In situ growth of iron incorporated Ni3S2 nanosheet on nickel foam in mediating electron transfer to peroxymonosulfate for pollutant abatement.

Catalytic oxidation of organic pollutants is a well-known and effective technique for pollutant abatement. Unfortunately, this method is significantly hindered in practical applications by the low efficiency and difficult recovery of the catalysts in a powdery form. Herein, a three-dimensional (3D) framework of Fe-incorporated Ni3S2 nanosheets in-situ grown on Ni foam (Fe-Ni3S2@NF) was fabricated by a facile two-step hydrothermal process and applied to trigger peroxymonosulfate (PMS) oxidation of organic compounds in water. A homogeneous growth environment enabled the uniform and scalable growth of Fe-Ni3S2 nanosheets on the Ni foam. Fe-Ni3S2@NF possessed outstanding activity and durability in activating PMS, as it effectively facilitated electron transfer from organic pollutants to PMS. Fe-Ni3S2@NF initially supplied electrons to PMS, causing the catalyst to undergo oxidation, and subsequently accepted electrons from organic compounds, returning to its initial state. The introduction of Fe into the Ni3S2 lattice enhanced electrical conductivity, promoting mediated electron transfer between PMS and organic compounds. The 3D conductive Ni foam provided an ideal platform for the nucleation and growth of Fe-Ni3S2, accelerating pollutant abatement due to its porous structure and high conductivity. Furthermore, its monolithic nature simplified the catalyst recycling process. A continuous flow packed-bed reactor by encapsulating Fe-Ni3S2@NF catalyst achieved complete pollutant abatement with continuous operation for 240 h, highlighting its immense potential for practical environmental remediation. This study presents a facile synthesis method for creating a novel type of monolithic catalyst with high activity and durability for decontamination through Fenton-like processes.

Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive. AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms. MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L = 5.46 mg/ml, SSP-M = 10.92 mg/ml or SSP-H = 16.38 mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin & Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1G93A NSC-34 cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway. RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1ß mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-ß mRNA, but also the levels of cGAS and STING protein in hSOD1G93A NSC-34 cells. CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.

Shuangdan Jiedu Decoction improved LPS-induced acute lung injury by regulating both cGAS-STING pathway and inflammasome.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuangdan Jiedu Decoction (SJD) is a formula composed of six Chinese herbs with heat-removing and detoxifying, antibacterial, and anti-inflammatory effects, which is clinically used in the therapy of various inflammatory diseases of the lungs including COVID-19, but the therapeutic material basis of its action as well as its molecular mechanism are still unclear. AIM OF THE STUDY: The study attempted to determine the therapeutic effect of SJD on LPS-induced acute lung injury (ALI), as well as to investigate its mechanism of action and assess its therapeutic potential for the cure of inflammation-related diseases in the clinical setting. MATERIALS AND METHODS: We established an ALI model by tracheal drip LPS, and after the administration of SJD, we collected the bronchoalveolar lavage fluid (BALF) and lung tissues of mice and examined the expression of inflammatory factors in them. In addition, we evaluated the effects of SJD on the cyclic guanosine monophosphate-adenosine monophosphate synthase -stimulator of interferon genes (cGAS-STING) and inflammasome by immunoblotting and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: We demonstrated that SJD was effective in alleviating LPS-induced ALI by suppressing the levels of pro-inflammatory cytokines in the BALF, improving the level of lung histopathology and the number of neutrophils, as well as decreasing the inflammatory factor-associated gene expression. Importantly, we found that SJD could inhibit multiple stimulus-driven activation of cGAS-STING and inflammasome. Further studies showed that the Chinese herbal medicines in SJD had no influence on the cGAS-STING pathway and inflammasome alone at the formulated dose. By increasing the concentration of these herbs, we observed inhibitory effects on the cGAS-STING pathway and inflammasome, and the effect exerted was maximal when the six herbs were combined, indicating that the synergistic effects among these herbs plays a crucial role in the anti-inflammatory effects of SJD. CONCLUSIONS: Our research demonstrated that SJD has a favorable protective effect against ALI, and its mechanism of effect may be associated with the synergistic effect exerted between six Chinese medicines to inhibit the cGAS-STING and inflammasome abnormal activation. These results are favorable for the wide application of SJD in the clinic as well as for the development of drugs for ALI from herbal formulas.

Naoxintong capsule accelerates mitophagy in cerebral ischemia-reperfusion injury via TP53/PINK1/PRKN pathway based on network pharmacology analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence and mortality of cerebrovascular diseases are increasing year by year. Cerebral ischemia-reperfusion injury (CIRI) is common in patients with ischemic stroke. Naoxintong (NXT) is composed of a variety of Chinese medicines and has the ability to treat CIRI. AIM OF THE STUDY: The aim of this study is to investigate whether NXT regulates mitophagy in CIRI based on network pharmacology analysis and experimental validation. MATERIALS AND METHODS: Oxygen and glucose deprivation/re-oxygenation (OGD/R, 2/22 h) model of PC12 cells and transient middle cerebral artery occlusion (tMCAO, 2/22 h) model of rats were established. Pharmacodynamic indicators include neurological deficit score, 2,3,5-triphenyte-trazoliumchloride (TTC) staining, hematoxylin-eosin (HE) staining and cell viability. Network pharmacology was used to predict pharmacological mechanisms. Pharmacological mechanism indexes include transmission electron microscopy (TEM), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), immunohistochemistry (IHC), western blot (WB) and immunofluorescence (IF). Kevetrin (an agonists of p53) and pifithrin-α (an inhibitor of p53) used to detect the key role of p53 in mitophagy of NXT. RESULTS: NXT (1% serum containing NXT and 110 mg/kg) improved the damage of OGD/R PC12 cells and tMCAO rats, and this protective effect was related to the anti-oxidation and ability to promote mitophagy of NXT. NXT and pifithrin-α increased the expression of promoting-mitophagy targets (PINK1, PRKN and LC3B) and inhibited the expression of inhibiting-mitophagy targets (p52) via restraining p53, and finally accelerated mitophagy caused by CIRI. CONCLUSION: This study demonstrates that NXT promotes mitophagy in CIRI through restraining p53 and promoting PINK1/PRKN in vivo and in vitro.

Syzygium cumini (L.) skeels mitigate diabetic nephropathy by regulating Nrf2 pathway and mitocyhondrial dysfunction: In vitro and in vivo studies.

ETHNOPHARMACOLOGICAL PREVALENCE: Hyperglycemia in diabetes increases the generation of advanced glycation end products (AGEs) through non-enzymatic reactions. The interaction between AGEs and their receptors (RAGE) leads to oxidative and inflammatory stress, which plays a pivotal role in developing diabetic nephropathy. Syzygium cumini (SC) L. (DC.) homeopathic preparations viz. 200C, 30C, and mother tincture [MT] are used to treat diabetes. This study aimed to elucidate the regulatory effects of SC preparations (200C, 30C, and MT) on the nuclear factor erythroid 2-related factor 2 (Nrf2) - nuclear factor-κB (NF-κB) pathways and mitochondrial dysfunction in mitigating diabetic nephropathy (DN). MATERIALS AND METHODS: Streptozotocin-induced diabetic rats were treated with SC preparations (200C, 30C, MT; 1:20 dilution in distilled water; 600 µL/kg body weight) and metformin (45 mg/kg body weight) twice daily for 40 days. DN was evaluated through biochemical parameters and histological examination. Renal tissue lysates were analyzed for glycation markers. Protein and gene levels of Nrf2, NF-κB, and mitochondrial dysfunctional signaling were determined via western blotting and RT-qPCR. An immunohistochemical analysis of the kidneys was performed. In vitro, human serum albumin (HSA - 10 mg/ml) was glycated with methylglyoxal (MGO - 55 mM) in the presence of SC preparations (200C, 30C, MT) for eight days. Glycated samples (400 µg/mL) were incubated with renal cells (HEK-293) for 24 h. Further reactive oxygen species production, Nrf2 nuclear translocation, and protein or gene expression of Nrf2 and apoptosis markers were analyzed by western blotting, RT-qPCR, and flow cytometry. Molecular docking of gallic and ellagic acid with the HSA-MGO complex was performed. RESULT: In vivo experiments using streptozotocin-induced diabetic rats treated with SC preparations exhibited improved biochemical parameters, preserved kidney function, and reduced glycation adduct formation in a dose-dependent manner. Furthermore, SC preparations downregulated inflammatory mediators such as RAGE, NF-κB, vascular endothelial growth factor (VEGF), and Tumor necrosis factor α (TNF-α) while upregulating the Nrf2-dependent antioxidant and detoxification pathways. They downregulated B-cell lymphoma 2 (Bcl-2) associated X-protein (BAX), C/EBP homologous protein (CHOP), Dynamin-related protein 1 (DRP1), and upregulated BCL 2 gene expression. Notably, SC preparations facilitated nuclear translocation of Nrf2, leading to the upregulation of antioxidant enzymes and the downregulation of oxidative stress markers. Molecular docking studies revealed favorable interactions between gallic (-5.26 kcal/mol) and ellagic acid (-4.71 kcal/mol) with the HSA-MGO complex. CONCLUSION: SC preparations mitigate renal cell apoptosis and mitochondrial dysfunction through Nrf2-dependent mechanisms.

Engineering mesoporous polydopamine-based potentiate STING pathway activation for advanced anti-biofilm therapy.

The biofilm-induced "relatively immune-compromised zone" creates an immunosuppressive microenvironment that is a significant contributor to refractory infections in orthopedic endophytes. Consequently, the manipulation of immune cells to co-inhibit or co-activate signaling represents a crucial strategy for the management of biofilm. This study reports the incorporation of Mn2+ into mesoporous dopamine nanoparticles (Mnp) containing the stimulator of interferon genes (STING) pathway activator cGAMP (Mncp), and outer wrapping by M1-like macrophage cell membrane (m-Mncp). The cell membrane enhances the material's targeting ability for biofilm, allowing it to accumulate locally at the infectious focus. Furthermore, m-Mncp mechanically disrupts the biofilm through photothermal therapy and induces antigen exposure through photodynamic therapy-generated reactive oxygen species (ROS). Importantly, the modulation of immunosuppression and immune activation results in the augmentation of antigen-presenting cells (APCs) and the commencement of antigen presentation, thereby inducing biofilm-specific humoral immunity and memory responses. Additionally, this approach effectively suppresses the activation of myeloid-derived suppressor cells (MDSCs) while simultaneously boosting the activity of T cells. Our study showcases the efficacy of utilizing m-Mncp immunotherapy in conjunction with photothermal and photodynamic therapy to effectively mitigate residual and recurrent infections following the extraction of infected implants. As such, this research presents a viable alternative to traditional antibiotic treatments for biofilm that are challenging to manage.

Bioactive nanocomposite hydrogel enhances postoperative immunotherapy and bone reconstruction for osteosarcoma treatment.

Osteosarcoma, a malignant bone tumor often characterized by high hedgehog signaling activity, residual tumor cells, and substantial bone defects, poses significant challenges to both treatment response and postsurgical recovery. Here, we developed a nanocomposite hydrogel for the sustained co-delivery of bioactive magnesium ions, anti-PD-L1 antibody (αPD-L1), and hedgehog pathway antagonist vismodegib, to eradicate residual tumor cells while promoting bone regeneration post-surgery. In a mouse model of tibia osteosarcoma, this hydrogel-mediated combination therapy led to remarkable tumor growth inhibition and hence increased animal survival by enhancing the activity of tumor-suppressed CD8+ T cells. Meanwhile, the implanted hydrogel improved the microenvironment of osteogenesis through long-term sustained release of Mg2+, facilitating bone defect repair by upregulating the expression of osteogenic genes. After 21 days, the expression levels of ALP, COL1, RUNX2, and BGLAP in the Vis-αPD-L1-Gel group were approximately 4.1, 5.1, 5.5, and 3.4 times higher than those of the control, respectively. We believe that this hydrogel-based combination therapy offers a potentially valuable strategy for treating osteosarcoma and addressing the tumor-related complex bone diseases.

Golden Gate Cloning for Efficient Biosynthesis of Lycopene in Synthetic Yeast.

Golden Gate Assembly (GGA) represents a versatile method for assembling multiple DNA fragments into a single molecule, which is widely used in rapid construction of complex expression cassettes for metabolic engineering. Here we describe the GGA method for facile construction and optimization of lycopene biosynthesis pathway by the combinatorial assembly of different transcriptional units (TUs). Furthermore, we report the method for characterizing and improving lycopene production in the synthetic yeast chassis.

T-2 toxin induces cardiac fibrosis by causing metabolic disorders and up-regulating Sirt3/FoxO3α/MnSOD signaling pathway-mediated oxidative stress.

T-2 toxin, an omnipresent environmental contaminant, poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity. This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin. Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0, 10, and 100 nanograms per gram body weight per day (ng/(g·day)), respectively. Morphological, pathological, and ultrastructural alterations in cardiac tissue were meticulously examined. Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites. The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected. The results showed that exposure to T-2 toxin elicited myocardial tissue disorders, interstitial hemorrhage, capillary dilation, and fibrotic damage. Mitochondria were markedly impaired, including swelling, fusion, matrix degradation, and membrane damage. Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiac metabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway. T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress. In conclusion, the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway. This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury.

4-Nitrophenol at environmentally relevant concentrations mediates reproductive toxicity in Caenorhabditis elegans via metabolic disorders-induced estrogen signaling pathway.

4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, ß-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.

Protein Kinase R (PKR) as a Novel dsRNA Sensor in Antiviral Innate Immunity.

Protein kinase R (PKR), a key double-stranded RNA (dsRNA)-activated sensor, is pivotal for cellular responses to diverse stimuli. This protocol delineates a comprehensive methodological framework employing single luciferase assays, yeast assays, immunoblot assays, and quantitative PCR (qPCR) to discern and validate PKR activities and their downstream impacts on NF-κB-activating signaling pathways. These methodologies furnish a systematic approach to unraveling the role of PKR as a dsRNA sensor and effector in antiviral innate immunity, enabling in-depth analyses of dsRNA sensor activities.

Predictors of the length of stay in psychiatric inpatient units: a retrospective study for the Paris Psychiatry Hospital Group.

Objective: Shortening the length of hospital stay (LOS) has become a major challenge for psychiatric hospitals in reducing unnecessary costs and improving the patient healthcare experience. We investigated the key factors associated with a long psychiatric hospitalization. Method: This was a retrospective study of 8,870 full-time psychiatric hospital stays (6,216 patients) in the Paris Psychiatry Hospital Group, with a discharge in 2022. We used machine learning tools and univariate and multivariate methods to explore the impact of demographic, pathway-related, and clinical variables on the LOS. Results: LOS >30 days was associated with age >55 years {odds ratio [OR] =2 [95% confidence interval 1.7-2.3]}, admission from outside the sectorization zone [OR=1.2 (1.1-1.3)], admission via a psychiatric emergency unit [OR, 1.2 (1.1-1.4)], and some clinical severity markers, such as psychotic disorder diagnosis [OR, 1.5 (1.3-1.7)], mandatory care [request of a third party, OR, 2.5 (2.1-2.9); case of imminent danger, OR, 2.3 (1.9-2.7)], the presence of seclusion and mechanical restraint measures (highlighting the positive effect of restraint duration), the somatic comorbidity for female sex [OR, 1.4 (1.2-1.7)], and treatment resistance [OR, 1.4 (1.2-1.6)]. Conversely, LOS ≤30 days was associated with being in a relationship [OR, 0.6 (0.5-0.8)], admission during a travel-related psychiatric episode [OR, 0.5 (0.3-0.6)], and personality and behavior disorders [OR, 0.7 (0.6-0.9)]. We found no significant association for features such as sex and a lack of treatment compliance. Conclusion: To our knowledge, this is the first recent study to investigate and highlight the impact of factors related to various illness severity markers, medication adherence, and patient journeys on the length of psychiatric hospital stay. A better understanding of long-stay risk factors might be helpful for optimizing the allocation of medical resources and anticipating tailored therapeutic programs.

Risk Factors in Serrated Pathway Lesions: N-Glycosylation Profile as a Potential Biomarker of Progression to Malignancy.

Introduction: The serrated pathway contributes to interval colorectal cancers, highlighting the need for new biomarkers to assess lesion progression risk. The ß1,6-GlcNAc branched N-glycans expression in CRC cells was associated with an invasive phenotype and with immune evasion. Therefore, this study aims to identify potential risk factors for progression of serrated lesions (SLs) to malignancy, analyzing the N-glycosylation profile of epithelial/infiltrating immune cells. Methods: A retrospective cohort study was performed with data from 53 colonoscopies (48 patients). Sixty-three serrated pathway lesions (SPLs) were characterized based on N-glycosylation profile (lectin histochemistry/flow cytometry) and MGAT5 expression. Statistical analysis was performed to search for associations between the glycoprofile and clinical variables from each patient. Results: Increased ß1,6-GlcNAc branched N-glycans expression in epithelial cells is found associated with age (p = 0.007 in SPL), smoking (p = 0.038 in SL), increased BMI (p = 0.036 in sessile serrated lesions [SSL]), and polyp dimensions ≥10 mm (p = 0.001 in SL), while increased expression of these structures on immune cells is associated with synchronous CA number (CD4+T cells: p = 0.016; CD8+T cells: p = 0.044 in SL) and female gender (p = 0.026 in SL). Moreover, a lower high-mannose N-glycans expression in immune cells is associated with smoking (p = 0.010 in SPL) and synchronous CA presence (p = 0.010 in SPL). Higher expression of these glycans is associated with female (p = 0.016 in SL) and male (p = 0.044 in SL) gender, left colon location (p = 0.028), dysplasia (p = 0.028), and adenocarcinoma (p = 0.010). Conclusions: We identified an association between an abnormal glycoprofile and several clinical risk factors, proposing the N-glycosylation profile as a potential biomarker of tumor progression in the serrated pathway. The N-glycosylation anatomopathological profile analysis could be further used to decide shorter interval follow-up in patients with SPL.

Introdução: A via serreada contribui para os cancros colorretais de intervalo, destacando a necessidade de novos biomarcadores para determinar o risco de progressão destas lesões. A expressão de ß1,6-GlcNAc N-glicanos ramificados foi associada a um fenótipo invasivo e a evasão imune. Assim, este estudo tem como objetivo identificar potenciais fatores de risco de progressão das lesões serreadas para malignidade, analisando o perfil de N-glicosilação das células epiteliais/células imunitárias. Métodos: Foi realizado um estudo retrospetivo com dados de 53 colonoscopias (48 doentes). 63 lesões da via serreada foram caracterizadas segundo o perfil de N-glicosilação (histoquímica de lectinas/citometria de fluxo) e expressão de MGAT5. A análise estatística foi realizada para encontrar associações entre o perfil de N-glicosilação e as variáveis clínicas de cada doente. Resultados: O aumento da expressão de ß1,6-GlcNAc N-glicanos ramificados nas células epiteliais encontra-se associado com a idade (p = 0.007 nas SPL), tabagismo (p = 0.038 nas SL), aumento do BMI (p = 0.036 nas SSL), e pólipos com dimensões ≥10 mm (p = 0.001 nas SL), enquanto que o aumento destas estruturas nas células imunitárias está associado com o número de CA síncronos (células TCD4+: p = 0.016; células TCD8+: p = 0.044 nas SL) e o género feminino (p = 0.026 nas SL). Além disso, uma diminuição da expressão de N-glicanos ricos em manose está associada ao tabagismo (p = 0.010 para SPL) e a presença de adenomas síncronos (p = 0.010 nas SPL). A expressão aumentada destas estruturas está associado com o género feminino (p = 0.016 nas SSL), género masculino (p = 0.044 nas SSL), localização no cólon esquerdo (p = 0.028), displasia (p = 0­028) e adenocarcinoma (p = 0.010). Discussão/Conclusão: Identificámos uma associação entre um perfil de glicosilação anormal e vários fatores de risco clínicos, propondo o perfil de N-glicosilação como um potencial biomarcador de progressão tumoral na via serreada. A análise anatomopatológica do perfil de N-glicosilação pode vir a ser usada para decidir intervalos de follow-up mais curtos em doentes com SPL.

Solubilization and enhanced degradation of benzene phenolic derivatives-Bisphenol A/Triclosan using a biosurfactant producing white rot fungus Hypocrea lixii S5 with plant growth promoting traits.

Introduction: Endocrine disrupting chemicals (EDCs) as benzene phenolic derivatives being hydrophobic partition to organic matter in sludge/soil sediments and show slow degradation rate owing to poor bioavailability to microbes. Methods: In the present study, the potential of a versatile white rot fungal isolate S5 identified as Hypocrea lixii was monitored to degrade bisphenol A (BPA)/triclosan (TCS) under shake flask conditions with concomitant production of lipopeptide biosurfactant (BS) and plant growth promotion. Results: Sufficient growth of WRF for 5 days before supplementation of 50 ppm EDC (BPA/TCS) in set B showed an increase in degradation rates by 23% and 29% with corresponding increase in secretion of lignin-modifying enzymes compared to set A wherein almost 84% and 97% inhibition in fungal growth was observed when BPA/TCS were added at time of fungal inoculation. Further in set B, EDC concentration stimulated expression of laccase and lignin peroxidase (Lip) with 24.44 U/L of laccase and 281.69 U/L of Lip in 100 ppm BPA and 344 U/L Lip in 50 ppm TCS supplemented medium compared to their respective controls (without EDC). Biodegradation was also found to be correlated with lowering of surface tension from 57.02 mN/m (uninoculated control) to 44.16 mN/m in case of BPA and 38.49 mN/m in TCS, indicative of biosurfactant (BS) production. FTIR, GC-MS, and LC-ESI/MSMS confirmed the presence of surfactin lipopeptide isoforms. The WRF also displayed positive plant growth promoting traits as production of ammonia, indole acetic acid, siderophores, Zn solubilization, and 1-1-aminocyclopropane-1-carboxylate (ACC) deaminase activity, reflecting its soil restoration ability. Discussion: The combined traits of biosurfactant production, EDC degradation and plant growth promotion displayed by WRF will help in emulsifying the hydrophobic pollutants favoring their fast degradation along with restoration of contaminated soil in natural conditions.

Endogenous histidine peptides are physiological antioxidants that prevent oligodendrocyte cell death and myelin loss in vivo.

Histidine dipeptides (HDs) are synthesized in brain oligodendrocytes by carnosine synthase (carns1), but their role is unknown. Using metabolomics and in vivo experiments with both constitutive and oligodendrocyte-selective carns1-KO mouse models, we found that HDs are critical for oligodendrocyte survival and protect against oxidative stress. Carns1-KO mouse models had lower numbers of mature oligodendrocytes, increased lipid peroxidation, and behavioral changes. Cuprizone administration, which increases reactive oxygen species in vivo, resulted in higher oligodendrocyte death, demyelination, axonal alterations, and oxidative damage in the corpus callosum of carns1-KO mice. Gliosis and oxidative damage by cuprizone were prevented by pretreatment with the antioxidant N-acetylcysteine. NADPH levels were increased threefold in the brains of carns1-KO mice as an antioxidant response to oxidative stress through acceleration of the pentose phosphate pathway (PPP). This was due to overexpression of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Likewise, expression of NAD kinase, the biosynthetic enzyme for NADP+, and NAMPT, which replenishes the NAD+ pool, was higher in carns1-KO mice brains than in controls. Our observations suggest that HDs cell-autonomously protect oligodendrocytes from oxidative stress, with implications for demyelinating diseases.

Soluble PD-L1 as a novel biomarker predicts poor outcomes and disease progression in de novo myelodysplastic syndromes.

The role of the compromised immune microenvironment, including immune checkpoints, in myelodysplastic syndromes (MDS) has been identified as critical This study aimed to investigate the expression patterns of immune checkpoints, particularly soluble PD-1/PD-L1 (sPD-1/sPD-L1) as well as PD-1 on effector T cell subsets, and assess their prognostic value and potential regulatory roles in MDS. 161 MDS patients were enrolled, including 129 patients were primarily diagnosed with de novo MDS, together with 59 MDS patients who underwent hypomethylating agents (HMAs) therapy. Plasma sPD-L1 level was elevated in newly diagnosed MDS patients, which was also found to be associated with MDS disease progression that further increase in higher IPSS-R score group. Patients with increased sPD-L1 expression at diagnosis exhibited notably poorer overall survival, and multivariate Cox analysis indicated that elevated sPD-L1 was an independent risk factor. Furthermore, the levels of multiple cytokines and membrane-bound PD-1 on T cells were found to correlate with sPD-1/sPD-L1 levels in plasma. Importantly, we also found sPD-L1 levels significantly increased in MDS patients who showed progression of disease following HMAs therapy. In conclusion, we found elevated plasma sPD-L1 levels in MDS patients are associated with disease progression and poorer overall survival. This study showed that sPD-L1 is a potential biomarker for prognosis and a target for immunotherapy in MDS.

SLAMF8 regulates osteogenesis and adipogenesis of bone marrow mesenchymal stem cells via S100A6/Wnt/ß-catenin signaling pathway.

BACKGROUND: The inflammatory microenvironment plays an essential role in bone healing after fracture. The signaling lymphocytic activation molecule family (SLAMF) members deeply participate in inflammatory response and make a vast difference. METHODS: We identified SLAMF8 in GEO datasets (GSE129165 and GSE176086) and co-expression analyses were performed to define the relationships between SLAMF8 and osteogenesis relative genes (RUNX2 and COL1A1). In vitro, we established SLAMF8 knockdown and overexpression mouse bone marrow mesenchymal stem cells (mBMSCs) lines. qPCR, Western blot, ALP staining, ARS staining, Oil Red O staining and Immunofluorescence analyses were performed to investigate the effect of SLAMF8 in mBMSCs osteogenesis and adipogenesis. In vivo, mice femoral fracture model was performed to explore the function of SLAMF8. RESULTS: SLAMF8 knockdown significantly suppressed the expression of osteogenesis relative genes (RUNX2, SP7 and COL1A1), ALP activity and mineral deposition, but increased the expression of adipogenesis relative genes (PPARγ and C/EBPα). Additionally, SLAMF8 overexpression had the opposite effects. The role SLAMF8 played in mBMSCs osteogenic and adipogenic differentiation were through S100A6 and Wnt/ß-Catenin signaling pathway. Moreover, SLAMF8 overexpression mBMSCs promoted the healing of femoral fracture. CONCLUSIONS: SLAMF8 promotes osteogenesis and inhibits adipogenesis of mBMSCs via S100A6 and Wnt/ß-Catenin signaling pathway. SLAMF8 overexpression mBMSCs effectively accelerate the healing of femoral fracture in mice.

Exploring the significance and potential mechanisms of hippo pathway-associated genes in prognosis of glioma patients.

PURPOSE: Despite the efforts of countless researchers to develop glioma treatment strategies, the current therapeutic effect of glioma is still not ideal, and it is necessary to further explore the mechanism to guide treatment. Thus, this study aims to introduce a novel approach for predicting patient prognosis and guiding further treatment interventions. METHODS: Initially, we conducted a differential gene expression analysis to identify Hippo pathway-associated genes overexpressed in tumors and determined genes correlated with prognosis. Subsequently, employing cluster analysis, we categorized samples into two groups and performed further analyses including prediction, immune cell infiltration abundance, and drug response rates. We utilized weighted gene co-expression analysis to reveal gene sets with high co-variation, delineate inter-sample gene correlation patterns, and conduct enrichment analysis. Prognostic models were built using ten machine learning algorithms combined in 101 different combinations, followed by evaluation and validation. Immune infiltration analysis, differential expression analysis of depleted T cell-related markers, drug sensitivity analysis, and exploration of pathway dysregulation were performed for different risk groups. Quality control and batch integration were performed, and single-cell data were analyzed using dimensionality reduction clustering algorithms and annotation tools to evaluate the activity of the prognostic model in malignant cells. RESULTS: We conducted data filtering to identify genes overexpressed in tumors, intersecting these genes with Hippo pathway-related genes, identifying 62 genes correlated with prognosis, and performing cluster analysis to divide tumor tissues into two groups. Cluster 2 exhibited a poorer prognosis and demonstrated differences in immune cell infiltration. Utilizing weighted gene co-expression analysis on Cluster 2, we identified gene modules, conducted functional enrichment analysis, and delineated pathways. Employing a combined model based on ten machine learning algorithm combinations, we selected the optimal prognostic model system and validated the model's predictive ability within the dataset. Through immune-related analysis and drug sensitivity analysis, we uncovered differences in immune infiltration and varying sensitivities to chemotherapy drugs. Additionally, the enrichment analysis of gene set revealed discrepancies in upregulation within relevant pathways between the high and low-risk groups. Finally, annotation and evaluation of malignant cells via single-cell analysis showed increased activity of the prognostic model and variations in distribution across different prognostic levels in malignant cells. CONCLUSION: This study introduces a novel approach utilizing the Hippo pathway and associated genes for glioma prognosis research, demonstrating the potential and significance of this method in evaluating the outcome for patients with glioma. These findings hold substantial clinical significance in guiding therapy and predicting outcomes for individuals diagnosed with glioma, offering significant clinical utility.

Acupuncture improves spatial learning and memory impairment caused by herpes simplex virus type-1 in rats through the p38 MAPK/CREB pathway.

BACKGROUND: Acupuncture can improve herpes simplex encephalitis (HSE), but the underlying mechanism is not clear. Therefore, we evaluated the cognitive function and apoptosis in hippocampus caused by herpes simplex virus type-1 (HSV-1) in rats after acupuncture and described the molecular mechanism. METHODS: Sprague-Dawley rats were induced into HSE models by HSV-1 infection. After 3 days, they received acupuncture at the acupoints of Xuanzhong (GB39), Baihui (GV20), Shenmen (HT7), Shenting (GV24), and Sanyinjiao (SP6), and/or intraperitoneal injection of the p38 MAPK inhibitor SB203580. Morris water maze test was performed on rats. The hippocampus of rats was obtained, and the expression of apoptosis-related genes in the tissues was detected by qRT-PCR. In addition, apoptosis-related proteins and proteins related to the p38 MAPK/CREB pathway in the tissues was detected by western blot. RESULTS: After HSV-1 induction, the rat's escape latency was increased, the time spent on the platform in the target quadrant and the number of platform crossings significantly decreased. In addition, there was an increase in apoptosis in the hippocampus, accompanied by elevated levels of p-p38 and decreased levels of p-CREB. However, these effects could be improved by acupuncture treatment. Interestingly, SB203580 plays a similar role to acupuncture, and acupuncture could further enhance the impacts of SB203580 on cognitive function and apoptosis in hippocampus in HSE rats. CONCLUSION: Acupuncture improves spatial learning and memory impairment caused by HSV-1 in rats. The functional mechanism of acupuncture may be through the p38 MAPK/CREB pathway.

Dihydroartemisinin suppresses the susceptibility of Anopheles stephensi to Plasmodium yoelii by activating the Toll signaling pathway.

BACKGROUND: Malaria is a serious public health concern. Artemisinin and its derivatives are first-line drugs for the treatment of Plasmodium falciparum malaria. In mammals, artemisinin exhibits potent anti-inflammatory and immunoregulatory properties. However, it is unclear whether artemisinin plays a regulatory role in the innate immunity of mosquitoes, thereby affecting the development of Plasmodium in Anopheles when artemisinin and its metabolites enter mosquitoes. This study aims to determine the effect of dihydroartemisinin (DHA), a first-generation semisynthetic derivative of artemisinin, on innate immunity and malaria vector competence of Anopheles stephensi. METHODS: Anopheles stephensi was fed Plasmodium-infected mice treated with DHA via gavage, Plasmodium-infected blood containing DHA in vitro, or DHA-containing sugar, followed by Plasmodium yoelii infection. The engorged female mosquitoes were separated and dissected 8 and 17 days after infection. Plasmodium oocysts and sporozoites were counted and compared between the control and DHA-treated groups. Additionally, total RNA and proteins were extracted from engorged mosquitoes 24 and 72 h post infection (hpi). Real-time polymerase chain reaction (PCR) and western blotting were performed to detect the transcriptional levels and protein expression of immune molecules in mosquitoes. Finally, the Toll signaling pathway was inhibited via RNA interference and the infection density was analyzed to confirm the role of the Toll signaling pathway in the effect of DHA on the vector competence of mosquitoes. RESULTS: DHA treatment via different approaches significantly reduced the number of Plasmodium oocysts and sporozoites in mosquitoes. The transcriptional levels of anti-Plasmodium immune genes (including TEP1, LRIM1, and APL1C), Toll pathway genes (including Tube, MyD88, and Rel1), and the effector defensin 1 were upregulated by DHA treatment at 24 and 72 hpi. TEP1 and Rel1 protein expression was significantly induced under DHA treatment. However, Rel1 knockdown in DHA-treated mosquitoes abrogated DHA-mediated refractoriness to Plasmodium infection. CONCLUSIONS: DHA treatment effectively inhibited the development of P. yoelii in A. stephensi by upregulating mosquitoes' Toll signaling pathway, thereby influencing the susceptibility of Anopheles to Plasmodium.