The effect of dual antioxidant modification on oxidative stress resistance and anti-dysfunction of non-split HDL and recombinant HDL.

Recombinant high-density lipoprotein (rHDL) as anti-atherosclerosis (AS) vehicle has unique advantages including multiple anti-atherogenic functions and homing features to plaques. However, rHDL may be converted into dysfunctional forms due to complex treatment during preparation. Herein, oxidation-induced dysfunction of non-split HDL and rHDL was initially investigated. It was found that although both non-split HDL and rHDL showed oxidative dysfunction behavior, non-split HDL demonstrated superior oxidation defense compared to rHDL due to its intact composition and avoidance of overprocessing such as split and recombination. Unfortunately, in vivo oxidative stress could compromise the functionality of HDL. Therefore, surface engineering of non-split HDL and rHDL with cascade antioxidant enzyme analogues Ebselen and mitochondrial-targeted TPGS-Tempo was conducted to construct a dual-line defense HDL nano system (i.e., T@E-HDLs/rHDL), aiming to restore plaque redox balance and preserving the physiological function of HDL. Results indicated that both T@E-HDLs and rHDLs performed without distinction and exhibited greater resistance to oxidative stress damage as well as better functions than unmodified HDLs in macrophage foam cells. Overall, the modification of dual antioxidants strategy bridges the gap between non-split HDL and rHDL, and provides a promising resolution for the dilemmas of oxidative stress in plaques and HDL self dysfunction.

Electroacupuncture and methotrexate cooperate to ameliorate psoriasiform skin inflammation by regulating the immune balance of Th17/Treg.

Psoriasis is an autoinflammatory dermatosis, while methotrexate (MTX) is an immunosuppressant used to treat psoriasis. However, conventional immunosuppressants may cause various side effects. Acupuncture has potential benefits in treating psoriasis based on its anti-inflammatory effects. However, the immune mechanisms underlying its effects remain unclear. In this study, imiquimod-induced psoriatic mice were used to investigate the effects and mechanisms of electroacupuncture (EA) and, in particular, its joint treatment with MTX. We found that treatment with either EA or MTX ameliorated psoriasiform skin lesions, improved skin pathology and reduced proinflammatory cytokines in the skin, while joint treatment with both EA and MTX further alleviated the skin lesions and inflammation compared to either one alone. Moreover, percentages of CD4+ IL-17A+ Th17 cells in the skin and lymph nodes were decreased by EA or MTX and further lowered by combined EA+MTX treatment. Similarly, EA or MTX also reduced their RORγt expression. On the contrary, CD4+ FoxP3+ Treg frequency in psoriatic mice was augmented by EA or MTX and further increased by the joint treatment. However, depleting Tregs mostly reversed the therapeutic effects of EA or EA plus MTX. Additionally, the phosphorylated NF-κB (p65) expression was suppressed by treatment with EA, MTX or better with EA+MTX. Meanwhile, the anti-inflammatory effects of EA plus MTX were offset by an NF-κB agonist. Thus, this study has revealed that EA cooperates with MTX to balance Th17/Treg responses and to ameliorate psoriasiform skin inflammation through suppressing NF-κB activation. Our findings may be implicated for treating human psoriasis.

Long-lived isospin excitations in magic-angle twisted bilayer graphene.

Numerous correlated many-body phases, both conventional and exotic, have been reported in magic-angle twisted bilayer graphene (MATBG)1-24. However, the dynamics associated with these correlated states, crucial for understanding the underlying physics, remain unexplored. Here we combine exciton sensing and optical pump-probe spectroscopy to investigate the dynamics of isospin orders in MATBG with WSe2 substrate across the entire flat band, achieving sub-picosecond resolution. We observe remarkably slow isospin dynamics in a broad filling range around ν = 2 and between ν = -3 and -2, with lifetimes of up to 300 ps that decouple from the much faster cooling of electronic temperature (about 10 ps). This non-thermal behaviour demonstrates the presence of abnormally long-lived modes in the isospin degrees of freedom. This observation, not anticipated by theory, implies the existence of long-range propagating collective modes, strong isospin fluctuations and memory effects and is probably associated with an intervalley coherent or incommensurate Kekulé spiral ground state. We further demonstrate non-equilibrium control of the isospin orders previously found around integer fillings. Specifically, through ultrafast manipulation, it can be transiently shifted away from integer fillings. Our study demonstrates a unique probe of collective excitations in MATBG and paves the way for actively controlling non-equilibrium phenomena in moiré systems.

Interface Structures on Mechanically Polished Surface of Spinel Ferrite and Its Effect on the Magnetic Domains.

Soft magnetic spinel ferrites are indispensable parts in devices such as transformers and inductors. Mechanical surface processing is a necessary step to realize certain shapes and surface roughness in producing the ferrite but also has a negative effect on the magnetic properties of the ferrite. In the past few years, a new surface layer was always believed to form during the mechanical surface processing, but the change of atomic structure on the surface and its effect on the magnetic structure remain unclear. Herein, an interface structure consisting of a rock-salt sublayer, distorted NiFe2O4 sublayer, and pristine NiFe2O4 was found to form on mechanically polished single-crystal NiFe2O4 ferrite. Such an interface structure is produced by phase transformation and lattice distortion induced by the mechanical processing. The magnetic domain observation and electrical property measurement also indicate that the magnetic and electrical anisotropy are both enhanced by the interface structure. This work provides deep insight into the surface structure evolution of spinel ferrite by mechanical processing.

Integrative analyses of multi-omics data constructing tumor microenvironment and immune-related molecular prognosis model in human colorectal cancer.

The increasing prevalence and incidence of colorectal cancer (CRC), particularly in young adults, underscore the imperative to comprehend its fundamental mechanisms, discover novel diagnostic and prognostic markers, and enhance therapeutic strategies. Here, we integrated multi-omics data, including gene expression, somatic mutation data and DNA methylation data, to unravel the intricacies of tumor microenvironment (TME) in CRC and search for novel prognostic markers. By calculating the immune score for each patient from the expression profile, we delineated the differential immune cell fraction, constructed an immune-related multi-omics atlas, and identified molecular characteristics. The entire colorectal dataset (n = 343) was randomly divided into training (n = 249) and testing datasets (n = 94). We screened 144 immune-related genes, 6 mutant genes, and 38 methylation probes associated with overall survival (OS). These makers were then incorporated into a 10-gene prognostic model using Lasso and Cox regression in the training dataset, and the model's performance was evaluated in an independent validation dataset. The model exhibited satisfactory results (average concordance index [C-index] = 0.77), with the average 1-year, 3-year, and 5-year AUCs being 0.79, 0.76, and 0.76 in the training dataset and 0.74, 0.80, and 0.90 in the testing dataset. Furthermore, the prognostic model demonstrated applicability in guiding chemotherapy for CRC patients and exhibited a degree of pan-cancer utility in risk stratification. In conclusion, our integrated analysis of multi-omics data revealed immune-related genetic and epigenetic characteristics of the TME. We propose an integrative prognostic model that can stratify risk and guide chemotherapy for CRC patients. The generalizability of the model in risk stratification across different cancer types was validated in Pan-Cancer cohort.

Photoreactivation Activities of Rad5, Rad16A and Rad16B Help Beauveria bassiana to Recover from Solar Ultraviolet Damage.

In budding yeast, Rad5 and Rad7-Rad16 play respective roles in the error-free post-replication repair and nucleotide excision repair of ultraviolet-induced DNA damage; however, their homologs have not yet been studied in non-yeast fungi. In the fungus Beauveria bassiana, a deficiency in the Rad7 homolog, Rad5 ortholog and two Rad16 paralogs (Rad16A/B) instituted an ability to help the insect-pathogenic fungus to recover from solar UVB damage through photoreactivation. The fungal lifecycle-related phenotypes were not altered in the absence of rad5, rad16A or rad16B, while severe defects in growth and conidiation were caused by the double deletion of rad16A and rad16B. Compared with the wild-type and complemented strains, the mutants showed differentially reduced activities regarding the resilience of UVB-impaired conidia at 25 °C through a 12-h incubation in a regime of visible light plus dark (L/D 3:9 h or 5:7 h for photoreactivation) or of full darkness (dark reactivation) mimicking a natural nighttime. The estimates of the median lethal UVB dose LD50 from the dark and L/D treatments revealed greater activities of Rad5 and Rad16B than of Rad16A and additive activities of Rad16A and Rad16B in either NER-dependent dark reactivation or photorepair-dependent photoreactivation. However, their dark reactivation activities were limited to recovering low UVB dose-impaired conidia but were unable to recover conidia impaired by sublethal and lethal UVB doses as did their photoreactivation activities at L/D 3:9 or 5:7, unless the night/dark time was doubled or further prolonged. Therefore, the anti-UV effects of Rad5, Rad16A and Rad16B in B. bassiana depend primarily on photoreactivation and are mechanistically distinct from those for their yeast homologs.

Cla4A, a Novel Regulator of Gene Expression Networks Required for Asexual and Insect-Pathogenic Lifecycles of Beauveria bassiana.

Cla4, an orthologous p21-activated kinase crucial for non-entomopathogenic fungal lifestyles, has two paralogs (Cla4A/B) functionally unknown in hypocrealean entomopathogens. Here, we report a regulatory role of Cla4A in gene expression networks of Beauveria bassiana required for asexual and entomopathogenic lifecycles while Cla4B is functionally redundant. The deletion of cla4A resulted in severe growth defects, reduced stress tolerance, delayed conidiation, altered conidiation mode, impaired conidial quality, and abolished pathogenicity through cuticular penetration, contrasting with no phenotype affected by cla4B deletion. In ∆cla4A, 5288 dysregulated genes were associated with phenotypic defects, which were restored by targeted gene complementation. Among those, 3699 genes were downregulated, including more than 1300 abolished at the transcriptomic level. Hundreds of those downregulated genes were involved in the regulation of transcription, translation, and post-translational modifications and the organization and function of the nuclear chromosome, chromatin, and protein-DNA complex. DNA-binding elements in promoter regions of 130 dysregulated genes were predicted to be targeted by Cla4A domains. Samples of purified Cla4A extract were proven to bind promoter DNAs of 12 predicted genes involved in multiple stress-responsive pathways. Therefore, Cla4A acts as a novel regulator of genomic expression and stability and mediates gene expression networks required for insect-pathogenic fungal adaptations to the host and environment.

Small molecule NMD and MDM2 inhibitors synergistically trigger apoptosis in HeLa cells.

The nonsense-mediated mRNA decay (NMD) pathway and the p53 pathway, linked to tumorgenesis, are also promising targets for cancer treatment. NMD plays an important role in RNA quality control, while the p53 pathway is involved in cancer suppression. However, their individual and combined effects on cervical cancer are poorly understood. In this study, we evaluated the impacts of NMD inhibitor, Mouse double minute 2 homolog (MDM2) inhibitor, and their combination on cell apoptosis, cell cycle, and p53 target genes in human papillomavirus-18-positive HeLa cells. Our findings revealed that XR-2 failed to activate p53 or induce apoptosis in HeLa cells, whereas SMG1 (serine/threonine-protein kinase 1) inhibitor repressed cell proliferation at high concentrations. Notably, the combination of these 2 agents significantly inhibited cell proliferation, arrested the cell cycle, and triggered cell apoptosis. Mechanistically, MDM2 inhibitor and NMD inhibitor likely exert a synergistically through the truncated E6 protein. These results underscore the potential of employing a combination of MDM2 inhibitor and NMD inhibitor as a promising candidate for the clinical treatment of human papillomavirus-infected tumors.

Physiological and genetic responses of the benthic dinoflagellate Prorocentrum lima to polystyrene microplastics.

Microplastics are well known as contaminants in marine environments. With the development of biofilms, most microplastics will eventually sink and deposit in benthic environment. However, little research has been done on benthic toxic dinoflagellates, and the effects of microplastics on benthic dinoflagellates are unknown. Prorocentrum lima is a cosmopolitan toxic benthic dinoflagellate, which can produce a range of polyether metabolites, such as diarrhetic shellfish poisoning (DSP) toxins. In order to explore the impact of microplastics on marine benthic dinoflagellates, in this paper, we studied the effects of polystyrene (PS) on the growth and toxin production of P. lima. The molecular response of P. lima to microplastic stress was analyzed by transcriptomics. We selected 100 nm, 10 µm and 100 µm PS, and set three concentrations of 1 mg L-1, 10 mg L-1 and 100 mg L-1. The results showed that PS exposure had limited effects on cell growth, but increased the OA and extracellular polysaccharide content at high concentrations. After exposure to PS MPs, genes associated with DSP toxins synthesis, carbohydrate synthesis and energy metabolism, such as glycolysis, TCA cycle and pyruvate metabolism, were significantly up-regulated. We speculated that after exposure to microplastics, P. lima may increase the synthesis of DSP toxins and extracellular polysaccharides, improve the level of energy metabolism and gene expression of ABC transporter, thereby protecting algal cells from damage. Our findings provide new insights into the effects of microplastics on toxic benthic dinoflagellates.

Comparative Proteomics Identified EXOSC1 as a Target Protein of Anticancer Peptide LVTX-8 in Nasopharyngeal Carcinoma Cells.

Nasopharyngeal carcinoma (NPC) is a prevalent malignancy that usually occurs among the nose and throat. Due to mild initial symptoms, most patients are diagnosed in the late stage, and the recurrence rate of tumors is high, resulting in many deaths every year. Traditional radiotherapy and chemotherapy are prone to causing drug resistance and significant side effects. Therefore, searching for new bioactive drugs including anticancer peptides is necessary and urgent. LVTX-8 is a peptide toxin synthesized from the cDNA library of the spider Lycosa vittata, which is consisting of 25 amino acids. In this study, a series of in vitro cell experiments such as cell toxicity, colony formation, and cell migration assays were performed to exam the anticancer activity of LVTX-8 in NPC cells (5-8F and CNE-2). The results suggested that LVTX-8 significantly inhibited cell proliferation and migration of NPC cells. To find the potential molecular targets for the anticancer capability of LVTX-8, high-throughput proteomic and bioinformatics analysis were conducted on NPC cells. The results identified EXOSC1 as a potential target protein with significantly differential expression levels under LVTX-8+/LVTX-8- conditions. The results in this research indicate that spider peptide toxin LVTX-8 exhibits significant anticancer activity in NPC, and EXOSC1 may serve as a target protein for its anticancer activity. These findings provide a reference for the development of new therapeutic drugs for NPC and offer new ideas for the discovery of biomarkers related to NPC diagnosis. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the data set identifier PXD050542.

Synergy of nodal factors in predicting recurrence after treatment of N1b papillary thyroid carcinoma.

BACKGROUND: Nodal factors are important predictors of prognosis for papillary thyroid carcinoma (PTC), but their synergy effect is not well understood. We aimed to explore their synergy effect in predicting recurrence of clinical N1b PTC. METHODS: Patients who underwent surgery for cN1b PTC from 2013 to 2017 were enrolled. The association between nodal factors and recurrence was assessed using Cox proportional hazards regression models. Interaction and stratified analyses were conducted according to significant nodal factors. RESULTS: Of 1067 cN1b PTC patients included, all nodal factors (bilateral metastasis, largest dimension>3cm, micro and gross extranodal extension (mENE, gENE), No. of metastatic lymph nodes (MLN), lymph node yield (LNY) and ratio (LNR)) were significantly associated with all site and nodal recurrence in the univariate analysis (all P<0.05). Multivariate analyses revealed largest dimension>3cm, gENE and LNR>0.21 were associated with elevated both all site (HR [95%CI], 2.58 [1.67-4.00], 1.87[1.26-3.01], 1.68[1.11-2.42], all P<0.01) and nodal recurrences (HR[95%CI], 2.63[1.67-4.13], 1.90[1.15-3.12], 1.76[1.17-2.66], all P<0.01). LNR and gENE had interactive effect (all site recurrence: P for interaction = 0.009; nodal recurrence: P for interaction = 0.02). LNR was significantly associated with recurrence in patients without gENE (HR[95% CI], all site recurrence: 2.41[1.50-3.87]; nodal recurrence: 2.51[1.52-4.14], all P< 0.001), while when gENE appeared, LNR was no longer associated with recurrence (HR [95% CI], all site recurrence: 0.81[0.43-1.54], P=0.53; nodal recurrence: 0.85[0.43-1.67], P=0.64). CONCLUSIONS: Nodal factors have synergy effect in predicting recurrence in cN1b PTC patients. Increasing lymph nodes harvest may only decrease recurrence in patients without gENE, while not in gENE patients.

Extent of surgery for unilateral papillary thyroid cancer with nonsuspicious contralateral nodules by ultrasound.

BACKGROUND: The discussion about surgical treatment of patients with papillary thyroid cancer(PTC) has been an ongoing issue, which is mainly focused on characteristics of tumor, but rarely on nonsuspicious contralateral nodules. We aimed to compare recurrence-free survival(RFS)/progression-free survival(PFS) of unilateral PTC patients with nonsuspicious contralateral nodules after different extents of surgery. METHODS: Unilateral PTC patients with nonsuspicious contralateral nodules underwent surgery from 2015 to 2017 were enrolled. The association between surgical extent and RFS/PFS was analyzed by Kaplan-Meier method and Cox proportional hazards model. RESULTS: A total of 1293 PTC patients (595[46.0%]TT,523[40.4%]lobectomy+nodule enucleation(LNE),175[13.5%]lobectomy) were analyzed. Patients with a greater surgical extent were more likely to be older, have a greater multifocality of the tumor and contralateral nodules, larger contralateral nodules and primary tumors, and more micro extrathyroidal extension (P < 0.05). After a median follow-up of 45 months, significant growth(>3 mm) was identified in 24 (4.6%) and 19 (10.9%) patients in the LNE and lobectomy group, 7 (1.2%), 14 (2.7%) and 11 (6.3%) structural recurrences and 7 (1.2%), 11 (2.1%) and 7 (4.0%) progression in disease were identified in the TT, LNE and lobectomy groups, respectively. Unadjusted and adjusted RFS/PFS were significantly worse for patients treated with lobectomy than for those who underwent LNE or TT(3-year RFS, 95.5%, 98.2% vs. 99.0%; 3-year PFS, 97.9%, 98.9% vs. 99.0%, P < 0.05), but difference in PFS between LNE and TT lost statistical significance (unadjusted P = 0.226, adjusted P = 0.150). CONCLUSIONS: Due to subtle changes in nodules and acceptable prognosis, lobectomy is a considerable option for unilateral PTC patients with nonsuspicious nodules, when a similar prognosis to TT is expected, LNE may be an effective alternative to optimize quality of life.

Computational Screening of Promising Deep-Ultraviolet Light Emitters.

Deep-ultraviolet (DUV) light sources are technologically highly important, but DUV light-emitting materials are extremely rare; AlN and its alloys are the only materials known so far, significantly limiting the chemical and structural spaces for materials design. Here, we perform a high-throughput computational search for DUV light emitters based on a set of carefully designed screening criteria relating to the sophisticated electronic structure. In this way, we successfully identify 5 promising material candidates that exhibit comparable or higher radiative recombination coefficients than AlN, including BeGeN2, Mg3NF3, KCaBr3, KHS, and RbHS. Further, we unveil the unique features in the atomic and electronic structures of DUV light emitters and elucidate the fundamental genetic reasons why DUV light emitters are extremely rare. Our study not only guides the design and synthesis of efficient DUV light emitters but also establishes the genetic nature of ultrawide-band-gap semiconductors in general.

A frogspawn inspired twin Mo2C/Ni composite with a conductive fibrous network as a robust bifunctional catalyst for advanced anion exchange membrane electrolyzers.

Anion exchange membrane water electrolysis (AEMWE) is considered one of the most cost-effective methods for producing green hydrogen. However, the performance of AEMWE is still restrained by the slow reaction kinetics and poor ion/electron transport of catalysts. Herein, inspired by frogspawn, Mo2C nanoparticles coupled with Ni were in situ embedded into a N-doped porous carbon nanofiber network (Mo2C/NCNTs@Ni) by chemical crosslinking electrospinning combined with carbonization. The unique bionic structure can guarantee favorable overall structural flexibility and fast ion/electron transport kinetics. As a result of the robust hydrogen binding energy of Mo2C, as well as the synergistic impact between Ni and Mo2C nanoparticles and the conductive network resembling frogspawn, the catalyst developed demonstrates excellent performance in both the HER and OER. When employed as a bifunctional catalyst in water electrolysis, Mo2C/NCNTs@Ni delivers overpotentials of 155 mV and 320 mV at 10 mA cm-2 for the HER and OER, respectively. In addition, the Mo2C/NCNTs@Ni also displays excellent long-term durability during a continuous operation test under different currents for 50 h. The assembled AEMWE electrolyzers with Mo2C/NCNTs@Ni as both the anode and cathode can achieve a current density of 82.5 mA cm-2 at 1.99 V, indicating great potential for industrial water splitting. These results give an insight for the development of advanced bifunctional electrocatalysts for the next generation of green and efficient H2 production by water electrolysis.

Comprehensive analysis of m6 A methylome and transcriptome by Nanopore sequencing in clear cell renal carcinoma.

N6 -methyladenosine (m6 A) is the most prevalent epigenetic modification on eukaryotic messenger RNAs. Recent studies have focused on elucidating the key role of m6 A modification patterns in tumor progression. However, the relationship between m6 A and transcriptional regulation remains elusive. Nanopore technology enables the quantification of m6 A levels at each genomic site. In this study, a pair of tumor tissues and adjacent normal tissues from clear cell renal cell carcinoma (ccRCC) surgical samples were collected for Nanopore direct RNA sequencing. We identified 9644 genes displaying anomalous m6 A modifications, with 5343 genes upregulated and 4301 genes downregulated. Among these, 5224 genes were regarded as dysregulated genes, encompassing abnormal regulation of both m6 A modification and RNA expression. Gene Set Enrichment Analysis revealed an enrichment of these genes in pathways related to renal system progress and fatty acid metabolic progress. Furthermore, the χ2 test demonstrated a significant association between the levels of m6 A in dysregulated genes and their transcriptional expression levels. Additionally, we identified four obesity-associated genes (FTO, LEPR, ADIPOR2, and NPY5R) among the dysregulated genes. Further analyses using public databases revealed that these four genes were all related to the prognosis and diagnosis of ccRCC. This study introduced the novel approach of employing conjoint analysis of m6 A modification and RNA expression based on Nanopore sequencing to explore potential disease-related genes. Our work demonstrates the feasibility of the application of Nanopore sequencing technology in RNA epigenetic regulation research and identifies new potential therapeutic targets for ccRCC.

Rad6, a ubiquitin conjugator required for insect-pathogenic lifestyle, UV damage repair, and genomic expression of Beauveria bassiana.

The E2 ubiquitin conjugator Rad6 is required for DNA damage bypass in budding yeast but remain functionally unknown in filamentous fungi. Here, we report pleiotropic effect of Rad6 ortholog in Beauveria bassiana, a wide-spectrum fungal insecticide. Global ubiquitination signal was greatly attenuated in the absence of rad6. The blocked ubiquitination led to severe growth defect, blocked asexual development, and abolished infectivity/insect pathogenicity, which correlated with compromised conidial quality (including viability, hydrophobicity, adherence to insect cuticle, and thermotolerance) and blocked secretion of cuticle-degrading enzymes including Pr1 family proteases. Importantly, Rad6 played much greater role in photoreactivation of UVB-impaired conidia by a 3- or 5-h light plus 9- or 7-h dark incubation than in dark reactivation of those impaired conidia by a 12-h dark incubation. The high activity of Rad6 in photoreactivation in vivo was derived from its link to a protein complex cored by the photolyase regulators WC1 and WC2 via the strong interactions of Rad6 with the E3 partner Rad18 and Rad18 with WC2 revealed in yeast two-hybrid assays. Transcriptomic analysis resulted in identification of 2700 differentially regulated genes involved in various function categories and metabolism pathways, indicating a regulatory role of Rad6-mediated ubiquitination in gene expression networks and genomic stability. Conclusively, Rad6 is required for asexual and insect-pathogenic lifecycles, solar UV damage repair, and genomic expression of B. bassiana. The primary dependence of its strong anti-UV role on photoreactivation in vivo unveils a scenario distinct from the core role of its yeast ortholog in DNA damage bypass.

High photoreactivation activities of Rad2 and Rad14 in recovering insecticidal Beauveria bassiana from solar UV damage.

Anti-ultraviolet (UV) roles of Rad2 and Rad14 depend on nucleotide excision repair (NER) of UV-induced DNA lesions in budding yeast but remain unexplored yet in filamentous fungi. Here, nucleus-specific Rad2 and Rad14 orthologs are shown to recover Beauveria bassiana, a main source of wide-spectrum mycoinsecticides, from solar UV damage through photorepair-depending photoreactivation. As a photorepair index, photoreactivation (germination) rates of lethal UVB dose-irradiated conidia via a 3- or 5-h light plus 9- or 7-h dark incubation at 25 °C were drastically reduced in the Δrad2 and Δrad14 mutants versus a wild-type strain. As an NER index, nighttime-mimicking 12-h dark reactivation rates of low UVB dose-impaired conidia decreased sharply compared to the corresponding photoreactivation rates in the presence or absence of either ortholog, indicating that its extant NER activity was limited to recovering light UVB damage in the field. The high photoreactivation activity of either Rad2 or Rad14 was derived from its tight link to a large protein complex formed by photolyase regulators and other anti-UV proteins through multiple protein-protein interactions revealed by yeast two-hybrid assays. Therefore, Rad2 and Rad14 recover B. bassiana from solar UV damage through photoreactiovation in vivo that depends primarily on photorepair, although they contribute little to the fungal lifecycle-related phenotypes. These findings unveil a novel scenario distinguished from the NER-depending anti-UV roles of Rad2 and Rad14 in the model yeast and broaden a biological basis crucial for rational application of fungal insecticides to improve pest control efficacy via feasible recovery of solar UV damage.

Celastrol inhibits angiogenesis and the biological processes of MDA-MB-231 cells via the DEGS1/S1P signaling pathway.

Celastrol (Cel) shows potent antitumor activity in various experimental models. This study examined the relationship between Cel's antivascular and antitumor effects and sphingolipids. CCK-8 assay, transwell assay, Matrigel, PCR-array/RT-PCR/western blotting/immunohistochemistry assay, ELISA and HE staining were used to detect cell proliferation, migration and invasion, adhesion and angiogenesis, mRNA and protein expression, S1P production and tumor morphology. The results showed that Cel could inhibit proliferation, migration or invasion, adhesion and angiogenesis of human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 cells by downregulating the expression of degenerative spermatocyte homolog 1 (DEGS1). Transfection experiments showed that downregulation of DEGS1 inhibited the above processes and sphingosine-1-phosphate (S1P) production of HUVECs and MDA-MB-231 cells, while upregulation of DEGS1 had the opposite effects. Coculture experiments showed that HUVECs could promote proliferation, migration and invasion of MDA-MB-231 cells through S1P/sphingosine-1-phosphate receptor (S1PR) signaling pathway, while Cel inhibited these processes in MDA-MB-231 cells induced by HUVECs. Animal experiments showed that Cel could inhibit tumor growth in nude mice. Western blotting, immunohistochemistry and ELISA assay showed that Cel downregulated the expression of DEGS1, CD146, S1PR1-3 and S1P production. These data confirm that DEGS1/S1P signaling pathway may be related to the antivascular and antitumor effects of cel.

Protective effect of Amauroderma rugosum ethanol extract and its primary bioactive compound, ergosterol, against acute gastric ulcers based on LXR-mediated gastric mucus secretions.

BACKGROUND: Amauroderma rugosum (Blume & T. Nees) Torrend (Ganodermataceae) is an edible mushroom with a wide range of medicinal values. Our previous publication demonstrated the therapeutic effects of the water extract of A. rugosum (WEA) against gastric ulcers. However, the protective effects of the ethanol extract of A. rugosum (EEA) on gastric mucosa and its major active constituents have not yet been elucidated. PURPOSE: This study aims to evaluate the gastroprotective effects and underlying mechanisms of EEA and its fat-soluble constituent, ergosterol, in acute gastric ulcers. STUDY DESIGN AND METHOD: SD rats were pre-treated with EEA (50, 100, and 200 mg/kg) or ergosterol (5, 10, and 20 mg/kg), and acute gastric ulcer models were constructed using ethanol, gastric mucus secretion inhibitor (indomethacin) or pyloric-ligation. The gastric ulcer area, histological structure alterations (H&E staining), and mucus secretion (AB-PAS staining) were recorded. Additionally, Q-PCR, western blotting, immunohistochemistry, ELISA, molecular docking, molecular dynamics simulations, MM-GBSA analysis, and surface plasmon resonance assay (SPR) were used to investigate the underlying mechanisms of the gastroprotective effect. RESULT: Compared with WEA, which primarily exerts its anti-ulcer effects by inhibiting inflammation, EEA containing fat-soluble molecules showed more potent gastroprotective effect through the promotion of gastric mucus secretion, as the anti-ulcer activity was partly blocked by indomethacin. Meanwhile, EEA exhibited anti-inflammatory effects by suppressing the production of IL-6, IL-1ß, TNF-α, and NO, thereby inhibiting the MAPK pathway. Significantly, ergosterol (20 mg/kg), the bioactive water-insoluble compound in EEA, exhibited a gastroprotective effect comparable to that of lansoprazole (30 mg/kg). The promotion of gastric mucus secretion contributed to the effects of ergosterol, as indomethacin can completely block it. The upregulations of COX1-PGE2 and C-fos, an activator protein 1 (AP-1) transcription factor, were observed after the ergosterol treatment. Ergosterol acted as an LXRß agonist via van der Waals binding and stabilizing the LXRß protein without compromising its flexibility, thereby inducing the upregulation of AP-1 and COX-1. CONCLUSION: EEA and its primary bioactive compound, ergosterol, exert anti-ulcer effects by promoting gastric mucus secretion through the LXRß/C-fos/COX-1/PGE2 pathway.

A Chinese longitudinal maternity cohort study (2013-2021) on intrahepatic cholestasis phenotypes: Risk associations from environmental exposure to adverse pregnancy outcomes.

Intrahepatic cholestasis of pregnancy (ICP) is an idiopathic disease that occurs during mid-to-late pregnancy and is associated with various adverse pregnancy outcomes, including intrauterine fetal demise. However, since the underlying cause of ICP remains unclear, there is an ongoing debate on the phenotyping criteria used in the diagnostic process. Here, we identified single- and multi-symptomatic ICP (ICP-S and ICP-M) in 104,221 Chinese females from the ZEBRA maternity cohort, with the objective of exploring the risk implications of the two phenotypes on pregnancy outcomes and from environmental exposures. We employed multivariate binary logistic regression to estimate confounder-adjusted odds ratios and found that ICP-M was more strongly associated with preterm birth and low birth weight compared to ICP-S. Throughout pregnancy, incremental exposure to PM2.5, O3, and greenness could alter ICP risks by 17.3%, 12.5%, and -2.3%, respectively, with more substantial associations observed with ICP-M than with ICP-S. The major scientific advancements lie in the elucidation of synergistic risk interactions between pollutants and the protective antagonistic effects of greenness, as well as highlighting the risk impact of preconceptional environmental exposures. Our study, conducted in the context of the "three-child policy" in China, provides epidemiological evidence for policy-making to safeguard maternal and neonatal health.