Loss of PTPRS elicits potent metastatic capability and resistance to temozolomide in glioblastoma.

Glioblastoma (GBM) is the most aggressive brain tumor type with worse clinical outcome due to the hallmarks of strong invasiveness, high rate of recurrence, and therapeutic resistance to temozolomide (TMZ), the first-line drug for GBM, representing a major challenge for successful GBM therapeutics. Understanding the underlying mechanisms that drive GBM progression will shed novel insight into therapeutic strategies. Receptor-type tyrosine-protein phosphatase S (PTPRS) is a frequently mutated gene in human cancers, including GBM. Its role in GBM has not yet been clarified. Here, inactivating PTPRS mutation or deficiency was frequently found in GBM, and deficiency in PTPRS significantly induced defects in the G2M checkpoint and limited GBM cells proliferation, leading to potent resistance to TMZ treatment in vitro and in vivo. Surprisingly, loss of PTPRS triggered an unexpected mesenchymal phenotype that markedly enhances the migratory capabilities of GBM cells through upregulating numerous matrix metalloproteinases via MAPK-MEK-ERK signaling. Therefore, this work provides a therapeutic window for precisely excluding PTPRS-mutated patients who do not respond to TMZ.

The XPO1 inhibitor selinexor ameliorates bleomycin-induced pulmonary fibrosis in mice via GBP5/NLRP3 inflammasome signaling.

Pulmonary fibrosis is an irreversible and progressive lung disease with limited treatments available. Selinexor (Sel), an orally available, small-molecule, selective inhibitor of XPO1, exhibits notable antitumor, anti-inflammatory and antiviral activities. However, its potential role in treating pulmonary fibrosis is unknown. C57BL/6J mice were used to establish a pulmonary fibrosis model by intratracheal administration of bleomycin (BLM). Subsequently, Sel was administered intraperitoneally. Our data demonstrated that Sel administration ameliorated BLM-induced pulmonary fibrosis by increasing mouse body weights; reducing H&E staining, Masson staining scores, and shadows in mouse lung computed tomography (CT) images, decreasing the total cell and neutrophil counts in the lung and bronchoalveolar lavage fluid (BALF); and decreasing the levels of TGF-ß1. We next confirmed that Sel reduced the deposition of extracellular matrix (ECM) components in the lungs of BLM-induced pulmonary fibrosis mice. We showed that collagen I, alpha-smooth muscle actin (α-SMA), and hydroxyproline levels and the mRNA levels of Col1a1, Eln, Fn1, Ctgf, and Fgf2 were reduced. Mechanistically, tandem mass tags (TMT)- based quantitative proteomics analysis revealed a significant increase in GBP5 in the lungs of BLM mice but a decrease in that of BLM + Sel mice; this phenomenon was confirmed by western blotting and RT-qPCR. NLRP3 inflammasome signaling was significantly enriched in both the BLM group and BLM + Sel group based on GO and KEGG analyses of differentially expressed proteins between the groups. Furthermore, Sel reduced the expression of NLRP3, cleaved caspase 1, and ASC in vivo and in vitro, and decreased the levels of IL-1ß, IL-18, and IFN-r in lung tissue and BALF. SiRNA-GBP5 inhibited NLRP3 signaling in vitro, and overexpression of GBP5 inhibited the protective effect of Sel against BLM-induced cellular injury. Taken together, our findings indicate that Sel ameliorates BLM-induced pulmonary fibrosis by targeting GBP5 via NLRP3 inflammasome signaling. Thus, the XPO1 inhibitor - Sel might be a potential therapeutic agent for pulmonary fibrosis.

Prognostic and immunological roles of heat shock protein A4 in lung adenocarcinoma.

BACKGROUND: Heat shock protein A4 (HSPA4) belongs to molecular chaperone protein family which plays important roles within variable cellular activities, including cancer initiation and progression. However, the prognostic and immunological significance of HSPA4 in lung adenocarcinoma (LUAD) has not been revealed yet. AIM: To explore the prognostic and immunological roles of HSPA4 to identify a novel prognostic biomarker and therapeutic target for LUAD. METHODS: We assessed the prognostic and immunological significance of HSPA4 in LUAD using data from The Cancer Genome Atlas database. The association between HSPA4 expression and clinical-pathological features was assessed through Kruskal-Wallis and Wilcoxon signed-rank test. Univariate/multivariate Cox regression analyses and Kaplan-Meier curves were employed to evaluate prognostic factors, including HSPA4, in LUAD. Gene set enrichment analysis (GSEA) was conducted to identify the key signaling pathways associated with HSPA4. The correlation between HSPA4 expression and cancer immune infiltration was evaluated using single-sample gene set enrichment analysis (ssGSEA). RESULTS: Overexpressing HSPA4 was significantly related to advanced pathologic TNM stage, advanced pathologic stage, progression disease status of primary therapy outcome and female subgroups with LUAD. In addition, increased HSPA4 expression was found to be related to worse disease-specific survival and overall survival. GSEA analysis indicated a significant correlation between HSPA4 and cell cycle regulation and immune response, particularly through diminishing the function of cytotoxicity cells and CD8 T cells. The ssGSEA algorithm showed a positive correlation between HSPA4 expression and infiltrating levels of Th2 cells, while a negative correlation was observed with cytotoxic cell infiltration levels. CONCLUSION: Our findings indicate HSPA4 is related to prognosis and immune cell infiltrates and may act as a novel prognostic biomarker and therapeutic target for LUAD.

Optimal dynamic pricing for public transportation considering consumer social learning.

Effective public transportation pricing strategies are critical to reducing traffic congestion and meeting consumer demand for sustainable urban development. In this study, we construct a dynamic game pricing model and a social learning network model for consumers of three modes of public transportation including metro, bus, and pa-transit. In the model, the metro, bus, and pa-transit operators maximize their profits through dynamic pricing optimization, and consumers maximize their utility by adjusting their travel habits through social learning in the social network. The reinforcement learning algorithm is applied to simulate the model, and the results show that: (1) as consumers' perceived sensitivity to different modes of travel increases, the market share and price of each mode of travel adjust accordingly. (2) When taking into account consumers' social learning behavior, the market share of metros remains high, while the market shares of buses and pa-transit are relatively low. (3) As consumers become more sensitive to their perception of each travel mode, operators invest more resources in improving service quality to gain market share, which in turn affects the price of each travel mode. Our results provide decision support for optimal pricing of urban public transportation.

Computational simulation-assisted design and experimental verification of molecularly imprinted polymers for selective extraction of chlorogenic acid.

Chlorogenic acid (CGA) is an active ingredient in honeysuckle with a broad-spectrum of antibacterial activity, suppressing tumor growth and other pharmacological effects. However, it is susceptible to damage during traditional extraction and separation processes. Therefore, developing selective and efficient extraction methods of CGA is essential. Based on computational molecular simulations, a reliable and efficient molecularly imprinted polymers (MIPs) were successfully developed for selective extraction of CGA. MIPs and non-molecularly imprinted polymers (NIPs) were synthesized using a precipitation polymerization method, employing three different functional monomers: [methacrylic acid (MAA), 4-vinylpyridine (4-VP), and methyl methacrylate (MMA)], with CGA serving as the template molecule. To simulate the polymers and predict the optimal ratio between the template and functional monomer, the computational studies and adsorption performance experiments were carried out. The adsorption characteristics and thermal stability of polymers were evaluated by isothermal adsorption, adsorption kinetics, selective adsorption and thermogravimetric analysis, aiming to obtain the MIPs with specific recognition and selectivity for CGA. When the molar ratio of template CGA to functional monomer 4-VP was 1:8, the prepared MIPs was found to have the maximum adsorption capacity (14.85 mg g-1) and the highest imprinting factor (1.74) at the CGA concentration of 100 mg L-1. These results were consistent with those obtained by computational molecular simulation. This study not only provides good guidance for developing separation materials for extracting CGA from natural plants but also inspires the application of computer simulation and molecular docking techniques in the preparation of specific MIPs materials.

Calcinosis universalis accompanied by symptomatic systemic sclerosis.

Calcinosis cutis is represented by the deposition of insoluble calcium salts in the skin and subcutaneous tissue. Calcinosis can lead to repeated episodes of local inflammation and repeated infections, resulting in pain and functional disability, and even death. Here, we present a case of a patient with SSc who experienced calcinosis universalis and eventually died from recurrent infections at the sacrococcygeal calcification.

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives.

Ischemic stroke (IS) poses a significant threat to global human health and life. In recent decades, we have witnessed unprecedented progresses against IS, including thrombolysis, thrombectomy, and a few medicines that can assist in reopening the blocked brain vessels or serve as standalone treatments for patients who are not eligible for thrombolysis/thrombectomy therapies. However, the narrow time windows of thrombolysis/thrombectomy, coupled with the risk of hemorrhagic transformation, as well as the lack of highly effective and safe medications, continue to present big challenges in the acute treatment and long-term recovery of IS. In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. Regretfully, there is no comprehensive overview to summarize all categories of anti-IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology. From medicinal chemistry view of point, this article reviews a multitude of anti-IS drugs/agents, including small molecule compounds, natural products, peptides, and others, which have been developed based on the molecular mechanism of IS pathophysiology, such as excitotoxicity, oxidative/nitrosative stresses, cell death pathways, and neuroinflammation, and so forth. In addition, several emerging medicines and strategies, including nanomedicines, stem cell therapy and noncoding RNAs, which recently appeared for the treatment of IS, are shortly introduced. Finally, the perspectives on the associated challenges and future directions of anti-IS drugs/agents are briefly provided to move the field forward.

ATAT1 deficiency enhances microglia/macrophage-mediated erythrophagocytosis and hematoma absorption following intracerebral hemorrhage.

MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage. Dynamic cytoskeletal changes accompany phagocytosis. However, whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear. In this study, we investigated the function of acetylated α-tubulin, a stabilized microtubule form, in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo. We first assessed the function of acetylated α-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines. Acetylated α-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis. Moreover, silencing α-tubulin acetyltransferase 1 (ATAT1), a newly discovered α-tubulin acetyltransferase, decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells. Consistent with these findings, in ATAT1-/- mice, we observed increased ionized calcium binding adapter molecule 1 (Iba1) and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage. Additionally, knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma, ultimately improving neurological recovery of mice after intracerebral hemorrhage. These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage. These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.

Development of Integrated Bioorthogonal Self-Catalyzed NO Donor/Platinum(IV) Prodrugs for Synergistical Intervention against Triple-Negative Breast Cancer.

The platinum(IV) prodrug strategy is attractive for the synergistic antitumor effect. High levels (>400 nM) of nitric oxide (NO) exert promising cancer inhibition effects via multiple mechanisms. Herein, we designed and synthesized a new group of integrated bioorthogonal self-catalyzed NO donor/Pt(IV) prodrugs bearing long alkyl chains to enhance the stability in circulation, while the cytoplasmic reductants trigger cascade activation to release Pt and NO in tumor cells. Specifically, compound 10c exhibited an improved stability, favorable pharmacokinetic properties (AUC(0-t) of 2210.10 h*ng/mL), potent anti-triple-negative breast cancer (TNBC) effects (71.08% tumor growth inhibition (TGI) against the MDA-MB-231 xenograft model), potent in vivo anti-TNBC lung metastasis activity, and acceptable low toxicity. Importantly, NO released from 10c leads to the S-nitrosation of metal transporters Atox1&ATP7a in TNBC cells, which increases the Pt retention and inhibits lysyl oxidase, generating synergistic tumoricidal and antimetastatic activity. These results may inspire further study on the synergistical therapy of Pt and NO for the treatment of TNBC.

Short-term transplantation effect of a tissue-engineered meniscus constructed using drilled allogeneic acellular meniscus and BMSCs.

During the construction of tissue-engineered meniscus, the low porosity of extracellular matrix restricts the flow of nutrient solution and the migration and proliferation of cells, thus affecting the tissue remodeling after transplantation. In this study, the canine allogeneic meniscus was drilled first and then decellularized. The drilled tissue-engineered menisci (Drilled Allogeneic Acellular Meniscus + Bone Marrow Mesenchymal Stem Cells, BMSCs) were transplanted into the knee joints of model dogs. On the basis of ensuring the mechanical properties, the number of the porosity and the cells implanted in allogeneic acellular meniscus was significantly increased. The expression levels of glycosaminoglycans and type II collagen in the drilled tissue-engineered meniscus were also improved. It was determined that the animals in the experimental group recovered well-compared with those in the control group. The graft surface was covered with new cartilage, the retraction degree was small, and the tissue remodeling was good. The surface wear of the femoral condyle and tibial plateau cartilage was light. The results of this study showed that increasing the porosity of allogeneic meniscus by drilling could not only maintain the mechanical properties of the meniscus and increase the number of implanted cells but also promote cell proliferation and differentiation. After transplantation, the drilled tissue-engineered meniscus provided a good remodeling effect in vivo and played a positive role in repairing meniscal injury, protecting articular cartilage and restoring knee joint function.

1,3-Substituted ß-Carboline Derivatives as Potent Chemotherapy for the Treatment of Cystic Echinococcosis.

Echinococcosis is a global public health issue that generally occurs in areas with developed animal husbandry. In search of safe and effective therapeutic agents against echinococcosis, we designed and synthesized new 1,3-substituted ß-carboline derivatives based on harmine. Among them, compounds 1a, 1c, and 1e displayed potent inhibitory activity against Echinococcus granulosus in vitro, significantly better than albendazole and harmine. The morphological detection revealed that 1a, 1c, and 1e significantly changed the ultrastructure of Echinococcus granulosus protoscolices (PSCs). Furthermore, pharmacokinetic studies suggested that 1a possessed a better metabolic property. Encouragingly, 1a exhibited a highest cyst inhibition rate as 76.8% in vivo and did not display neurotoxicity in mice. Further mechanistic research illustrated that 1a has the potential to induce autophagy in PSCs, which may be responsible for the therapeutic effect of the drugs. Together, 1a could be a promising therapeutic agent against echinococcosis, warranting further study.

Advances in nitric oxide regulators for the treatment of ischemic stroke.

Ischemic stroke (IS) is a life-threatening disease worldwide. Nitric oxide (NO) derived from l-arginine catalyzed by NO synthase (NOS) is closely associated with IS. Three isomers of NOS (nNOS, eNOS and iNOS) produce different concentrations of NO, resulting in quite unlike effects during IS. Of them, n/iNOSs generate high levels of NO, detrimental to brain by causing nerve cell apoptosis and/or necrosis, whereas eNOS releases small amounts of NO, beneficial to the brain via increasing cerebral blood flow and improving nerve function. As a result, a large variety of NO regulators (NO donors or n/iNOS inhibitors) have been developed for fighting IS. Regrettably, up to now, no review systematically introduces the progresses in this area. This article first outlines dynamic variation rule of NOS/NO in IS, subsequently highlights advances in NO regulators against IS, and finally presents perspectives based on concentration-, site- and timing-effects of NO production to promote this field forward.

Two-step phase manipulation by tailoring chemical bonds results in high-performance GeSe thermoelectrics.

In thermoelectrics, phase engineering serves a crucial function in determining the power factor by affecting the band degeneracy. However, for low-symmetry compounds, the mainstream one-step phase manipulation strategy, depending solely on the valley or orbital degeneracy, is inadequate to attain a high density-of-states effective mass and exceptional zT. Here, we employ a distinctive two-step phase manipulation strategy through stepwise tailoring chemical bonds in GeSe. Initially, we amplify the valley degeneracy via CdTe alloying, which elevates the crystal symmetry from a covalently bonded orthorhombic to a metavalently bonded rhombohedral phase by significantly suppressing the Peierls distortion. Subsequently, we incorporate Pb to trigger the convergence of multivalence bands and further enhance the density-of-states effective mass by moderately restraining the Peierls distortion. Additionally, the atypical metavalent bonding in rhombohedral GeSe enables a high Ge vacancy concentration and a small band effective mass, leading to increased carrier concentration and mobility. This weak chemical bond along with strong lattice anharmonicity also reduces lattice thermal conductivity. Consequently, this unique property ensemble contributes to an outstanding zT of 0.9 at 773 K for Ge0.80Pb0.20Se(CdTe)0.25. This work underscores the pivotal role of the two-step phase manipulation by stepwise tailoring of chemical bonds in improving the thermoelectric performance of p-bonded chalcogenides.

Metabolic regulation of forkhead box P3 alternative splicing isoforms and their impact on health and disease.

Forkhead Box P3 (FOXP3) is crucial for the development and suppressive function of human regulatory T cells (Tregs). There are two predominant FOXP3 splicing isoforms in healthy humans, the full-length isoform and the isoform lacking exon 2, with different functions and regulation mechanisms. FOXP3 splicing isoforms show distinct abilities in the cofactor interaction and the nuclear translocation, resulting in different effects on the differentiation, cytokine secretion, suppressive function, linage stability, and environmental adaptation of Tregs. The balance of FOXP3 splicing isoforms is related to autoimmune diseases, inflammatory diseases, and cancers. In response to environmental challenges, FOXP3 transcription and splicing can be finely regulated by T cell antigen receptor stimulation, glycolysis, fatty acid oxidation, and reactive oxygen species, with various signaling pathways involved. Strategies targeting energy metabolism and FOXP3 splicing isoforms in Tregs may provide potential new approaches for the treatment of autoimmune diseases, inflammatory diseases, and cancers. In this review, we summarize recent discoveries about the FOXP3 splicing isoforms and address the metabolic regulation and specific functions of FOXP3 splicing isoforms in Tregs.

Novel Nitric Oxide Donor-Azole Conjugation Strategy for Efficient Treatment of Cryptococcus neoformans Infections.

Invasive fungal infections (IFIs) such as cryptococcal meningitis (CM) remain a serious health issue worldwide due to drug resistance closely related to biofilm formation. Unfortunately, available antifungal drugs with ideal safety and promising potency are still lacking; thus, the research of new candidate and therapeutic approach is urgently needed. As an important gas messenger molecule, nitric oxide (NO) shows vital inhibition on various microorganism biofilms. Hence, three series of novel NO-donating azole derivatives were designed and synthesized, and the in vitro antifungal activity as well as the mechanism of action was investigated. Among them, 3a and 3e displayed excellent antifungal activity against Cryptococcus neoformans and biofilm depending on the release of NO. Moreover, a more stable analogue 3h of 3a demonstrated markedly anti-CM effects via intranasal dropping, avoiding the first-pass effects and possessing a better brain permeability bypass blood-brain barrier. These results present a promising antifungal candidate and intranasal dropping approach for the treatment of CM, warranting further studies.

SARS-COV-2 protein NSP9 promotes cytokine production by targeting TBK1.

SARS-COV-2 infection-induced excessive or uncontrolled cytokine storm may cause injury of host tissue or even death. However, the mechanism by which SARS-COV-2 causes the cytokine storm is unknown. Here, we demonstrated that SARS-COV-2 protein NSP9 promoted cytokine production by interacting with and activating TANK-binding kinase-1 (TBK1). With an rVSV-NSP9 virus infection model, we discovered that an NSP9-induced cytokine storm exacerbated tissue damage and death in mice. Mechanistically, NSP9 promoted the K63-linked ubiquitination and phosphorylation of TBK1, which induced the activation and translocation of IRF3, thereby increasing downstream cytokine production. Moreover, the E3 ubiquitin ligase Midline 1 (MID1) facilitated the K48-linked ubiquitination and degradation of NSP9, whereas virus infection inhibited the interaction between MID1 and NSP9, thereby inhibiting NSP9 degradation. Additionally, we identified Lys59 of NSP9 as a critical ubiquitin site involved in the degradation. These findings elucidate a previously unknown mechanism by which a SARS-COV-2 protein promotes cytokine storm and identifies a novel target for COVID-19 treatment.

Simultaneous Detection of Two Extracellular Vesicle Subpopulations in Saliva Assisting Tumor T Staging of Oral Squamous Cell Carcinoma.

Extracellular vesicles (EVs), acting as important mediators of intercellular communication, play an essential role in physiological processes, which have unique potential in the medical field. However, the heterogeneity of EVs limits their development for disease diagnosis and therapy, making the EV subpopulation analysis extremely valuable. In this article, a simple microfluidic approach was presented for the on-chip specific isolation and detection of two phenotypes of EVs (Annexin V+ EGFR+ EVs and Annexin V- EGFR+ EVs) based on different biomolecule-modified magnetic nanospheres and a fluorescence labeling technique. Combined with the control of the magnetic field in the microzone and fluid flow, it was easy to form two separate functional regions in the chip to capture different EV subpopulations. This method was successfully applied to the tests of clinical saliva samples in 75 oral squamous cell carcinoma (OSCC) patients and 10 healthy people. The results showed that the total level of EGFR+ EVs was much higher in OSCC patients that in healthy people. Meantime, the ratio of Annexin V+ EGFR+ EVs to Annexin V- EGFR+ EVs was found to be negatively correlated with tumor T stage of OSCC patients with a statistical difference, which suggested the ratio as a clinical index for monitoring the progression of OSCC in real time based on a noninvasive method. The approach provided a novel idea for evaluating the tumor T stage of OSCC and a powerful tool for clinical application.