Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.

Mitochondria are key regulators of hematopoietic stem cell (HSC) homeostasis. Our research identifies the transcription factor Nynrin as a crucial regulator of HSC maintenance by modulating mitochondrial function. Nynrin is highly expressed in HSCs under both steady-state and stress conditions. The knockout Nynrin diminishes HSC frequency, dormancy, and self-renewal, with increased mitochondrial dysfunction indicated by abnormal mPTP opening, mitochondrial swelling, and elevated ROS levels. These changes reduce HSC radiation tolerance and promote necrosis-like phenotypes. By contrast, Nynrin overexpression in HSCs diminishes irradiation (IR)-induced lethality. The deletion of Nynrin activates Ppif, leading to overexpression of cyclophilin D (CypD) and further mitochondrial dysfunction. Strategies such as Ppif haploinsufficiency or pharmacological inhibition of CypD significantly mitigate these effects, restoring HSC function in Nynrin-deficient mice. This study identifies Nynrin as a critical regulator of mitochondrial function in HSCs, highlighting potential therapeutic targets for preserving stem cell viability during cancer treatment.

ARBUR, a machine learning-based analysis system for relating behaviors and ultrasonic vocalizations of rats.

Deciphering how different behaviors and ultrasonic vocalizations (USVs) of rats interact can yield insights into the neural basis of social interaction. However, the behavior-vocalization interplay of rats remains elusive because of the challenges of relating the two communication media in complex social contexts. Here, we propose a machine learning-based analysis system (ARBUR) that can cluster without bias both non-step (continuous) and step USVs, hierarchically detect eight types of behavior of two freely behaving rats with high accuracy, and locate the vocal rat in 3-D space. ARBUR reveals that rats communicate via distinct USVs during different behaviors. Moreover, we show that ARBUR can indicate findings that are long neglected by former manual analysis, especially regarding the non-continuous USVs during easy-to-confuse social behaviors. This work could help mechanistically understand the behavior-vocalization interplay of rats and highlights the potential of machine learning algorithms in automatic animal behavioral and acoustic analysis.

Huangqin Qingre Chubi Capsule inhibits rheumatoid arthritis by regulating intestinal flora and improving intestinal barrier.

Background: Changes in intestinal flora and intestinal barrier in patients with preclinical and diagnosed rheumatoid arthritis (RA) suggest that intestinal flora and intestinal barrier play an important role in the induction and persistence of RA. Huangqin Qingre Chubi Capsule (HQC) is a clinically effective herbal formula for the treatment of RA, but its therapeutic mechanism has not been fully clarified. Materials and methods: In this study, real-time qPCR (RT-qPCR), 16SrRNA sequencing, Western blot (WB), immunofluorescence and other methods were used to investigate whether HQC inhibited RA. Results: Based on research in collages-induced arthritis (CIA) model in mice, human colon cancer cell line (Caco-2), and fibroblast-like synoviocytes (FLS) from RA patients, we found that intestinal flora was disturbed in CIA model group, intestinal barrier was damaged, and lipolyaccharide (LPS) level was increased, and HQC could regulate intestinal flora and intestinal barrier and reduce LPS translocation into blood. Antibiotic depletion weakened the anti-RA effect of HQC, and HQC fecal microbiota transplantation alleviated RA pathology. In addition, LPS increased the expression of RA pathologic factors MMP3, Fibronectin and inflammatory factors IL-6, TNF-α, IL-1ß and IL-8, indicating that elevated peripheral blood level of LPS was related to RA pathology. Conclusion: The dysregulation of intestinal flora and the disruption of intestinal barrier are significant factors in the development of RA. HQC improves RA by regulating intestinal flora, intestinal barrier and inhibiting LPS translocation into blood. The study unveiles RA's new pathogenesis and laid a scientific groundwork for advancing HQC therapy for RA.

Aerobic mechanochemical reversible-deactivation radical polymerization.

Polymer materials suffer mechano-oxidative deterioration or degradation in the presence of molecular oxygen and mechanical forces. In contrast, aerobic biological activities combined with mechanical stimulus promote tissue regeneration and repair in various organs. A synthetic approach in which molecular oxygen and mechanical energy synergistically initiate polymerization will afford similar robustness in polymeric materials. Herein, aerobic mechanochemical reversible-deactivation radical polymerization was developed by the design of an organic mechano-labile initiator which converts oxygen into activators in response to ball milling, enabling the reaction to proceed in the air with low-energy input, operative simplicity, and the avoidance of potentially harmful organic solvents. In addition, this approach not only complements the existing methods to access well-defined polymers but also has been successfully employed for the controlled polymerization of (meth)acrylates, styrenic monomers and solid acrylamides as well as the synthesis of polymer/perovskite hybrids without solvent at room temperature which are inaccessible by other means.

Research Note: Effects of different light-emitting diode lights during egg incubation on hatching performance and embryo development in White King pigeons.

The light provide during incubation can influence hatching characteristics (hatching time, hatchability, etc.) and embryo development in chickens, geese, and turkeys. However, relevant studies on this factor in pigeons are lacking. This study investigated the effects of in ovo photostimulation during embryogenesis on hatching performance, squab quality, and embryo development in pigeons. 400 eggs from paired- bred pigeons were randomly distributed into 4 incubation lighting treatments, with 2 replicates per treatment. The treatments included dark as a control (NL), 12-h light, and 12-h dark photoperiods of white light (WL), red light (RL), and green light (GL) (100 lx at egg level) during the first 15 d of incubation. A total of 1,600 eggs in 4 batches from White King pigeons were used. The results showed that hatching time of the WL group was significantly shorter than that of the dark light group (P < 0.05). The hatchability of fertile eggs in the WL group was significantly higher (P < 0.05), whereas the hatchability of fertile eggs in the RL group was significantly lower (P < 0.05) than that of in the control group. Light stimulation had no effect on time to 90% hatching or average hatching time (P > 0.05). In addition, the hatch window was not extended by light stimulation (P > 0.05). The group incubated under GL showed an increase in embryo weight and relative leg muscle on embryonic d 14 and the hatching day compared to the dark incubation (P < 0.05). Green light stimulated the heart and liver development during the early and middle stages of embryogenesis. It was concluded that white light stimulation during embryogenesis accelerated the hatching process, whereas monochromatic green light had a positive effect on embryo development. Our findings provide important guidance for developing light protocols for pigeon egg incubation.

Fabrication and Characterization of Docosahexaenoic Acid Algal Oil Pickering Emulsions Stabilized Using the Whey Protein Isolate-High-Methoxyl Pectin Complex.

In this study, the whey protein isolate-high-methoxyl pectin (WPI-HMP) complex prepared by electrostatic interaction was utilized as an emulsifier in the preparation of docosahexaenoic acid (DHA) algal oils in order to improve their physicochemical properties and oxidation stability. The results showed that the emulsions stabilized using the WPI-HMP complex across varying oil-phase volume fractions (30-70%) exhibited consistent particle size and enhanced stability compared to emulsions stabilized solely using WPI or HMP at different ionic concentrations and heating temperatures. Furthermore, DHA algal oil emulsions stabilized using the WPI-HMP complex also showed superior storage stability, as they exhibited no discernible emulsification or oil droplet overflow and the particle size variation remained relatively minor throughout the storage at 25 °C for 30 days. The accelerated oxidation of the emulsions was assessed by measuring the rate of DHA loss, lipid hydroperoxide levels, and malondialdehyde levels. Emulsions stabilized using the WPI-HMP complex exhibited a lower rate of DHA loss and reduced levels of lipid hydroperoxides and malondialdehyde. This indicated that WPI-HMP-stabilized Pickering emulsions exhibit a greater rate of DHA retention. The excellent stability of these emulsions could prove valuable in food processing for DHA nutritional enhancement.

Global burden and risk factors of chronic kidney disease in adolescents and young adults: a study from 1990 to 2019.

Background: Few studies have evaluated the global burden of chronic kidney disease (CKD) in adolescents and young adults (AYAs). Methods: Age-standardized rates of incidence (ASIR), mortality (ASMR), and disability-adjusted life-years (ASDR) were used to describe the CKD burden in AYAs. The estimated annual percentage changes (EAPCs) were calculated to evaluate the temporal trends from 1990 to 2019. Risk factors were calculated by population attributable fractions. Results: In 2019, the ASIR, ASMR, and ASDR of CKD in AYAs were 32.21 (95% uncertainty interval [UI], 23.73-40.81) per 100,000, 2.86 (2.61-3.11) per 100,000 and 236.85 (209.03-268.91) per 100,000, respectively. The ASIR was higher among females than males, whereas the ASMR was higher among males than females in 2019. From 1990 to 2019, significant increases in ASIR were found for CKD (EAPC, 0.98%; 95% confidence interval [CI], 0.95%-1.01%), although the ASMR had decreased (EAPC, -0.40%; 95% CI, -0.56% to -0.24%). The largest increase in ASIR was observed in countries with a middle sociodemographic index (SDI) (EAPC, 1.30%; 95% CI, 1.28%-1.33%), while the largest increase in ASMR was observed in high SDI. Globally, the proportional contribution of risk factors for CKD mortality varied across regions, with the highest proportions of high fasting plasma glucose being 14.04% in low SDI, compared with 24.01% in high SDI. Conclusion: CKD is a growing global health problem in AYAs, especially in countries with a middle SDI. Targeted measures are needed to address the rising burden of CKD in AYAs, focusing on prevention, early diagnosis, and reducing disparities.

Cross-sectional analysis of socioeconomic drivers of PM2.5 pollution in emerging SAARC economies.

Within the intricate interplay of socio-economic, natural and anthropogenic factors, haze pollution stands as a stark emblem of environmental degradation, particularly in the South Asian Association for Regional Cooperation (SAARC) region. Despite significant efforts to mitigate greenhouse gas emissions, several SAARC nations consistently rank among the world's most polluted. Addressing this critical research gap, this study employs robust econometric methodologies to elucidate the dynamics of haze pollution across SAARC countries from 1998 to 2020. These methodologies include the Pooled Mean Group (PMG) and Augmented Mean Group (AMG) estimator, Panel two-stage least squares (TSLS), Feasible Generalized Least Squares (FGLS) and Dumitrescu-Hurlin (D-H) causality test. The analysis reveals a statistically significant cointegrating relationship between PM2.5 and economic indicators, with economic development and consumption expenditure exhibiting positive associations and rainfall demonstrating a mitigating effect. Furthermore, a bidirectional causality is established between temperature and economic growth, both influencing PM2.5 concentrations. These findings emphasize the crucial role of evidence-based policy strategies in curbing air pollution. Based on these insights, recommendations focus on prioritizing green economic paradigms, intensifying forest conservation efforts, fostering the adoption of eco-friendly energy technologies in manufacturing and proactively implementing climate-sensitive policies. By embracing these recommendations, SAARC nations can formulate comprehensive and sustainable approaches to combat air pollution, paving the way for a healthier atmospheric environment for their citizens.

Dostarlimab in the treatment of mismatch repair deficient recurrent or advanced endometrial cancer.

Dostarlimab, a programmed death receptor-1 (PD-1)-blocking IgG4 humanized monoclonal antibody, gained accelerated approval from the US Food and Drug Administration (FDA) in April 2021, and received a full approval in February 2023. Dostarlimab was approved for treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (EC) that progressed during or after prior treatment who have no other suitable treatment options. Herein, we review the structure-based mechanism of action of dostarlimab and the results of a clinical study (GARNET; NCT02715284) to comprehensively clarify the efficacy and toxicity of the drug. The efficacy and safety of dostarlimab as monotherapy was assessed in a non-randomized, multicenter, open-label, multi-cohort trial that included 209 patients with dMMR recurrent or advanced solid tumors after receiving systemic therapy. Patients received 500 mg of dostarlimab intravenously every three weeks until they were given four doses. Then, patients received 1000 mg dostarlimab intravenously every six weeks until disease progression or unacceptable toxicity. The overall response rate, as determined by shrinkage in tumor size, was 41.6% (95% confidence interval [CI]; 34.9, 48.6), with 34.7 months as the median response duration. In conclusion, dostarlimab is an immunotherapy-based drug that has shown promising results in adult patients with recurrent or advanced dMMR EC. However, its efficacy in other cancer subtypes, the development of resistance to monotherapy, and efficacy and safety in combination with other immunotherapeutic drugs have not yet been studied.

Dietary calcium intake at breakfast is associated with a lower risk of cognitive impairment than at dinner in Chinese adults: the CHNS cohort study.

BACKGROUND AND OBJECTIVES: If the proportion of calcium intake over a whole day is related to the risk of cognitive impairment in adults is still largely unknown. This research aimed to examine the relation of dietary calcium intake at dinner versus breakfast with the risk of cognitive impairment by using data from the China Health and Nutrition Survey (CHNS). METHODS AND STUDY DESIGN: A total of 2,099 participants (including 668 cognitive impairment) in the CHNS (1997-2006) were included. The participants were categorized into 5 groups in accordance with the ratio of dietary calcium intake at dinner and breakfast (Δ = dinner/breakfast). After adjustment was conducted for a series of confounding factors, Cox hazard regression modelling was performed to discuss the relation of Δ with cognitive impairment. Dietary substitution models were used to explore the changes in cognitive impairment risk when a 5% dietary calcium intake at dinner was replaced with dietary calcium intake at breakfast. RESULTS: Participants in the highest distribution of Δ showed a greater susceptibility to cognitive impairment than those in the lowest quintile, with an adjusted hazard ratio of cognitive impairment of 1.38 (95% CI: 1.08-1.76). When maintaining total calcium intake, substituting 5% of dietary calcium intake at dinner with calcium intake at breakfast was related to an 8% decrease in the risk of cognitive impairment. CONCLUSIONS: Higher dietary calcium intake at dinner was associated with an increased risk of cognitive impairment, emphasizing the importance of appropriately distributing dietary calcium intake between breakfast and dinner.

Tagging large CNV blocks in wheat boosts digitalization of germplasm resources by ultra-low-coverage sequencing.

BACKGROUND: The massive structural variations and frequent introgression highly contribute to the genetic diversity of wheat, while the huge and complex genome of polyploid wheat hinders efficient genotyping of abundant varieties towards accurate identification, management, and exploitation of germplasm resources. RESULTS: We develop a novel workflow that identifies 1240 high-quality large copy number variation blocks (CNVb) in wheat at the pan-genome level, demonstrating that CNVb can serve as an ideal DNA fingerprinting marker for discriminating massive varieties, with the accuracy validated by PCR assay. We then construct a digitalized genotyping CNVb map across 1599 global wheat accessions. Key CNVb markers are linked with trait-associated introgressions, such as the 1RS·1BL translocation and 2NvS translocation, and the beneficial alleles, such as the end-use quality allele Glu-D1d (Dx5 + Dy10) and the semi-dwarf r-e-z allele. Furthermore, we demonstrate that these tagged CNVb markers promote a stable and cost-effective strategy for evaluating wheat germplasm resources with ultra-low-coverage sequencing data, competing with SNP array for applications such as evaluating new varieties, efficient management of collections in gene banks, and describing wheat germplasm resources in a digitalized manner. We also develop a user-friendly interactive platform, WheatCNVb ( http://wheat.cau.edu.cn/WheatCNVb/ ), for exploring the CNVb profiles over ever-increasing wheat accessions, and also propose a QR-code-like representation of individual digital CNVb fingerprint. This platform also allows uploading new CNVb profiles for comparison with stored varieties. CONCLUSIONS: The CNVb-based approach provides a low-cost and high-throughput genotyping strategy for enabling digitalized wheat germplasm management and modern breeding with precise and practical decision-making.

Dynamics of polarization-tuned mirror symmetry breaking in a rotationally symmetric system.

Lateral momentum conservation is typically kept in a non-absorptive rotationally symmetric system through mirror symmetry via Noether's theorem when illuminated by a homogeneous light wave. Therefore, it is still very challenging to break the mirror symmetry and generate a lateral optical force (LOF) in the rotationally symmetric system. Here, we report a general dynamic action in the SO(2) rotationally symmetric system, originating from the polarization-tuned mirror symmetry breaking (MSB) of the light scattering. We demonstrate theoretically and experimentally that MSB can be generally applied to the SO(2) rotationally symmetric system and tuned sinusoidally by polarization orientation, leading to a highly tunable and highly efficient LOF (9.22 pN/mW/µm-2) perpendicular to the propagation direction. The proposed MSB mechanism and LOF not only complete the sets of MSB of light-matter interaction and non-conservative force only using a plane wave but also provide extra polarization manipulation freedom.

Lansoprazole (LPZ) reverses multidrug resistance (MDR) in cancer through impeding ATP-binding cassette (ABC) transporter-mediated chemotherapeutic drug efflux and lysosomal sequestration.

AIMS: Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, in vitro and in vivo. METHODS: Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR in vivo. RESULTS: Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. In vivo experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2. CONCLUSIONS: These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.

Wutou decoction alleviates arthritis inflammation in CIA mice by regulating Treg cell stability and Treg/Th17 balance via the JAK2/STAT3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Wutou Decoction (WTD) is a classic traditional Chinese medicine formula, which has shown clinical efficacy in treating rheumatoid arthritis (RA). The Treg stability and Th17/Treg imbalance is an important immunological mechanism in RA progression. Whether WTD regulates CD4+ T cell subsets has not been thoroughly investigated yet. AIM OF THE STUDY: This study aimed to explore the potential role and mechanisms of WTD in regulating the diminished stability of Treg cells and the imbalance of CD4+ T cell subsets via in vivo and in vitro experiments. MATERIALS AND METHODS: Firstly, the therapeutic effects of WTD on the collagen-induced arthritis (CIA) mouse and its potential regulatory function on CD4+ T cell subsets were evaluated in vivo. Animal specimens were collected after 31 days of treatment with WTD. The anti-arthritic and anti-inflammatory effects of WTD were assessed through arthritis scoring, body weight, spleen index, serum IL-6 levels, and micro-PET/CT imaging. Gene enrichment analysis was performed to evaluate the activation T cell-related signaling pathway. Flow cytometry was used to determine the proportions of CD4+ T cell subsets in vitro and in vitro. Additionally, ELISA was used to assess the secretion of IL-10 and TGF-ß by Treg cells under inflammatory conditions. The suppressive function of Treg cells on cell proliferation under inflammatory conditions was examined using CFSE labeling. Immunofluorescence staining was performed to detect the phosphorylation levels of STAT3 in CD4+ T cells from mouse spleen tissues. Western blotting was used to evaluate the phosphorylation levels of JAK2/STAT3 in Treg cells. RESULTS: WTD significantly alleviated joint inflammation in CIA mice. WTD reduced serum IL-6 levels in CIA mice, improved their body weight and spleen index. WTD treatment inhibited the activation of CD4+ T cell subgroup-related signaling in the joint tissues of CIA mice. In vitro and in vitro experiments showed that WTD increased the proportion of Treg cells and decreased the proportion of Th17 cells in CIA mice spleen. Furthermore, WTD promoted the secretion of IL-10 and TGF-ß by Treg cells and enhanced the inhibitory capacity of Treg cells on cell proliferation under inflammatory conditions. Immunofluorescence detected decreased STAT3 phosphorylation levels in CD4+ T cells from CIA mice spleen, while western blotting revealed a decrease in JAK2/STAT3 phosphorylation levels in Treg cells in vitro. CONCLUSIONS: Inhibiting JAK2/STAT3 phosphorylation is a potential mechanism through which WTD improves Treg cell stability, balances CD4+ T cell subsets, and attenuates RA joint inflammation.

Tsallis Entropy-Based Complexity-IPE Casualty Plane: A Novel Method for Complex Time Series Analysis.

Due to its capacity to unveil the dynamic characteristics of time series data, entropy has attracted growing interest. However, traditional entropy feature extraction methods, such as permutation entropy, fall short in concurrently considering both the absolute amplitude information of signals and the temporal correlation between sample points. Consequently, this limitation leads to inadequate differentiation among different time series and susceptibility to noise interference. In order to augment the discriminative power and noise robustness of entropy features in time series analysis, this paper introduces a novel method called Tsallis entropy-based complexity-improved permutation entropy casualty plane (TC-IPE-CP). TC-IPE-CP adopts a novel symbolization approach that preserves both absolute amplitude information and inter-point correlations within sequences, thereby enhancing feature separability and noise resilience. Additionally, by incorporating Tsallis entropy and weighting the probability distribution with parameter q, it integrates with statistical complexity to establish a feature plane of complexity and entropy, further enriching signal features. Through the integration of multiscale algorithms, a multiscale Tsallis-improved permutation entropy algorithm is also developed. The simulation results indicate that TC-IPE-CP requires a small amount of data, exhibits strong noise resistance, and possesses high separability for signals. When applied to the analysis of heart rate signals, fault diagnosis, and underwater acoustic signal recognition, experimental findings demonstrate that TC-IPE-CP can accurately differentiate between electrocardiographic signals of elderly and young subjects, achieve precise bearing fault diagnosis, and identify four types of underwater targets. Particularly in underwater acoustic signal recognition experiments, TC-IPE-CP achieves a recognition rate of 96.67%, surpassing the well-known multi-scale dispersion entropy and multi-scale permutation entropy by 7.34% and 19.17%, respectively. This suggests that TC-IPE-CP is highly suitable for the analysis of complex time series.

The use of Panax notoginseng saponins injections after intravenous thrombolysis in acute ischemic stroke: a systematic review and meta-analysis.

Background: As a bioactive metabolite preparation widely used in acute ischemic stroke (AIS), the efficacy and safety of Panax notoginseng saponins injections (PNSI) in patients with AIS after intravenous thrombolysis remain to be evaluated. Methods: This study included randomized controlled trials published before 26 April 2024 in 8 databases. AIS patients who received intravenous thrombolysis were included. The control group receiving conventional treatment and the treatment group receiving additional PNSI. Primary outcomes were selected as mortality, disability, and adverse events. Secondary outcomes were selected as all-cause mortality, improvement of neurological deficit, quality of life, and cerebral injury indicators. The revised Cochrane Risk of Bias tool was used to assess risk of bias. Risk ratio (RR) and mean differences (MD) were calculated for binary variables and continuous variables, respectively, based on a 95% confidence interval (CI). Results: A total of 20 trials involving 1,856 participants were included. None of them reported mortality or disability. There was no significant difference in the adverse events [RR: 1.04; 95% CI: 0.60 to 1.81] and hemorrhagic transformation [RR: 0.99; 95% CI: 0.36 to 2.70] between the two groups. Compared to the control group, the treatment group had a better effect in neurological improvement assessed by National Institutes of Health Stroke Scale [MD: -2.91; 95% CI: -4.76 to -1.06], a better effect in activities of daily living changes in Barthel Index [MD: 9.37; 95% CI: 1.86 to 16.88], and a lower serum neuron-specific enolase level [MD: -2.08; 95% CI: -2.67 to -1.49]. Conclusion: For AIS patients undergoing intravenous thrombolysis, the use of PNSI improved neurological deficits and enhanced activity of daily living in the short term without increasing the occurrence rate of adverse events. However, due to the moderate to very low certainty of evidence, it is advisable to conduct high-quality clinical trials to validate the findings of this study. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=466851, Identifier CRD42023466851.

Hepatocellular carcinoma and lipid metabolism: Novel targets and therapeutic strategies.

Hepatocellular carcinoma (HCC) is an increasingly prevalent disease that is associated with high and continually rising mortality rates. Lipid metabolism holds a crucial role in the pathogenesis of HCC, in which abnormalities pertaining to the delicate balance of lipid synthesis, breakdown, and storage, predispose for the pathogenesis of the nonalcoholic fatty liver disease (NAFLD), a disease precursor to HCC. If caught early enough, HCC treatment may be curative. In later stages, treatment is only halting the inevitable outcome of death, boldly prompting for novel drug discovery to provide a fighting chance for this patient population. In this review, we begin by providing a summary of current local and systemic treatments against HCC. From such we discuss hepatic lipid metabolism and highlight novel targets that are ripe for anti-cancer drug discovery. Lastly, we provide a targeted summary of current known risk factors for HCC pathogenesis, providing key insights that will be essential for rationalizing future development of anti-HCC therapeutics.

Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression.

Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays critical oncogenic roles in multiple cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in patients with HCC. Genetic depletion of Fto dramatically attenuated HCC progression in mice. Pharmacological inhibition of FTO by FB23/FB23-2 markedly suppressed the proliferation and migration of HCC cell lines in vitro and inhibited HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decrease in ERBB3 expression resulted in the inhibition of Akt-mTOR signaling, which subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 disturbed the stability of the tubulin cytoskeleton, whereas overexpression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrates that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells and highlights the potential of FTO inhibitors for targeting HCC.

[Dynamic Response of Aerobic Denitrification Bacteria to Water Quality in Baiyangdian Lake Under Different Hydrological Scenarios].

In order to explore the evolution law and driving mechanism of aerobic denitrification bacteria in Baiyangdian Lake under different hydrological scenarios, based on water quality survey and high-throughput sequencing technology, this study conducted a water quality factor analysis and aerobic denitrification bacteria α-diversity analysis, species composition, and network analysis. The results showed that the water body of Baiyangdian Lake was weakly alkaline, with the highest T and the lowest DO in the rainy season and the lowest T and the highest DO in the freezing season. There were significant differences between NH4+-N, NO2--N, NO3--N, TN, permanganate index, Fe, and Mn in Baiyangdian water under different hydrological scenarios (P < 0.01), and there was no significant difference in TP under different hydrological scenarios (P > 0.05). The largest category in water bodies under different hydrological scenarios was Proteobacteria, and the genera with a higher relative abundance were Magnetospirillum, Aeromonas, Pseudomonas, Azospirillum, and Bradyrhizobium. In addition, within the aerobic denitrifying bacteria community, there were significant differences in α-diversity (P < 0.001), with the highest abundance of microbial communities occurring during the freezing period, and the highest diversity and evenness of microbial communities during the dry and freezing periods. According to the RDA and Mantel analyses, the water quality driving factors of flora were different under different hydrological scenarios. The water quality driving factors of flora in the dry season were pH, NO3--N, NO2--N, and permanganate index; the driving factors of flora in the rainy season were pH, T, DO, NO2--N, and TP; the driving factors of flora in the normal season were NO2--N, Fe, and permanganate index; and the driving factors of flora in the freezing season were NO3--N and NONO2--N. Network analysis showed that there were temporal differences in species related to water quality driving factors. The genera related to water quality driving factors during the dry season were Magnetospirillum, Aeromonas, and Azoarcus, whereas the genera related to the rainy season were Magnetospirillum, Pseudomonas, and Aeromonas. The genera related to the normal season were Magnetospirillum, Pseudomonas, and Limnohabitans, and the genera related to the freezing period were Magnetospirillum, Azoarcus, and Pseudomonas. The relationship between key water quality factors (mainly T, DO, NO3--N, and permanganate index) and aerobic denitrification flora in different hydrological scenarios was gradually changing with time. In conclusion, the study on the evolution characteristics of aerobic denitrification bacteria in Baiyangdian Lake under different hydrological scenarios and the driving mechanism of environmental factors could provide a basis for understanding the evolution mechanism of aerobic denitrification bacteria in the natural environment.