Terrace-Like 2D Hierarchically Porous Iron/Cobalt Metal-Organic Framework: Ambient Fast Synthesis and Efficient Oxygen Evolution Reaction Application.

It is urgent to design a low-cost electrocatalyst with high activity to enhance the efficiency of oxygen evolution reaction (OER), which is limited by the slow four-electron transfer kinetics process. Nevertheless, traditional synthetic methods, including calcination and solvothermal, of the electrocatalysts are high-cost, low-yield, and energy-hogging, which limits their industrial application. Herein, an ambient fast synthetic method is developed to prepare terrace-like Fe/Co bimetal-organic framework (TFC-MOF) electrocatalyst materials in gram scale in 1 h. The method in this paper is designable based on coordination chemistry. Fe and Co ions can coordinate with the carboxyl groups on benzene-1,3,5-tricarboxylic acid (H3 BTC) to form a 2D-MOF structure. Structural characterizations, including SEM, TEM, and XRD are conducted to verify that the TFC-MOF is a terrace-like layered structure with uniform-sized mesoporous, which reduces the adsorption steric hindrance and facilitates the mass and electron transfer efficiency of OER. The TFC-MOF shows low overpotential, 255 mV at a current density of 10 mA cm-2 , and a low Tafel slope of 49.9 mV dec-1 , in an alkaline solution. This work provides a planar coordination strategy to synthesize 2D-MOF OER electrocatalyst on a large scale with low cost and low energy consumption, which will promote its practical OER applications.

Mitochondria-Targeted Nanosystem with Reactive Oxygen Species-Controlled Release of CO to Enhance Photodynamic Therapy of PCN-224 by Sensitizing Ferroptosis.

The apoptosis-resistant mechanism of photodynamic therapy (PDT) usually results in limited therapeutic efficacy. The development of new strategies for sensitizing targeted ferroptosis that bypass apoptosis resistance is of great significance to improve the antitumor efficacy of PDT. In this study, a novel amphiphilic copolymer whose main chain contains reactive oxygen species (ROS)-responsive groups and the end of side chains contains triphenylphosphine is synthesized, to encapsulate porphyrinic metal-organic framework PCN-224 via self-assembly which are hydrothermally synthesized by coordination of zirconium (IV) with tetra-kis(4-caboxyphenyl) porphyrin, and loaded carbon monoxide releasing molecule 401 (CORM-401) by their hollow structures (PCN-CORM), and finally, surface-coated with hyaluronic acid. The nanosystem can sequentially localize to mitochondria which is an important target to induce apoptosis and ferroptosis in cancer cells. Upon excitation with near-infrared light, PCN-224 is activated to produce amounts of ROS, and simultaneously triggers the rapid intracellular release of CO. More importantly, the released CO can sensitize ferroptosis and promote apoptosis to significantly enhance the antitumor efficacy of PCN-224 both in vitro and in vivo. These results illustrate that the mitochondria-targeted drug delivery system combined PDT with CO leads to an effective antitumor efficacy, which maybe a promising way to enhance the treatment efficiency of PDT.

The aryl hydrocarbon receptor in immune regulation and autoimmune pathogenesis.

As a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR) is activated by structurally diverse ligands derived from the environment, diet, microorganisms, and metabolic activity. Recent studies have demonstrated that AhR plays a key role in modulating both innate and adaptive immune responses. Moreover, AhR regulates innate immune and lymphoid cell differentiation and function, which is involved in autoimmune pathogenesis. In this review, we discuss recent advances in understanding the mechanism of activation of AhR and its mediated functional regulation in various innate immune and lymphoid cell populations, as well as the immune-regulatory effect of AhR in the development of autoimmune diseases. In addition, we highlight the identification of AhR agonists and antagonists that may serve as potential therapeutic targets for the treatment of autoimmune disorders.

Akkermansia muciniphila improves heat stress-impaired intestinal barrier function by modulating HSP27 in Caco-2 cells.

OBJECTIVE: Heat stress causes an elevation of intestinal epithelial barrier permeability and leads to multiple organ dysfunction in heatstroke. Akkermansia muciniphila (A. muciniphila) plays a role in maintaining intestinal integrity and improving the inflammatory state. This study aimed to investigate whether A. muciniphila could alleviate heat stress-induced dysfunction of intestinal permeability in Caco-2 monolayers and have the preventive effects on heatstroke. METHODS: Human intestinal epithelial Caco-2 cells were preincubated with live or pasteurized A. muciniphila then exposed to heat stress at 43 °C. Transepithelial electrical resistance (TEER) and the flux of horseradish peroxidase (HRP) across cell monolayers were measured to determine intestinal permeability. The levels of the tight junction proteins Occludin, ZO-1 and HSP27 were analyzed by Western blotting. These proteins were immunostained and localized by fluorescence microscopy. TJ morphology was observed using transmission electron microscopy (TEM). RESULTS: Both live and pasteurized A. muciniphila effectively attenuated the decrease in TEER and impairment of intestinal permeability in HRP flux induced by heat exposure. A. muciniphila significantly elevated the expression of Occludin and ZO-1 by promoting HSP27 phosphorylation. The distortion and redistribution of tight junction proteins and disruption of morphology were also effectively prevented by pretreatment with A. muciniphila. CONCLUSION: This study indicates for the first time that both live and pasteurized A. muciniphila play an important protective role against heat-induced permeability dysfunction and epithelial barrier damage.

Role of non-canonical post-translational modifications in gastrointestinal tumors.

Post-translational modifications (PTMs) of proteins contribute to the occurrence and development of tumors. Previous studies have suggested that canonical PTMs such as ubiquitination, glycosylation, and phosphorylation are closely implicated in different aspects of gastrointestinal tumors. Recently, emerging evidence showed that non-canonical PTMs play an essential role in the carcinogenesis, metastasis and treatment of gastrointestinal tumors. Therefore, we summarized recent advances in sumoylation, neddylation, isoprenylation, succinylation and other non-canonical PTMs in gastrointestinal tumors, which comprehensively describe the mechanisms and functions of non-classical PTMs in gastrointestinal tumors. It is anticipated that targeting specific PTMs could benefit the treatment as well as improve the prognosis of gastrointestinal tumors.

Fluviispira vulneris sp. nov., isolated from human wound secretions.

Human infections by environmental bacteria is becoming an increasing problem and has become a matter of great concern due to the adverse effects worldwide. In this study, we reported a new environmental pathogen. Isolate GX5518T was a novel Gram-negative, aerobic, non-motile, pleomorphic and red-pigmented bacterium, was isolated from human wound secretions (GuangXi, People's Republic of China). Growth occurred at pH 6.0-8.0 (optimum, pH 7.0) and 10-37 °C (optimum, 28-32 °C) with 0-1.5% (w/v) NaCl in R2A agar. Comparative analysis of the 16S rRNA gene sequences revealed that isolate GX5518T was closely related to Fluviispira sanaruensis JCM 31447T (99.73%) and Fluviispira multicolorata 33A1-SZDPT (98.49%). However, the estimated ANI values of the isolate GX5518T compared to the F. sanaruensis JCM 31447T and F. multicolorata 33A1-SZDPT were 88.67% and 77.35%, respectively. The estimated dDDH, ANI and AAI values between isolate GX5518T and its closely related strains were below the threshold values generally considered for recognizing a new species. The genome size was 3.6 Mbp and the DNA G + C content was 33.1%. The predominant fatty acids (> 5%) in GX5518T cells were iso-C15:0, C16:0, C17:0, C17:1 ω8c and C16:1 ω7c/C16:1 ω6c. The major menaquinone was MK-8 (86.9%). The polar lipids were phosphatidylethanolamine (PE), phosphatidylglycerol (PG) and three unknown lipids (L1-3). The chemical composition was different from that of the F. sanaruensis JCM 31447T. Comparative genomics analysis between isolate GX5518T and its related strains revealed that there were a number of genes involved in resistance to antibiotics and toxic compounds in isolate GX5518T, which were responsible for the copper homeostasis, cobalt-zinc-cadmium resistance, resistance to fluoroquinolones, and zinc resistance. Based on the phenotypic, chemotaxonomic, and genomic analyses, isolate GX5518T (= CGMCC 1.18685T = KCTC 82149T) represents a novel species of the genus Fluviispira, for which the name Fluviispira vulneris sp. nov. is proposed.

Prediction of in-hospital mortality in patients with exertional heatstroke: a 13-year retrospective study.

Hyperactivity of coagulation is common in exertional heatstroke (EHS). Disseminated intravascular coagulation (DIC) is the most severe form of coagulation dysfunction and associated with poor outcome. DIC, temperature and Glasgow coma scale score were identified as independent risk factors for in-hospital mortality by multivariate logistic regression analysis, and we developed a nomogram for predicting in-hospital mortality in a 13-year EHS patient cohort. The nomogram was assessed by calibration curves and bootstrap with 1,000 resamples. The receiver operating characteristic curve was constructed, and the area under the curve (AUC) was compared. Two hundred and ten patients were included. The in-hospital mortality was 9.0%, and the incidence of DIC was 17.6%. The AUC of the nomogram was 0.897 (95% CI 0.848-0.935, p < .0001) and was non-inferior to SOFA and APACHE II scores but superior to SIRS score, which were widely-used score systems of disease severity. The nomogram contributed to the adverse outcome prediction of EHS.

Light-Activated Reactive Oxygen Species-Responsive Nanocarriers for Enhanced Photodynamic Immunotherapy of Cancer.

Exploring polymeric nanoplatforms combined with reactive oxygen species (ROS) responsiveness with mitochondria targeting has emerged as an effective strategy for enhanced photodynamic therapy (PDT). Amphiphilic copolymers were synthesized by reacting acrylamide thioketal (TK) linkers with amino-terminated triphenylphosphonium-polyethylene glycol and dodecylamine for encapsulating chlorin e6 (Ce6) via self-assembly. Then, anionic cladding with tumor targeting deshelled in tumor acidic microenvironments was surface-anchored by electrostatic forces (BioPEGDMA@RM). After sequential targeting to the mitochondria of cancerous cells, BioPEGDMA@RM could be light-activated with Ce6 released upon ROS cleavage of TK linkages. It was found that Ce6-loaded BioPEGDMA@RM exhibited higher cytotoxicity on CT26 cells and performed stronger ability on the production of ROS than that without TK linkers. Moreover, a minimum illumination of 3 and 5 min could be required for achieving the maximum release of Ce6 and high in vitro cytotoxicity for Ce6-loaded BioPEGDMA@RM, respectively. Furthermore, Ce6-loaded BioPEGDMA@RM showed 1.29-fold and 1.21-fold higher tumor inhibition on BALB/c nude mice and Kunming mice and stimulated immunologic reactions with more generation of IFN-γ and TNF-α and activation of CD3+, CD4+, and CD8+ T-lymphocytes and DCs than that of Ce6-loaded nanoparticles without TK bonds. This work provided an academic reference for the development of ROS-responsive drug delivery systems for advanced PDT efficiency.

GITRL impairs the immunosuppressive function of MDSCs via PTEN-mediated signaling pathway in experimental Sjögren syndrome.

BACKGROUND: Recent studies have revealed a role of the ligand for glucocorticoid-induced TNFR family-related protein (GITRL) in mediating functional dysregulations of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of primary Sjögren syndrome (pSS), but the underlying molecular mechanism is largely unclear. In this study, we aimed to elucidate GITRL-mediated signaling pathways in MDSCs during the development of experimental SS (ESS). METHODS: MDSCs were stimulated with recombinant GITRL, the activation of PTEN, AKT and STAT3 in MDSCs was analyzed by Western blot. MDSCs with different treatment were adoptively transferred to ESS mice. ELISA was used to detect the level of autoantibodies. Proportions of Th1 and Th17 cells were examined by flow cytometry. Histological evaluation of glandular destruction was analyzed by hematoxylin and eosin (HE) staining. The interaction of GITR, TRAF3 and PP2A was detected by CoIP. RESULTS: Upon the engagement of GITR on MDSCs, PTEN was activated and led to the inhibition of downstream AKT/STAT3 signaling pathway, therefore, resulting in the impaired immunosuppressive function of MDSCs. In ESS mice, blocking the activity of PTEN could efficiently restore the immunomodulatory effect of MDSCs and alleviate the progression of ESS. Furthermore, TRAF3 was found to bind to GITR, and then recruited PP2A to dephosphorylate PTEN, thus enhancing the activity of PTEN. CONCLUSION: This study elucidated the molecular mechanism underlying the effect of GITRL in regulating the function of MDSCs, which may provide a new therapeutic target for the treatment of pSS.

Characteristics of ST11 KPC-2-producing carbapenem-resistant hypervirulent Klebsiella pneumoniae causing nosocomial infection in a Chinese hospital.

BACKGROUND: The purpose of our study is to analyze the microbiological and clinical characteristics of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) that causes nosocomial infection. METHODS: We collected the carbapenem-resistant K. pneumoniae (CRKP) strains that caused nosocomial infection in a hospital in China and collected the relevant clinical data. We characterized these strains for their antimicrobial and virulence-associated phenotype and genotype and analyzed the clonal relatedness. We screened hypervirulent strains and compared them with non-hypervirulent strains. RESULTS: We retrospectively analyzed 62 CRKP strains that caused nosocomial infection in a tertiary hospital within 1 year, of which 41 (41/62, 66.1%) CRKP were considered as CR-hvKP. All CR-hvKP strains were multi-drug resistance (MDR) and the vast majority of isolates (39/41, 95.1%) were ST11 KPC-2-producing strains. Two hypermucoviscous isolates and 4 capsular types were found in 41 CR-hvKP. Twenty-nine isolates (29/41, 70.7%) showed hypervirulence in Galleria mellonella infection model. PFGE showed that ST11-KL47 CR-hvKP and ST11-KL64 CR-hvKP exhibited a high degree of clonality, while non-hypervirulent strains were not significant. CR-hvKP had higher positive rates of blaKPC-2 and blaCTX-M-65 and higher levofloxacin resistance (p < 0.001, p = 0.005 and p = 0.046, respectively) when compared to the non-hypervirulent strains. There was no significant difference between the two groups in terms of in-hospital mortality (7/41, 17.1% vs 5/21, 23.8%, p = 0.743). CONCLUSION: Our research finds that ST11 KPC-2-producing CR-hvKP is the main type of CRKP that caused nosocomial infection, and clonal spread has occurred. We provide more information about CR-hvKP in health care.

[Effect of light intensity on growth, accumulation of ginsenosides, and expression of related enzyme genes of Panax quinquefolius].

Appropriate light intensity is favorable for the photosynthesis, biomass accumulation, key enzyme activity, and secondary metabolite synthesis of medicinal plants. This study aims to explore the influence of light intensity on growth and quality of Panax quinquefolius. To be specific, sand culture experiment was carried out in a greenhouse under the light intensity of 40, 80, 120, and 160 µmol·m~(-2)·s~(-1), respectively. The growth indexes, photosynthetic characteristics, content of 6 ginsenosides of the 3-year-old P. quinquefolius were determined, and the expression of ginsenoside synthesis-related enzyme genes in leaves, main roots, and fibrous roots was determined. The results showed that the P. quinquefolius growing at 80 µmol·m~(-2)·s~(-1) light intensity had the most biomass and the highest net photosynthetic rate. The total biomass of P. quinquefolius treated with 120 µmol·m~(-2)·s~(-1) light intensity was slightly lower than that with 80 µmol·m~(-2)·s~(-1). The root-to-shoot ratio in the treatment with 120 µmol·m~(-2)·s~(-1) light intensity was up to 6.86, higher than those in other treatments(P<0.05),and the ginsenoside content in both aboveground and underground parts of P. quinquefolius in this treatment was the highest, which was possibly associated with the high expression of farnesylpyrophosphate synthase(FPS), squalene synthase(SQS), squalene epoxidase(SQE), oxidosqualene cyclase(OSC), dammarenediol-Ⅱ synthase(DS), and P450 genes in leaves and SQE and DS genes in main roots. In addition, light intensities of 120 and 160 µmol·m~(-2)·s~(-1) could promote PPD-type ginsenoside synthesis in leaves by triggering up-regulation of the expression of upstream ginsenoside synthesis genes. The decrease in underground biomass accumulation of the P. quinquefolius grown under weak light(40 µmol·m~(-2)·s~(-1)) and strong light(160 µmol·m~(-2)·s~(-1)) was possibly attributed to the low net photosynthetic rate, stomatal conductance, and transpiration rate in leaves. In the meantime, the low expression of SQS, SQE, OSC, and DS genes in the main roots might led to the decrease in ginsenoside content. However, there was no significant correlation between the ginsenoside content and the expression of synthesis-related genes in the fibrous roots of P. quinquefolius. Therefore, the light intensity of 80 and 120 µmol·m~(-2)·s~(-1) is beneficial to improving yield and quality of P. quinquefolius. The above findings contributed to a theoretical basis for reasonable shading in P. quinquefolius cultivation, which is of great significance for improving the yield and quality of P. quinquefolius through light regulation.

Intercalation-Activated Layered MoO3 Nanobelts as Biodegradable Nanozymes for Tumor-Specific Photo-Enhanced Catalytic Therapy.

The existence of natural van der Waals gaps in layered materials allows them to be easily intercalated with varying guest species, offering an appealing strategy to optimize their physicochemical properties and application performance. Herein, we report the activation of layered MoO3 nanobelts via aqueous intercalation as an efficient biodegradable nanozyme for tumor-specific photo-enhanced catalytic therapy. The long MoO3 nanobelts are grinded and then intercalated with Na+ and H2 O to obtain the short Na+ /H2 O co-intercalated MoO3-x (NH-MoO3-x ) nanobelts. In contrast to the inert MoO3 nanobelts, the NH-MoO3-x nanobelts exhibit excellent enzyme-mimicking catalytic activity for generation of reactive oxygen species, which can be further enhanced by the photothermal effect under a 1064 nm laser irradiation. Thus, after bovine serum albumin modification, the NH-MoO3-x nanobelts can efficiently kill cancer cells in vitro and eliminate tumors in vivo facilitating with 1064 nm laser irradiation.

Iodine-Initiated Dioxygenation of Aryl Alkenes Using tert-Butylhydroperoxides and Water: A Route to Vicinal Diols and Bisperoxides.

An environment-friendly and efficient dioxygenation of aryl alkenes for the construction of vicinal diols has been developed in water with iodine as the catalyst and tert-butylhydroperoxides (TBHPs) as the oxidant. The protocol was efficient, sustainable, and operationally simple. Detailed mechanistic studies indicated that one of the hydroxyl groups is derived from water and the other one is derived from TBHP. Additionally, the bisperoxides could be obtained in good yields with iodine as the catalyst, Na2CO3 as the additive, and propylene carbonate as the solvent, instead.

Pigmentibacter ruber gen. nov., sp. nov., a novel bacterium of the family Silvanigrellaceae isolated from human blood.

A Gram-negative, aerobic, non-motile, pleomorphic, red-pigmented bacterium, designated HNSRY-1T, was isolated from the blood sample of a near drowning patient in Republic of China. Strain HNSRY-1T grew at 15-37 °C (optimum, 35 °C), with pH 6.0-8.0 (optimum, pH 7.0) and 0-1.5% (W/V) NaCl (optimum, 1%). The predominant fatty acids (> 5%) in HNSRY-1T cells are iso-C15:0, C17:0, C17:1 ω8c, C16:0, and C16:1 ω6c/C16:1 ω7c. The major respiratory quinone is MK-8. The polar lipids are phosphatidylglycerol, phosphatidylethanolamine, three unidentified lipids and four unidentified aminolipids. The 16S rRNA gene sequence-based phylogenetic analysis indicated that strain HNSRY-1T belonged to the family Silvanigrellaceae, forming a distinct phylogenetic line distantly related (< 96.4% sequence similarity) to known species of the family. The ANI values of strain HNSRY-1T compared to the closely related species were below the determined genus division threshold limit (92-94% ANI), and AAI values were lower than the determined genus division threshold limit (80% AAI). Whole genome sequencing revealed a genome size of 3.63 Mb with a DNA G + C content at 29.6%. The half-lethal dose of strain HNSRY-1T on KM mice is about 1.12 × 108 CFU/ml. Virulence gene analysis showed that the pathogenicity of HNSRY-1T may be related to tufA, htpB, katA, wbtL, wbtM, pseB, clpP, cheY, cheV3, acpXL, pilB, fliN, ggt, flgG, fliP, nueB, pseA, bioB and flil. Based on these findings from the polyphasic taxonomy studies, a novel genus and species of the family Silvanigrellaceae. Pigmentibacter ruber gen. nov., sp. nov. is proposed, with type strain HNSRY-1T (= KCTC 72920T = CGMCC 1.18525T).

The developing trends and driving factors of environmental information disclosure in China.

Environmental Information Disclosure (EID) is a new tool for environmental governance in the era of big data and information. Based on the Pollution Information Disclosure Index (PITI) of 120 cities in China from 2003 to 2019, spatial data exploratory analysis and dynamic spatial panel model were adopted to analyze the spatial-temporal evolution characteristics and influencing factors of EID in China. The results show that (1) great progress of China's EID has been made in legislation and practice and its ways and channels are gradually becoming diversified, while it is accompanied by the problem of inadequate and unbalanced development; (2) EID shows the "superposition effect" promoted by previous accumulation has the "peer effect" of mutual imitation and learning and presents "demonstration effect", which shows significant agglomeration distribution pattern of spatial "club", while the spillover effect within the region is significant while the radiation effect between regions is weak. (3) In a dynamic process, cities with better economic development, firm performance, environmental performance and regulation, disclosure more environmental information, while the role of government competition and public participation needs further discussion. (4) Negative factors have a great influence during the economic crisis, while positive factors play a significant role in promoting the disclosure of environmental information during the economic expansion after crises. Cities in the developed regions (coastal, east and large cities) disclosure more than developing regions (inland, west, and small cities), and the positive factors are more likely to take effect.

The exopolysaccharide-eDNA interaction modulates 3D architecture of Bacillus subtilis biofilm.

BACKGROUND: Bacterial biofilms are surface-adherent microbial communities in which individual cells are surrounded by a self-produced extracellular matrix of polysaccharides, extracellular DNA (eDNA) and proteins. Interactions among matrix components within biofilms are responsible for creating an adaptable structure during biofilm development. However, it is unclear how the interactions among matrix components contribute to the construction of the three-dimensional (3D) biofilm architecture. RESULTS: DNase I treatment significantly inhibited Bacillus subtilis biofilm formation in the early phases of biofilm development. Confocal laser scanning microscopy (CLSM) and image analysis revealed that eDNA was cooperative with exopolysaccharide (EPS) in the early stages of B. subtilis biofilm development, while EPS played a major structural role in the later stages. In addition, deletion of the EPS production gene epsG in B. subtilis SBE1 resulted in loss of the interaction between EPS and eDNA and reduced the biofilm biomass in pellicles at the air-liquid interface. The physical interaction between these two essential biofilm matrix components was confirmed by isothermal titration calorimetry (ITC). CONCLUSIONS: Biofilm 3D structures become interconnected through surrounding eDNA and EPS. eDNA interacts with EPS in the early phases of biofilm development, while EPS mainly participates in the maturation of biofilms. The findings of this study provide a better understanding of the role of the interaction between eDNA and EPS in shaping the biofilm 3D matrix structure and biofilm formation.

Preparation and in Vitro Antitumor Study of Two-Dimensional Muscovite Nanosheets.

Inorganic nanosheets are endowed with many two-dimensional (2D) morphological features including ultra-high specific surface area, ultra-thin thickness, easy functionalization, and so on. They push forward an immense influence on effective cancer diagnosis and therapy, overcoming the inherent limitations of traditional treatment methods. However, long-term toxicity and poor biocompatibility are the critical issues for most inorganic nanosheets, which hinder their further oncological applications and clinical translations. Muscovite, also named white mica (WM), an aluminosilicate, is a major component of traditional Chinese medicine, which can be exfoliated into 2D nanosheets and expected to be a potential drug carrier. In this study, WM powder was exfoliated to prepare WM nanosheets (WMNs) through a polyamine intercalation method. In addition, doxorubicin hydrochloride (Dox) was loaded to WMNs via physical adsorption and electrostatic interaction to prepare Dox-loaded WMNs (Dox@WMNs). Then, we studied that Dox@WMNs released Dox in phosphate buffer saline. We also studied the cellular uptake and cytotoxicity of Dox@WMNs in vitro. The results illustrated that Dox@WMNs cumulatively released Dox much faster and more at acidic pH (6.0 and 4.6) compared with that at physiological pH. In addition, WMNs showed selective cytotoxicity. Within a certain concentration range, WMNs were cytotoxic to Hela cells but non-cytotoxic to RAW 264.7 cells. Compared with cytotoxicity at pH 7.4, the cytotoxicity of Dox@WMNs was significantly enhanced at pH 6.4 and 4.6. WMNs mainly promoted the immunostimulatory polarization of RAW 264.7 cells into M1 macrophages.

Unexpected Thymine Oxidation and Collision-Induced Thymine-Pt-guanine Cross-Linking on 5'-TpG and 5'-GpT by a Photoactivatable Diazido Pt(IV) Anticancer Complex.

The photochemical products of dinucleotides 5'-TpG/5'-GpT with a photoactivatable anticancer Pt(IV) complex (trans,trans,trans-[Pt(N3)2(OH)2(py)2], py = pyridine; 1) were characterized by electrospray ionization mass spectrometry. The primary MS showed the main products were monoplatinated and diplatinated adducts for both the dinucleotides accompanied by the formation of minor triplatinated dinucleotides, indicating that T-N3 and G-N1 may be platination sites additional to the well-known G-N7 site. Surprisingly, a series of minor platinated adducts with oxidation of guanine and/or thymine were observed. Although guanine is more sensitive to oxidation than thymine, thymine can compete with guanine for complex 1-induced oxidation, of which the oxidation adducts were identified as cis- and trans-diastereomers of 5,6-dihydroxy-5,6-dihydrothymidine (cis,trans-ThdGly), 5-formyl-2'-deoxyuridine (5-FormdUrd), and 5-(hydroxymethyl)-2'-deoxyuridine (5-HMdUrd), respectively. While for guanine, apart from 8-hydroxyguanine (8-OH-G) and N-formylamidoiminohydantoin (RedSp), other guanine oxidized adducts such as spiroiminodihydantoin (Sp), dehydroguanidinohydantoin (DGh), and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) were also identified. MS/MS analysis showed that unique fragments with a Pt moiety [Pt(N3)(py)] cross-linking the G and T bases were formed during the fragmentation of monoplatinated dinucleotides. Such binding mode to and oxidative damages on DNA bases imposed by the diazido Pt(IV) complex are apparently distinct from those of cisplatin, perhaps accounting for its unique mechanism of action.

A nomogramic model based on clinical and laboratory parameters at admission for predicting the survival of COVID-19 patients.

BACKGROUND: COVID-19 has become a major global threat. The present study aimed to develop a nomogram model to predict the survival of COVID-19 patients based on their clinical and laboratory data at admission. METHODS: COVID-19 patients who were admitted at Hankou Hospital and Huoshenshan Hospital in Wuhan, China from January 12, 2020 to March 20, 2020, whose outcome during the hospitalization was known, were retrospectively reviewed. The categorical variables were compared using Pearson's χ2-test or Fisher's exact test, and continuous variables were analyzed using Student's t-test or Mann Whitney U-test, as appropriate. Then, variables with a P-value of ≤0.1 were included in the log-binomial model, and merely these independent risk factors were used to establish the nomogram model. The discrimination of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUC), and internally verified using the Bootstrap method. RESULTS: A total of 262 patients (134 surviving and 128 non-surviving patients) were included in the analysis. Seven variables, which included age (relative risk [RR]: 0.905, 95% confidence interval [CI]: 0.868-0.944; P < 0.001), chronic heart disease (CHD, RR: 0.045, 95% CI: 0.0097-0.205; P < 0.001, the percentage of lymphocytes (Lym%, RR: 1.125, 95% CI: 1.041-1.216; P = 0.0029), platelets (RR: 1.008, 95% CI: 1.003-1.012; P = 0.001), C-reaction protein (RR: 0.982, 95% CI: 0.973-0.991; P < 0.001), lactate dehydrogenase (LDH, RR: 0.993, 95% CI: 0.990-0.997; P < 0.001) and D-dimer (RR: 0.734, 95% CI: 0.617-0.879; P < 0.001), were identified as the independent risk factors. The nomogram model based on these factors exhibited a good discrimination, with an AUC of 0.948 (95% CI: 0.923-0.973). CONCLUSIONS: A nomogram based on age, CHD, Lym%, platelets, C-reaction protein, LDH and D-dimer was established to accurately predict the prognosis of COVID-19 patients. This can be used as an alerting tool for clinicians to take early intervention measures, when necessary.

Preventing necroptosis by scavenging ROS production alleviates heat stress-induced intestinal injury.

Background: Worldwide heat stroke incidence has increased in recent years and is associated with high morbidity and mortality. Therefore, it is critical to identify mechanisms that mediate heat stroke. Previous studies suggested that damage to the small intestine may be a major factor in heat stroke-related morbidity and mortality. However, the mechanism underlying heat stroke related small intestine injury remains unclear.Methods: To explore how heat stroke promotes intestinal damage, we applied two well established models: mouse and IEC-6 cells heat stress (HS) to mimic heat stroke both in vivo and in vitro. The percentages of viability and cell death were assessed by WST-1 and LDH release assays. Induction of HS-induced cell death was analyzed by flow cytometry with Annexin V-FITC/PI staining. Flow cytometry was used to analyze HS-induced mitochondrial superoxide with MitoSOX staining. Malondialdehyde (MDA) levels and superoxide dismutase (SOD) levels were detected by ELISA. Flow cytometry was used to analyze HS-induced mitochondrial depolarization (low ΔΨm) with JC-1 staining. Histopathology changes in the ileum were detected by H&E staining.The ileum ultrastructure was observed by transmission electron microscopy (TEM). RIPK1, RIPK3, phosphorylated MLKL, and MLKL levels were detected by Western blot. RIPK1-RIPK3 complexes were measured by immunoprecipitation assay.Results: HS increased both necrotic cell rate and RIPK1, RIPK3, and phosphorylated MLKL expression levels in IEC-6 cells. These increased expression levels promoted higher RIPK1-RIPK3 complex formation, leading to necrosome formation both in vivo and in vitro. Moreover, HS caused dyshomeostasis, an oxidative stress response, and mitochondrial damage, along with small intestinal tissue injury and cell death. However, IEC-6 cells or mice pretreated with the RIPK1 activity chemical inhibitor Nec-1 or RIPK3 activity chemical inhibitor GSK'872 significantly reversed these phenomena and promoted balance in oxidative stress response homeostasis. More importantly, the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) pretreatment significantly inhibited HS-induced RIPK1/RIPK3-dependent necroptosis formation both in vivo and in vitro, suggesting that preventing necroptosis via scavenging ROS production might alleviate HS-induced small intestinal tissue injury and cell death.Conclusion: This study provides strong evidence that HS causes damage to both the small intestine and intestinal epithelial cells, scavenging ROS production can significantly alleviate such RIPK1/RIPK3-dependent necroptosis, mediating HS-induced intestinal damage both in vitro and in vivo. These findings provide a clear target for future mechanism-based therapeutic strategies for patients diagnosed with heat stroke.