The Impact and Mechanism of Action of Peptostreptococcus anaerobius on Chemotherapy Resistance in Human Colorectal Cancer.

Peptostreptococcus anaerobius plays an important role in the development of colorectal cancer, and previous studies by our group have demonstrated that Peptostreptococcus anaerobius promotes resistance to 5-Fu chemotherapy in animal models of colorectal cancer. In this study, the effects of Peptostreptococcus anaerobius on chemotherapy resistance in colorectal cancer and its possible mechanism of action were investigated from the clinical point of view. Patients were selected according to exclusion and inclusion criteria and divided into sensitive and chemotherapy groups (n = 20/group). Fecal samples were collected from the patients. The bacterial 16S rRNA genes in the samples were sequenced and the abundance and varieties in the fecal bacteria were compared between the 2 groups. Immunohistochemistry and Western blotting were used to assess interleukin 23 levels in tumor tissues. Significantly elevated abundance of Peptostreptococcus was observed in fecal samples from chemoresistant colorectal cancer patients compared to those from chemosensitive individuals. Immunohistochemistry and Western blotting results showed that chemoresistant patients had higher levels of interleukin 23 relative to chemosensitive patients and the levels were positively associated with Peptostreptococcus. Peptostreptococcus may mediate the development of chemoresistant colorectal cancer by promoting the upregulation of interleukin 23. Efforts to target Peptostreptococcus thus have the potential to alter the prognosis of colorectal cancer patients.

Oral administration of Sophora Flavescens-derived exosomes-like nanovesicles carrying CX5461 ameliorates DSS-induced colitis in mice.

Ulcerative colitis (UC) belongs to chronic inflammatory disease with a relapsing characterization. Conventional oral drugs of UC are restricted in clinical by premature degradation in the gastrointestinal tract, modest efficacy, and adverse effects. CX5461 can treat autoimmune disease, immunological rejection, and vascular inflammation. However, low solubility, intravenous administration, and non-inflammatory targeting limited its clinical application. Herein, this work aims to develop Sophora Flavescens-derived exosomes-like nanovesicles carrying CX5461 (SFELNVs@CX5461) for efficient CX5461 oral delivery for UC therapy. We identified SFELNVs as nano-diameter (80 nm) with negative zeta potential (-32mV). Cellular uptake has shown that SFELNVs were targeted uptake by macrophages, thus increasing drug concentration. Additionally, oral SFELNVs@CX5461 exhibited good safety and stability, as well as inflammation-targeting ability in the gastrointestinal tract of dextran sodium sulfate (DSS)-induced colitis mice. In vivo, oral administration of SFELNVs and CX5461 could relieve mice colitis. More importantly, combined SFELNVs and CX5461 alleviated mice colitis by inhibiting pro-inflammatory factors (TNF-α, IL-1ß, and IL-6) expression and promoting M2 macrophage polarization. Furthermore, SFELNVs promoted M2 polarization by miR4371c using miRNA sequencing. Our results suggest that SFELNVs@CX5461 represents a novel orally therapeutic drug that can ameliorate colitis, and a promising targeting strategy for safe UC therapy.

Quercetin is a foe in the heart by targeting the hERG potassium channel.

Objectives: Quercetin is a plant flavonoid known for its pharmacological activities, such as antioxidant, anti-inflammatory, and anti-cancer properties. However, there is limited information available regarding its potential toxicities. A previous study showed that quercetin can inhibit human ether-a-go-related gene (hERG, also named KCNH2) currents, which may lead to long QT syndrome, torsade de pointes (TdP), and even sudden cardiac death. This study aimed to investigate the effects of quercetin on hERG and its potential mechanism. Materials and Methods: hERG currents and action potential duration (APD) were assessed using the patch clamp technique. Molecular docking was employed to elucidate the binding sites between quercetin and hERG. Transfection of wild-type or mutant plasmids was used to verify the results of molecular docking. Western blot was performed to determine the expression levels of hERG, transcription factor SP1, molecular chaperones HSP70 and HSP90, phosphorylated E3 ubiquitin ligase p-Nedd4-2, serum- and glucocorticoid-inducible kinase (SGK1), and phosphatidylinositol 3-kinase (PI3K). Immunoprecipitation was conducted to evaluate hERG ubiquitination. Results: Quercetin acutely blocked hERG current by binding to F656 amino acid residue, subsequently accelerating channel inactivation. Long-term incubation of quercetin accelerates Nedd4-2-mediated ubiquitination degradation of hERG channels by inhibiting the PI3K/SGK1 signaling pathway. Moreover, the APD of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) is significantly prolonged by 30 µM quercetin. Conclusion: Quercetin has a potential risk of proarrhythmia, which provided useful information for the usage and development of quercetin as a medication.

Mechanism of Guishao Yigong decoction in treating colorectal cancer based on network pharmacology and experimental validation.

OBJECTIVES: To explore the effective components of Guishao Yigong decoction (GYD) in the treatment of colorectal cancer and reveal its potential mechanism of action. METHODS: Through network pharmacology, the main target and signaling pathway of GYD therapy for colorectal cancer (CRC) were found. Subsequently, the effect of GYD was verified by in vitro cell viability measurements, colony formation, and scratch healing tests. The effects of GYD on metabolic pathways in vivo were found through plasma metabolomics. Finally, flow cytometry and qPCR experiments were used to verify the cycle-blocking effect of GYD on CRC cells. KEY FINDINGS: Based on the network pharmacological analysis and molecular docking technology, it was found that GYD could restrain the growth of CRC cells by affecting lipid metabolic pathways and mitogen-activated protein kinase (MAPK) signaling pathways. A series of cell experiments showed that GYD could inhibit the proliferation, migration and clonogenic ability of CRC cells. Furthermore, the plasma metabolomics results showed that GYD could affect the production of unsaturated fatty acids in mice. Flow cytometry and qPCR experiments further proved that GYD blocked the CRC cells in the G1 phase and modulated the expression of cell cycle-related targets, such as AKT, TP53, CDKN1A, and CDK2. CONCLUSIONS: All the results indicated that GYD could regulate the related metabolism of unsaturated fatty acids. Thus, the cell cycle was blocked and the expressions of the key proteins such as AKT and TP53 were regulated, which achieved the purpose of intervention in colorectal cancer.

Improving the mechanical property of silk by feeding silkworm with chiral carbon dots.

The influence of chiral materials on organisms is crucial. However, there is little research on the impact of chiral carbon dots (CDs), a kind of typical chiral materials, on biology. Herein, chiral CDs (L-/D-CDs) were synthesized using the thermal polymerization method from citric acid and chiral cysteine. The effect of chiral CDs on silkworms was explored through feeding silkworms with chiral CDs. The breaking strength of silk fibers (667.9 MPa) in D-CDs group exhibit a 71.4 % increase compared with control-silk (389.5 MPa), while the breaking strength of silk fibers in L-CDs group increases by 51.6 %. In addition, Fourier transform infrared spectra display CDs can prevent the transformation from random coil/α-helix structures to ß-sheet structures. Furthermore, D-CDs group exhibit the highest percentage of four primary amino acids (glycine, alanine, serine, and tyrosine) relative to the total amino acids in silkworm hemolymph. This percentage is elevated by 70.5 % compared to the control group, thereby furnishing an ample supply of raw materials for the synthesis of silk proteins. In contrast, L-CDs group exhibit increase by 39.3 %. Our work provides new ideas and approaches for studying the effects of chiral materials on living organisms.

Introduction of a Hydroxyl Self-Sacrificing Surface on Ultrathin Poly(heptazine imide) Nanosheets by KCl Grafting: A New Strategy to Improve the Photocatalytic Production of H2O2.

The generation of H2O2 through photocatalysis is increasingly recognized as a viable approach for addressing the energy and environmental challenges encountered in industrial production processes. In this research, we synthesized ultrathin (1 nm) poly(heptazine imide) (PHI) nanosheets as a photocatalyst by a one-step KCl molten salt process. The utilization of Fourier transform infrared and X-ray photoelectron spectroscopy substantiated that the interlayer-bonded potassium atoms induce polarization in water molecules, facilitating the attachment of hydroxyl groups on the surfaces of nanosheets. These groups serve as self-sacrificing entities, promoting the reaction that leads to the generation of H2O2. The preparation temperature and KCl doping amount factors for the H2O2 generation rate were investigated, and the mechanism of the KCl-bonded structure on photogeneration charge separation transport was analyzed. Owing to the elevated crystallization and the presence of surface self-sacrificing hydroxyl groups, the rate of H2O2 production reaches 6117.5 and 308.35 µmol·g-1·h-1 under visible-light irradiation (λ ≥ 420 nm) in isopropanol solution and pure water, respectively. These rates are 30 and 18.7 times higher than those observed for bulk g-C3N4, respectively. The photocatalytic kinetic processes for H2O2 formation and decomposition were also calculated to investigate the catalyst activities.

Knockout of a single Pax6 gene (toy but not ey) leads to compound eye deficiency and small head in honeybees.

The compound eyes are crucial to honeybees, playing pivotal roles in color recognition, orientation, localization, and navigation processes. The development of compound eyes is primarily mastered by an evolutionarily conserved transcription factor Pax6. In honeybees, there are two Pax6 homologs: ey and toy. To gain a deeper understanding of their functions, we knock out both homologs using CRISPR/Cas9 technology. Intriguingly, we observe that toy knockout mutants have smaller heads without compound eyes and exhibit brain atrophy, while ey knockout mutants develop normal compound eyes, most of which die before/during their metamorphosis from pupa to adult. By comparing the head transcriptomes of four stages (larva, prepupa, pupa, and adult) in toy-knockout mutants versus normal controls, we identify significantly perturbed genes related to DNA binding transcription factors, neuron differentiation, and insect visual primordium development. Additionally, we find the interaction network of toy in honeybees differs obviously from that of D. melanogaster. Our findings suggest the two Pax6 genes serve distinct functions in honeybees and toy takes over the central function of ey in master-regulating the development of honeybee compound eyes. This adds new evidence for breaking the simplified view that some of conservative developmental toolkit genes function as all-or-nothing master regulators.

G6PC3 is involved in spermatogenesis by maintaining meiotic sex chromosome inactivation.

Meiosis, a process unique to germ cells, involves formation and repair of double-stranded nicks in DNA, pairing and segregation of homologous chromosomes, which ultimately achieves recombination of homologous chromosomes. Genetic abnormalities resulted from defects in meiosis are leading causes of infertility in humans. Meiotic sex chromosome inactivation (MSCI) plays a crucial role in the development of male germ cells in mammals, yet its underlying mechanisms remain poorly understood. In this study, we illustrate the predominant presence of a protein known as glucose 6 phosphatase catalyzed 3 (G6PC3) in pachytene spermatocytes, with a high concentration in the sex body (XY body), suggesting its significant involvement in male germ cell development. By employing CRISPR-Cas9 technology, we generate mice deficient in the G6pc3 gene, resulting in complete meiotic arrest at the pachytene stage in spermatocytes and are completely sterile. Additionally, we observe abnormal XY body formation and impaired MSCI in G6pc3-knockout spermatocytes. These findings underscore G6pc3 as a new essential regulator that is essential for meiotic progression. G6PC3 is involved in spermatocyte during male spermatogenesis development by the maintenance of meiosis chromosome silencing.

CSEL-BGC: A Bioinformatics Framework Integrating Machine Learning for Defining the Biosynthetic Evolutionary Landscape of Uncharacterized Antibacterial Natural Products.

The sluggish pace of new antibacterial drug development reflects a vulnerability in the face of the current severe threat posed by bacterial resistance. Microbial natural products (NPs), as a reservoir of immense chemical potential, have emerged as the most promising avenue for the discovery of next generation antibacterial agent. Directly accessing the antibacterial activity of potential products derived from biosynthetic gene clusters (BGCs) would significantly expedite the process. To tackle this issue, we propose a CSEL-BGC framework that integrates machine learning (ML) techniques. This framework involves the development of a novel cascade-stacking ensemble learning (CSEL) model and the establishment of a groundbreaking model evaluation system. Based on this framework, we predict 6,666 BGCs with antibacterial activity from 3,468 complete bacterial genomes and elucidate a biosynthetic evolutionary landscape to reveal their antibacterial potential. This provides crucial insights for interpretating the synthesis and secretion mechanisms of unknown NPs.

Metformin reprograms tryptophan metabolism via gut microbiome-derived bile acid metabolites to ameliorate depression-Like behaviors in mice.

As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed that Akkermansia muciniphila (A. muciniphila), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct A. muciniphila-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside.

Multiple cell death modalities and immune response in pulpitis.

AIM: To investigate the level and distribution of apoptosis, pyroptosis, necroptosis, and NETosis in pulpitis with or without necrosis on a basis of histological classification. Additionally, to examine the effect of pulpitis with necrosis (PWN) on the number and activation of peripheral and bone marrow (BM) neutrophils, as well as spleen lymphocytes, in a mouse model of pulpitis. METHODOLOGY: The material comprised 20 permanent teeth, with or without caries, which were classified into three histological categories based on the distribution of inflammatory cells and the presence or absence of necrosis: (i) healthy pulp (HP), (ii) pulpitis without necrosis (PWON), and (iii) PWN. The levels of the four regulated cell death (RCD) pathways were detected by immunohistochemical and immunofluorescent staining with specific markers: apoptosis (caspase-8, cleaved caspase-3), pyroptosis (cleaved caspase-1, membrane-binding gasdermin D), necroptosis (receptor-interacting kinase 3, phosphorylated MLKL), and NETosis (myeloperoxidase, citrullinated histone H3). Acute pulpitis was induced in C57BL/6J mice via pulp exposure, and the mice were divided into four groups: (i) control (no tooth preparation, n = 6), (ii) Day 1 (sacrificed at 1 day after pulp exposure, n = 3), (iii) Day 3 (n = 3), and (iv) Day 5 (n = 7). The control and Day 5 groups were used for further immunofluorescent analysis to assess the levels of RCD and flow cytometry to monitor the changes in peripheral and BM neutrophils, as well as spleen lymphocytes. Human dental pulp stem cells (hDPSCs) were isolated and cultured from extracted healthy third molars. Apoptosis and necroptosis in hDPSCs were induced by staurosporine, whilst pyroptosis was induced by lipopolysaccharide and nigericin. One-way analysis of variance (ANOVA) with Tukey's test, Welch's ANOVA with Tamhane's test, and Student's t-tests were used to compare immunohistochemical labelling and flow cytometric data amongst groups (p < .05). RESULTS: The pulpal tissue of PWN can be divided into the abscess core (PWN-AC) and fibrous tissue (PWN-FT). The ratio of total necrotic cells (TUNEL-positive) in PWN-AC was significantly higher than in PWN-FT and PWON (both p < .01). Compared with HP, the expression levels of markers for apoptosis and pyroptosis were increased in PWON, whilst the expression levels of markers for apoptosis, pyroptosis, and NETosis were elevated in PWN, primarily detected in PWN-AC. Interestingly, myeloperoxidase (MPO) was exclusively observed in PWN-AC, with minimal detection in PWN-FT and PWON. Additionally, the frequency of MPO+ cells was significantly higher than that of MB-GSDMD+ cells and Cl-cas3+ cells in PWN-AC (both p < .01). Histological observation and TUNEL staining showed abundant necrotic cells in mouse pulpal tissue after pulp exposure, indicating a simulation of human PWN. In mouse pulpitis tissue, markers of apoptosis, pyroptosis, and NETosis were detected. In vitro, various cell deaths including apoptosis, pyroptosis, and necroptosis were also triggered in hDPSCs under various cell death treatments. Furthermore, in terms of systemic changes, pulp exposure-induced pulpitis could increase the number (p < .05) and cellular activity (p < .01) of neutrophils from BM in a mouse model. No significant changes in peripheral blood neutrophils, spleen T cells, B cells, or the CD4/CD8 ratio were detected between the control and pulpitis mice. CONCLUSIONS: Our findings uncover distinct patterns of mixed cell death at different histological stages of human pulpitis and the impact of pulpitis on the number and activity of BM neutrophils. Notably, NETosis occurs specifically and predominates in the abscess area of pulpitis, suggesting a potential effect of neutrophil extracellular traps (NETs) on pulpitis progression and NETs-targeted diagnostic strategy may play a role in decision making for vital pulp therapy.

Lactylation signature identifies liver fibrosis phenotypes and traces fibrotic progression to hepatocellular carcinoma.

Introduction: Precise staging and classification of liver fibrosis are crucial for the hierarchy management of patients. The roles of lactylation are newly found in the progression of liver fibrosis. This study is committed to investigating the signature genes with histone lactylation and their connection with immune infiltration among liver fibrosis with different phenotypes. Methods: Firstly, a total of 629 upregulated and 261 downregulated genes were screened out of 3 datasets of patients with liver fibrosis from the GEO database and functional analysis confirmed that these differentially expressed genes (DEGs) participated profoundly in fibrosis-related processes. After intersecting with previously reported lactylation-related genes, 12 DEGs related to histone lactylation were found and narrowed down to 6 core genes using R algorithms, namely S100A6, HMGN4, IFI16, LDHB, S100A4, and VIM. The core DEGs were incorporated into the Least absolute shrinkage and selection operator (LASSO) model to test their power to distinguish the fibrotic stage. Results: Advanced fibrosis presented a pattern of immune infiltration different from mild fibrosis, and the core DEGs were significantly correlated with immunocytes. Gene set and enrichment analysis (GSEA) results revealed that core DEGs were closely linked to immune response and chemokine signaling. Samples were classified into 3 clusters using the LASSO model, followed by gene set variation analysis (GSVA), which indicated that liver fibrosis can be divided into status featuring lipid metabolism reprogramming, immunity immersing, and intermediate of both. The regulatory networks of the core genes shared several transcription factors, and certain core DEGs also presented dysregulation in other liver fibrosis and idiopathic pulmonary fibrosis (IPF) cohorts, indicating that lactylation may exert comparable functions in various fibrotic pathology. Lastly, core DEGs also exhibited upregulation in HCC. Discussion: Lactylation extensively participates in the pathological progression and immune infiltration of fibrosis. Lactylation and related immune infiltration could be a worthy focus for the investigation of HCC developed from liver fibrosis.

Unveiling the hidden link: fungi and HPV in cervical lesions.

Background: Cervical cancer, primarily driven by high-risk human papillomavirus (HR-HPV) infection, ranks as the second most common cancer globally. Understanding combined infections' role, including Cervical fungi, is crucial in cervical carcinogenesis. This study aims to explore the potential correlation between HR-HPV, cervical fungi, and cervical cancer, while adjusting for various factors. Methods: The study population comprised patients undergoing colposcopy and conization due to abnormal cervical screening results. Clinical data including age, gravidity, HPV (human papillomavirus) genotypes, cervical pathology, and p16/Ki67 expression were extracted. Cervical TCT (ThinPrep Pap Test) and HPV testing are utilized for screening cervical lesions, with fungal presence suggested by TCT results. 5,528 participants were included in this study. Statistical analyses investigated associations between HPV/fungi co-infection and cervical lesions, employing multinomial logistic regression and interaction analysis. Results: Co-infection with fungi and HPV may decrease the risk of cervical lesions compared to HPV infection alone. In the co-infection group, compared with HPV infection alone, the risk of low-grade squamous intraepithelial lesions (LSIL) was reduced by 27% (OR = 0.73, 95% CI: 0.59-0.90), the risk of high-grade squamous intraepithelial lesions (HSIL) was reduced by 35% (OR = 0.65, 95% CI: 0.51-0.82), and the risk of cervical cancer was reduced by 43% (OR = 0.57, 95% CI: 0.35-0.92). The interaction analysis revealed a negative interaction between fungal and HPV infections in the development of cervical cancer (RERI = -6.25, AP = -0.79, SI = 0.52), HSIL (RERI = -19.15, AP = -0.37, SI = 0.72) and LSIL (RERI = -1.87, AP = -0.33, SI = 0.71), suggesting a sub-additive effect, where the combined effect of the two infections was less than the sum of their individual effects. This indicates that fungal infection may attenuate the promoting effect of HPV on cervical lesions. In exploring the potential mechanism, we found that the co-infection group had significantly lower p16 positivity (54.6%) compared to the HPV-only group (60.2%) (p = 0.004), while there was no statistically significant difference in Ki67 positivity. Conclusion: This study unveils the intricate relationship between cervical fungi and HPV in cervical lesions. Co-infection with fungi and HPV against cervical lesions compared to HPV infection alone, indicating a novel clinical interaction. Lower p16 positivity in co-infection hints at a protective mechanism, urging further exploration.

Thermosensitive hydrogel as a sustained release carrier for mesenchymal stem cell-derived extracellular vesicles in the treatment of intrauterine adhesion.

Intrauterine adhesion (IUA), a prevalent etiology of female infertility, is attributed to endometrial damage. However, conventional therapeutic interventions for IUA are plagued by high recurrence rates. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUCMSC-EVs) demonstrate the promising therapeutic effects on IUA, but the current efficacy of extracellular vesicles (EVs) is hindered by lower retention and bioavailability. In this study, a thermosensitive hydrogel was utilized as a prolonged release carrier to improve the retention and bioavailability of hUCMSC-EVs in IUA treatment. The hydrogel-EVs complex effectively prolonged EVs retention in human endometrial stromal cells and an IUA mouse model. The complex exhibited superior protection against cellular injury, significantly alleviated endometrial damage, inhibited fibrosis, suppressed inflammation, and improved fertility compared to EVs alone. The results indicated that thermosensitive hydrogel enhanced the therapeutic capacity of EVs for IUA by prolonging their retention in the uterine environment. The hydrogel-EVs complex provides a novel strategy for the sustained release of hUCMSC-EVs in the treatment of IUA.

Early identification of hepatocellular carcinoma patients at high-risk of recurrence using the ADV score: a multicenter retrospective study.

BACKGROUND: Postoperative recurrence is a vital reason for poor 5-year overall survival in hepatocellular carcinoma (HCC) patients. The ADV score is considered a parameter that can quantify HCC aggressiveness. This study aimed to identify HCC patients at high-risk of recurrence early using the ADV score. METHODS: The medical data of consecutive HCC patients undergoing hepatectomy from The First Affiliated Hospital of Nanjing Medical University (TFAHNJMU) and Nanjing Drum Tower Hospital (NJDTH) were retrospectively reviewed. Based on the status of microvascular invasion and the Edmondson-Steiner grade, HCC patients were divided into three groups: low-risk group (group 1: no risk factor exists), medium-risk group (group 2: one risk factor exists), and high-risk group (group 3: coexistence of two risk factors). In the training cohort (TFAHNJMU), the R package nnet was used to establish a multi-categorical unordered logistic regression model based on the ADV score to predict three risk groups. The Welch's T-test was used to compare differences in clinical variables in three predicted risk groups. NJDTH served as an external validation center. At last, the confusion matrix was developed using the R package caret to evaluate the diagnostic performance of the model. RESULTS: 350 and 405 patients from TFAHNJMU and NJDTH were included. HCC patients in different risk groups had significantly different liver function and inflammation levels. Density maps demonstrated that the ADV score could best differentiate between the three risk groups. The probability curve was plotted according to the predicted results of the multi-categorical unordered logistic regression model, and the best cut-off values of the ADV score were as follows: low-risk ≤ 3.4 log, 3.4 log < medium-risk ≤ 5.7 log, and high-risk > 5.7 log. The sensitivities of the ADV score predicting the high-risk group (group 3) were 70.2% (99/141) and 78.8% (63/80) in the training and external validation cohort, respectively. CONCLUSION: The ADV score might become a valuable marker for screening patients at high-risk of HCC recurrence with a cut-off value of 5.7 log, which might help surgeons, pathologists, and HCC patients make appropriate clinical decisions.

A natural compound-empowered podophyllotoxin prodrug nanoassembly magnifies efficacy-toxicity benefits in cancer chemotherapy.

Small-molecule prodrug nanoassembly technology with a unique advantage in off-target toxicity reduction has been widely used for antitumor drug delivery. However, prodrug activation remains a rate-limiting step for exerting therapeutic actions, which requires to quickly reach the minimum valid concentrations of free drugs. Fortunately, we find that a natural compound (BL-193) selectively improves the chemotherapy sensitivity of breast cancer cells to podophyllotoxin (PPT) at ineffective dose concentrations. Based on this, we propose to combine prodrug nanoassembly with chemotherapy sensitization to fully unleash the chemotherapeutic potential of PPT. Specifically, a redox-sensitive prodrug (PSSF) of PPT is synthesized by coupling 9-fluorenyl-methanol (Fmoc-OH) with PPT linked via disulfide bond. Intriguingly, PSSF with a π-conjugated structure readily co-assembles with BL-193 into stable nanoassembly. Significantly, BL-193 serves as an excellent chemosensitizer that creates an ultra-low-dose chemotherapeutic window for PPT. Moreover, prodrug design and precise hybrid nanoassembly well manage off-target toxicity. As expected, such a BL-193-empowered prodrug nanoassembly elicits potent antitumor responses. This study offers a novel paradigm to magnify chemotherapy efficacy-toxicity benefits.

Exploring the top 30 drugs associated with drug-induced constipation based on the FDA adverse event reporting system.

Objective: This project aims to identify the top 30 drugs most commonly associated with constipation and their signal values within the FDA Adverse Event Reporting System database. Methods: We extracted adverse drug events (ADEs) related to constipation from the FAERS database spanning from January 1, 2004, to September 30, 2023. We compiled the 30 most frequently reported drugs based on the frequency of constipation events. We employed signal detection methodologies to ascertain whether these drugs elicited significant signals, including reporting odds ratio, proportional reporting ratio, multi-item gamma Poisson shrinker, and information component given by the Bayesian confidence propagation neural network. Furthermore, we conducted a time-to-onset (TTO) analysis for drugs generating significant signals using the medians, quartiles, and the Weibull shape parameter test. Results: We extracted a total of 50, 659, 288 ADEs, among which 169,897 (0.34%) were related to constipation. We selected and ranked the top 30 drugs. The drug with the highest ranking was lenalidomide (7,730 cases, 4.55%), with the most prevalent drug class being antineoplastic and immunomodulating agents. Signal detection was performed for the 30 drugs, with constipation risk signals identified for 26 of them. Among the 26 drugs, 22 exhibited constipation signals consistent with those listed on the FDA-approved drug labels. However, four drugs (orlistat, nintedanib, palbociclib, and dimethyl fumarate) presented an unexpected risk of constipation. Ranked by signal values, sevelamer carbonate emerged as the drug with the strongest risk signal [reporting odds ratio (95% CI): 115.51 (110.14, 121.15); PRR (χ2): 83.78 (191,709.73); EBGM (EB05): 82.63 (79.4); IC (IC025): 6.37 (4.70)]. A TTO analysis was conducted for the 26 drugs that generated risk signals, revealing that all drugs exhibited an early failure type. The median TTO for orlistat was 3 days, the shortest of all the drugs, while the median TTO for clozapine was 1,065 days, the longest of all the drugs. Conclusion: Our study provides a list of drugs potentially associated with drug-induced constipation (DIC). This could potentially inform clinicians about some alternative medications to consider when managing secondary causes of constipation or caring for patients prone to DIC, thereby reducing the incidence and mortality associated with DIC.

Ostwald-Ripening Induced Interfacial Protection Layer Boosts 1,000,000-Cycled Hydronium-Ion Battery.

Collapsing and degradation of active materials caused by the electrode/electrolyte interface instability in aqueous batteries are one of the main obstacles that mitigate the capacity. Herein by reversing the notorious side reactions include the loss and dissolution of electrode materials: as we applied Ostwald ripening (OR) in the electrochemical cycling of a copper hexacyanoferrate electrode in a hydronium-ion batteries, the dissolved Cu and Fe ions undergo a crystallization process that creates a stable interface layer of cross-linked cubes on the electrode surface. The layer exposed the low-index crystal planes (100) and (110) through OR-induced electrode particle growth, supplemented by vacancy-ordered (100) superlattices that facilitated ion migration. Our design stabilized the electrode-electrolyte interface considerably, achieving a cycle life of one million cycles with capacity retention of 91.6%, and a capacity retention of 91.7% after 3000 cycles for a full battery.

Triiodothyronine acts on DAO to regulate pulmonary fibrosis progression by facilitating cell senescence through the p53/p21 signaling pathway.

Background: Idiopathic pulmonary fibrosis (IPF) is the result of multiple cycles of epithelial cell injury and fibroblast activation; currently, there is no clear etiology. Increasing evidence suggests that protein metabolism and amino acids play a crucial role in IPF, but the role of D-amino acids is not yet clear. The aim of this study was to identify novel mediators in order to test the hypothesis that D-amino acid oxidase (DAO) plays a significant role in the pathogenesis of IPF. Methods: We analyzed DAO gene expression in patients with IPF and mice with bleomycin (BLM)-induced lung fibrosis. We performed in vitro and in vivo assays to determine the effect of DAO on primary type II alveolar epithelial cells from mice and A549 cells. Results: DAO expression was downregulated in the lungs of IPF patients and BLM-induced fibrotic mice. Treatment with D-serine (D-Ser) or drug inhibition of DAO promoted cell senescence through the p53/p21 pathway. Dao -/- mice showed an intensified fibrotic response, and the anti-fibrotic role of T3 was abolished. Conclusion: We concluded that the DAO-p53/p21 axis might be a key anti-fibrotic pathway regulating the progress of fibrosis and facilitating the therapeutic role of T3.

High genetic diversity and limited regional population differentiation in populations of Calonectria pseudoreteaudii from Eucalyptus plantations.

Calonectria pseudoreteaudii causes a serious and widespread disease known as Calonectria leaf blight in Eucalyptus plantations of southern China. Little is known regarding the population biology or reproductive biology of this pathogen in the affected areas. The aims of this study were to investigate the genetic diversity, population structure and the reproductive mode of C. pseudoreteaudii from affected Eucalyptus plantations of southern China. Ten polymorphic SSR markers were developed for the species, and were used to genotype 311 isolates from eight populations. The mating types of all isolates were identified using the MAT gene primers. The results revealed a high level of genetic diversity of the pathogen in all investigated populations. Of the 90 multilocus genotypes detected, ten were shared between at least two populations. With the exception of one population from HuiZhou, GuangDong (7HZ), the most dominant genotype was shared in seven remaining populations. DAPC and population differentiation analyses showed that the 7HZ population was well differentiated from the others and that there was no significant differentiation between the remaining populations. AMOVA suggested that most molecular variation was within populations (86%). Index of association analysis was consistent with a predominantly asexual life cycle for C. pseudoreteaudii in the studied regions. Although both mating types were detected in seven of the eight populations, the MAT1-1/MAT1-2 ratios in these populations deviated significantly from the 1:1 ratio expected in a randomly mating population.