat deposition and obesity in humans and fatty animals. In vitro, the gain or loss function of GADD45A promoted or inhibited subcutaneous adipogenic differentiation and lipid accumulation, respectively. Using a Gadd45a-/- mouse model, we showed that compared to wild-type (WT) mice, knockout (KO) mice exhibited subcutaneous fat browning and resistance to high-fat diet (HFD)-induced obesity. GADD45A deletion also upregulated the expression of mitochondria-related genes. Importantly, we further revealed that the interaction of GADD45A with Stat1 prevented phosphorylation of Stat1, resulting in the impaired expression of Lkb1, thereby regulating subcutaneous adipogenesis and lipid metabolism. CONCLUSIONS: Overall, our results reveal the critical regulatory roles of GADD45A in subcutaneous fat deposition and lipid metabolism. We demonstrate that GADD45A deficiency induces the inguinal white adipose tissue (iWAT) browning and protects mice against HFD-induced obesity. Our findings provide new potential targets for combating obesity-related metabolic diseases and improving human health.

Functional Analysis of ß-Carotene Oxygenase 2 (BCO2) Gene in Yesso Scallop (Patinopecten yessoensis).

Carotenoids are essential nutrients for humans and animals, and carotenoid coloration represents an important meat quality parameter for many farmed animals. Increasingly, studies have demonstrated that vertebrate carotenoid cleavage oxygenases (CCOs) are essential enzymes in carotenoid metabolism and are therefore potential candidate genes for improving carotenoid deposition. However, our understanding of carotenoid bioavailability and CCOs functions in invertebrates, particularly marine species, is currently quite limited. We previously identified that a CCO homolog, PyBCO-like 1, was the causal gene for carotenoid coloration in the 'Haida golden scallop', a variety of Yesso scallop (Patinopecten yessoensis) characterized by carotenoid enrichment. Here, we found that another CCO-encoding gene named PyBCO2 (ß-carotene oxygenase 2) was widely expressed in P. yessoensis organs/tissues, with the highest expression in striated muscle. Inhibiting BCO2 expression in P. yessoensis through RNA interference led to increased carotenoid (pectenolone and pectenoxanthin) deposition in the striated muscle, and the color of the striated muscle changed from white to light orange. Our results indicate that PyBCO2 might be a candidate gene used for improving carotenoid content in normal Yesso scallops, and also in 'Haida golden scallops'.

The Interaction between Iron Cyanide and Lead Ions in Pyrite Flotation.

Despite being a major cyanide species in the process water, it is unclear how iron cyanide influences pyritic gold ore flotation as well as how lead ions influence pyritic gold ore flotation in the presence of iron cyanide. This study aims at revealing the interaction of Fe(CN)63- and lead ions in pyrite flotation to investigate the strong depressing effect of Fe(CN)63- on pyritic gold ore flotation and the significant activating effect of lead ions on pyritic gold ore flotation in the presence of Fe(CN)63- using flotation, zeta potential measurement and surface analysis methods. The flotation results showed that upon 5 × 10-5 mol/L Fe(CN)63- addition, pyrite recovery drastically decreased from about 51.3% to 8.6%, while the subsequent addition of 9.5 × 10-4 mol/L lead ions significantly activated pyrite with the recovery increasing from 8.6% to 91%, which demonstrated that Fe(CN)63- strongly depressed pyrite flotation, while lead ions completely activated pyrite in the presence of Fe(CN)63-. Zeta potential measurement, surface analysis using Cryogenic X-ray photoelectron spectroscopy (Cryo-XPS) and electrochemical impedance spectroscopy (EIS) revealed that Fe(CN)63- depression was attributed to the chemical adsorption of Fe(CN)63- on iron sites of pyrite as Prussian Blue (Fe[Fe(CN)6]); however, this hydrophilic layer could be covered totally by lead ions which adsorbed on as lead hydroxide/oxide through electrostatic interactions, which resulted in the significant activation effect of lead ions. The results from this study will lead to improved flotation of gold associated with pyrite in gold flotation plants.

Effect of a novel alkaline protease from Bacillus licheniformis on growth performance, carcass characteristics, meat quality, antioxidant capacity, and intestinal morphology of white feather broilers.

BACKGROUND: The present study was conducted to investigate the effects of dietary novel alkaline protease from Bacillus licheniformis on the growth performance, meat quality, antioxidant status and intestinal morphology of broilers. In total, 4000 broilers were randomly assigned into five groups and treated with normal control, normal control + 100 mg kg-1 protease, normal control + 200 mg kg-1 protease, normal control + 300 mg kg-1 protease and normal control + 400 mg kg-1 protease. RESULTS: Supplementing protease impacted final body weight (linear, P = 0.003; quadratic, P = 0.006) and decreased feed conversion rate (linear, P = 0.036) in broilers. Moreover, dietary protease significantly increased breast muscle rate (linear, P = 0.005; quadratic, P = 0.021) and decreased drip loss (linear, P < 0.001; quadratic, P < 0.001). In addition, dietary protease notably increased protein digestibility (linear, P = 0.001; quadratic, P = 0.006) and trypsin activity (linear, P = 0.002; quadratic, P = 0.009) in jejunum. Light microscopy revealed that the jejunum villi in the 300 mg kg-1 and 400 mg kg-1 groups exhibited greater height and a denser arrangement compared to those in the control group. The addition of protease decreased malondialdehyde content (linear, P < 0.001; quadratic, P < 0.001) and increased total antioxidant capacity (linear, P = 0.001; quadratic, P < 0.001) in pectoral muscles. CONCLUSION: The results of the present study suggest that dietary novel alkaline protease from B. licheniformis improved growth performance by affecting trypsin activity, protein digestibility, antioxidant capacity and intestinal health. © 2024 Society of Chemical Industry.

Adaptive Space-Aware Infotaxis II as a Strategy for Odor Source Localization.

Mobile robot olfaction of toxic and hazardous odor sources is of great significance in anti-terrorism, disaster prevention, and control scenarios. Aiming at the problems of low search efficiency and easily falling into a local optimum of the current odor source localization strategies, the paper proposes the adaptive space-aware Infotaxis II algorithm. To improve the tracking efficiency of robots, a new reward function is designed by considering the space information and emphasizing the exploration behavior of robots. Considering the enhancement in exploratory behavior, an adaptive navigation-updated mechanism is proposed to adjust the movement range of robots in real time through information entropy to avoid an excessive exploration behavior during the search process, which may lead the robot to fall into a local optimum. Subsequently, an improved adaptive cosine salp swarm algorithm is applied to confirm the optimal information adaptive parameter. Comparative simulation experiments between ASAInfotaxis II and the classical search strategies are carried out in 2D and 3D scenarios regarding the search efficiency and search behavior, which show that ASAInfotaxis II is competent to improve the search efficiency to a larger extent and achieves a better balance between exploration and exploitation behaviors.

Reply: Correspondence on NanoVar's performance outlined by Jiang T. et al. in 'Long-read sequencing settings for efficient structural variation detection based on comprehensive evaluation'.

We published a paper in BMC Bioinformatics comprehensively evaluating the performance of structural variation (SV) calling with long-read SV detection methods based on simulated error-prone long-read data under various sequencing settings. Recently, C.Y.T. et al. wrote a correspondence claiming that the performance of NanoVar was underestimated in our benchmarking and listed some errors in our previous manuscripts. To clarify these matters, we reproduced our previous benchmarking results and carried out a series of parallel experiments on both the newly generated simulated datasets and the ones provided by C.Y.T. et al. The robust benchmark results indicate that NanoVar has unstable performance on simulated data produced from different versions of VISOR, while other tools do not exhibit this phenomenon. Furthermore, the errors proposed by C.Y.T. et al. were due to them using another version of VISOR and Sniffles, which caused many changes in usage and results compared to the versions applied in our previous work. We hope that this commentary proves the validity of our previous publication, clarifies and eliminates the misunderstanding about the commands and results in our benchmarking. Furthermore, we welcome more experts and scholars in the scientific community to pay attention to our research and help us better optimize these valuable works.

Effects of HMGB1/RAGE/cathespin B inhibitors on alleviating hippocampal injury by regulating microglial pyroptosis and caspase activation in neonatal hypoxic-ischemic brain damage.

Microglia play a crucial role in regulating neuroinflammation in the pathogenesis of neonatal hypoxic-ischemic brain damage (HIBD). Pyroptosis, an inflammatory form of programmed cell death, has been implicated in HIBD; however, its underlying mechanism remains unclear. We previously demonstrated that high-mobility group box 1 protein (HMGB1) mediates neuroinflammation and microglial damage in HIBD. In this study, we aimed to investigate the association between HMGB1 and microglial pyroptosis and elucidate the mechanism involved in rats with HIBD (both sexes were included) and in BV2 microglia subjected to oxygen-glucose deprivation. Our results showed that HMGB1 inhibition by glycyrrhizin (20 mg/kg) reduced the expression of microglial pyroptosis-related proteins, including caspase-1, the N-terminus fragment of gasdermin D (N-GSDMD), and pyroptosis-related inflammatory factors, such as interleukin (IL) -1ß and IL-18. Moreover, HMGB1 inhibition resulted in reduced neuronal damage in the hippocampus 72 h after HIBD and ultimately improved neurobehavior during adulthood, as evidenced by reduced escape latency and path length, as well as increased time and distance spent in the target quadrant during the Morris water maze test. These results revealed that HIBD-induced pyroptosis is mediated by HMGB1/receptor for advanced glycation end products (RAGE) signaling (inhibition by FPS-ZM1, 1 mg/kg) and the activation of cathespin B (cat B). Notably, cat B inhibition by CA074-Me (5 mg/kg) also reduced hippocampal neuronal damage by suppressing microglial pyroptosis, thereby ameliorating learning and memory impairments caused by HIBD. Lastly, we demonstrated that microglial pyroptosis may contribute to neuronal damage through the HMGB1/RAGE/cat B signaling pathway in vitro. In conclusion, these results suggest that HMGB1/RAGE/cat B inhibitors can alleviate hippocampal injury by regulating microglial pyroptosis and caspase activation in HIBD, thereby reducing the release of proinflammatory mediators that destroy hippocampal neurons and induce spatial memory impairments.

Dibenzocyclooctadiene lignans from the family Schisandraceae: A review of phytochemistry, structure-activity relationship, and hepatoprotective effects.

Liver injury is a common pathological process characterized by massive degeneration and abnormal death of liver cells. With increase in dead cells and necrosis, liver injury eventually leads to nonalcoholic fatty liver disease (NAFLD), hepatic fibrosis, and even hepatocellular carcinoma (HCC). Consequently, it is necessary to treat liver injury and to prevent its progression. The drug Bicylol is widely employed in China to treat chronic hepatitis B virus (HBV) and has therapeutic potential for liver injury. It is the derivative of dibenzocyclooctadiene lignans extracted from Schisandra chinensis (SC). The Schisandraceae family is a rich source of dibenzocyclooctadiene lignans, which possesses potential liver protective activity. This study aimed to comprehensively summarize the phytochemistry, structure-activity relationship and molecular mechanisms underlying the liver protective activities of dibenzocyclooctadiene lignans from the Schisandraceae family. Here, we had discussed the analysis of absorption or permeation properties of 358 compounds based on Lipinski's rule of five. So far, 358 dibenzocyclooctadiene lignans have been reported, with 37 of them exhibited hepatoprotective effects. The molecular mechanism of the active compounds mainly involves antioxidative stress, anti-inflammation and autophagy through Kelch-like ECH-associating protein 1/nuclear factor erythroid 2 related factor 2/antioxidant response element (Keap1/Nrf2/ARE), nuclear factor kappa B (NF-кB), and transforming growth factor ß (TGF-ß)/Smad 2/3 signaling pathways. This review is expected to provide scientific ideas for future research related to developing and utilizing the dibenzocyclooctadiene lignans from Schisandraceae family.

Aryne and CO2-based formal [2 + 2 + 2] annulation to access tetrahydroisoquinoline-fused benzoxazinones.

Tetrahydroisoquinoline and its fused polyheterocycles are prevalent structural motifs found in numerous natural products. In this study, we report a highly efficient and convergent synthetic approach for the construction of tetrahydroisoquinoline-fused polyheterocycles through a three-component formal [2 + 2 + 2] annulation process by combining 3,4-dihydroisoquinolines, CO2, and benzynes. Notably, electron-rich 3,4-dihydroisoquinolines and electron-deficient benzynes exhibit greater reactivity in this annulation. Moreover, this method benefits from the convergent synthesis and the utilization of carbon dioxide, providing a valuable strategy for the facile synthesis of tetrahydroisoquinoline-fused polyheterocycles, with potential applications in the discovery and development of novel organic molecules.

Carbonized polyaniline-activated peracetic acid advanced oxidation process for organic removal: Efficiency and mechanisms.

Recently, advanced oxidation processes (AOPs) based upon peracetic acid (PAA) with high efficiency for degrading aqueous organic contaminants have attracted extensive attention. Herein, a novel metal-free N-doped carbonaceous catalyst, namely, carbonized polyaniline (CPANI), was applied to activate PAA to degrade phenolic and pharmaceutical pollutants. The results showed that the CPANI/PAA system could effectively degrade 10 µM phenol in 60 min with low concentrations of PAA (0.1 mM) and catalyst (25 mg L-1). This system also performed well within a wide pH range of 5-9 and displayed high tolerance to Cl-, HCO3- and humic acid. The nonradical pathway [singlet oxygen (1O2)] was found to be the dominant pathway for degrading organic contaminants in the CPNAI/PAA system. Systematic characterization revealed that the graphitic N, pyridinic N, carbonyl groups (CO) and defects played the role of active sites on CPANI during the activation of PAA. The catalytic capacity of spent CPANI could be conveniently recovered by thermal treatment. The findings will be helpful for the application of metal-free carbonaceous catalyst/PAA processes in decontaminating water.