Flexible solar cells based on foldable silicon wafers with blunted edges.

Flexible solar cells have a lot of market potential for application in photovoltaics integrated into buildings and wearable electronics because they are lightweight, shockproof and self-powered. Silicon solar cells have been successfully used in large power plants. However, despite the efforts made for more than 50 years, there has been no notable progress in the development of flexible silicon solar cells because of their rigidity1-4. Here we provide a strategy for fabricating large-scale, foldable silicon wafers and manufacturing flexible solar cells. A textured crystalline silicon wafer always starts to crack at the sharp channels between surface pyramids in the marginal region of the wafer. This fact enabled us to improve the flexibility of silicon wafers by blunting the pyramidal structure in the marginal regions. This edge-blunting technique enables commercial production of large-scale (>240 cm2), high-efficiency (>24%) silicon solar cells that can be rolled similarly to a sheet of paper. The cells retain 100% of their power conversion efficiency after 1,000 side-to-side bending cycles. After being assembled into large (>10,000 cm2) flexible modules, these cells retain 99.62% of their power after thermal cycling between -70 °C and 85 °C for 120 h. Furthermore, they retain 96.03% of their power after 20 min of exposure to air flow when attached to a soft gasbag, which models wind blowing during a violent storm.

Anisotropic sensing based on single ReS2flake for VOCs discrimination.

Selective and sensitive detection of volatile organic compounds (VOCs) holds paramount importance in real-world applications. This study proposes an innovative approach utilizing a single ReS2field-effect transistor (FET) characterized by distinct in-plane anisotropy, specifically tailored for VOC recognition. The unique responses of ReS2, endowed with robust in-plane anisotropic properties, demonstrate significant difference along thea-axis andb-axis directions when exposed to four kinds of VOCs: acetone, methanol, ethanol, and IPA. Remarkably, the responses of ReS2were significantly magnified under ultraviolet (UV) illumination, particularly in the case of acetone, where the response amplified by 10-15 times and the detection limit decreasing from 70 to 4 ppm compared to the dark conditions. Exploiting the discernible variances in responses along thea-axis andb-axis under both UV and dark conditions, the data points of acetone, ethanol, methanol and IPA gases were clearly separated in the principal component space without any overlap through principal component analysis, indicating that the single ReS2FET has a high ability to distinguish various gas species. The exploration of anisotropic sensing materials and light excitation strategies can be applied to a broad range of sensing platforms based on two-dimensional materials for practical applications.

Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys.

AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first-in-human dose escalation study.

A Game Model for Analyzing Wireless Sensor Networks of 5G Environment Based on Adaptive Equilibrium Optimizer Algorithm.

Wireless sensors networks (WSNs) play an important role in life. With the development of 5G, its security issues have also raised concerns. Therefore, it is an important topic to study the offense and defense confrontation in WSNs. A complete information static game model is established to analyze the offense and defense confrontation problem of WSNs in 5G. An adaptive equilibrium optimizer algorithm (AEO) based on parameter adaptive strategy is proposed, which can jump out of the local optimal solution better. Experiments show that the optimization ability of AEO outperforms other algorithms on at least 80% of the 23 classical test functions of CEC. The convergence speed of AEO is better in the early stage of population iteration. The optimal offensive and defensive strategy under different offense and defense resources through simulation experiments is analyzed. The conclusion shows that when the offensive resources are large, the offender takes an indiscriminate attack. When the defense resources are small, the defender should defend the most important elements, and when the defense resources are large, the defender should allocate the same resources to defend each element to obtain the maximum benefit. This paper provides new solution ideas for the security problems under the offense and defense game in WSNs.

The association of physical fitness with mental health in children: A serial multiple mediation model.

There is growing interest in the association between physical fitness and mental health. This study aimed to extend current knowledge by investigating the potential mediating roles of resilience and anxiety in the association between physical fitness and mental health in children. A total of 269 children were selected by stratified random sampling from three primary schools in China. Physical fitness was scored using the Chinese National Student Physical Fitness Standard. Resilience, anxiety, and mental health data were collected using the following questionnaires: Resilience Scale for Chinese Adolescents, Multidimensional Anxiety Scale for Children, and the Mental Health Test. The PROCESS macro developed by Hayes was used to conduct serial multiple mediation analysis. We found that physical fitness, resilience, anxiety, and mental health were significantly correlated. Children with higher physical fitness had lower mental health problems; however, this statistical significance was not detectable after controlling for resilience and anxiety. Serial multiple mediation analysis revealed that the association of physical fitness with mental health was partially mediated by resilience and anxiety. These results indicate that the positive association of physical fitness with mental health in children may be changed through resilience and anxiety, which appear to play serial multiple mediating roles in this association. These findings contribute to deeper understanding of the associations between these factors and suggest that promoting physical fitness independent of considering resilience and anxiety may be insufficient to achieve good mental health in children.

Functional CRISPR and shRNA Screens Identify Involvement of Mitochondrial Electron Transport in the Activation of Evofosfamide.

Evofosfamide (TH-302) is a hypoxia-activated DNA-crosslinking prodrug currently in clinical development for cancer therapy. Oxygen-sensitive activation of evofosfamide depends on one-electron reduction, yet the reductases that catalyze this process in tumors are unknown. We used RNA sequencing, whole-genome CRISPR knockout, and reductase-focused short hairpin RNA screens to interrogate modifiers of evofosfamide activation in cancer cell lines. Involvement of mitochondrial electron transport in the activation of evofosfamide and the related nitroaromatic compounds EF5 and FSL-61 was investigated using 143B ρ 0 (ρ zero) cells devoid of mitochondrial DNA and biochemical assays in UT-SCC-74B cells. The potency of evofosfamide in 30 genetically diverse cancer cell lines correlated with the expression of genes involved in mitochondrial electron transfer. A whole-genome CRISPR screen in KBM-7 cells identified the DNA damage-response factors SLX4IP, C10orf90 (FATS), and SLFN11, in addition to the key regulator of mitochondrial function, YME1L1, and several complex I constituents as modifiers of evofosfamide sensitivity. A reductase-focused shRNA screen in UT-SCC-74B cells similarly identified mitochondrial respiratory chain factors. Surprisingly, 143B ρ 0 cells showed enhanced evofosfamide activation and sensitivity but had global transcriptional changes, including increased expression of nonmitochondrial flavoreductases. In UT-SCC-74B cells, evofosfamide oxidized cytochromes a, b, and c and inhibited respiration at complexes I, II, and IV without quenching reactive oxygen species production. Our results suggest that the mitochondrial electron transport chain contributes to evofosfamide activation and that predicting evofosfamide sensitivity in patients by measuring the expression of canonical bioreductive enzymes such as cytochrome P450 oxidoreductase is likely to be futile.

Combining Orthogonal Chain-End Deprotections and Thiol-Maleimide Michael Coupling: Engineering Discrete Oligomers by an Iterative Growth Strategy.

Orthogonal maleimide and thiol deprotections were combined with thiol-maleimide coupling to synthesize discrete oligomers/macromolecules on a gram scale with molecular weights up to 27.4 kDa (128mer, 7.9 g) using an iterative exponential growth strategy with a degree of polymerization (DP) of 2n -1. Using the same chemistry, a "readable" sequence-defined oligomer and a discrete cyclic topology were also created. Furthermore, uniform dendrons were fabricated using sequential growth (DP=2n -1) or double exponential dendrimer growth approaches (DP=22n -1) with significantly accelerated growth rates. A versatile, efficient, and metal-free method for construction of discrete oligomers with tailored structures and a high growth rate would greatly facilitate research into the structure-property relationships of sophisticated polymeric materials.

[Acute renal failure caused by rhabdomyolysis in children: a clinical analysis of 26 cases].

OBJECTIVE: To investigate the clinical features and prognosis of acute renal failure (ARF) caused by rhabdomyolysis (RM) in children. METHODS: A retrospective analysis was performed for the clinical data, laboratory examination, and prognosis of 26 RM children with ARF. RESULTS: The causes for all 26 RM children with ARF were non-traumatic diseases, and the three most common causes were infection (69%), diabetes (12%), and metabolic disease (8%). In the RM children with ARF, the five most frequent clinical manifestations were fever (69%), multiple organ dysfunction syndrome (69%), convulsion (46%), oliguria or anuria (35%), and tea-colored urine (27%). All 26 children had a serum creatine kinase (CK) level of >1 000 IU/L, among whom 26 had increased aspartate aminotransferase, 25 had increased alanine aminotransferase, 25 had increased creatine kinase isoenzyme, and 23 had increased lactate dehydrogenase. Serum myoglobin (Mb) was measured in 22 children and was found to increase in all these children. The mean time for CK to decrease to below 1 000 IU/L was 10±5 d. There was no significant difference in the time to CK recovery between the 10 children who were treated with conventional treatment as well as continuous venous-venous hemofiltration and those who were not treated with blood purification (P>0.05). Of all 26 RM children with ARF, 7 were withdrawn from the treatment, and 19 had normal renal function after treatment. CONCLUSIONS: ARF and multiple organ dysfunction syndrome are major complications in RM children. The major primary disease for RM children with ARF is infectious disease. CK is the major marker for the diagnosis of RM. Early diagnosis and appropriate treatment may reverse ARF and improve prognosis.

Short-term MyD88 inhibition ameliorates cardiac graft rejection and promotes donor-specific hyporesponsiveness of skin grafts in mice.

Recognition of evolutionarily conserved ligands by Toll-like receptors (TLRs) triggers signaling cascades in innate immune cells to amplify adaptive immune responses. Nearly all TLRs require MyD88 to transduce downstream signaling. MyD88 deficiency has been shown to promote the allograft acceptance in mice. However, direct evidence for therapeutic potential of MyD88 inhibitors remains lacking. Herein, we used a MyD88 inhibitor, namely ST2825, to explore its therapeutic potential and mechanisms in fully allogeneic skin and heart transplant models. Phenotypic maturation of dendritic cells stimulated by TLR ligands was alleviated by ST2825 in parallel with reduced T-cell proliferation in vitro. A short-course treatment with ST2825 significantly prolonged cardiac graft survival (mean survival time = 18.5 ± 0.92 days vs. 7.25 ± 0.46 days). ST2825-treated group had significantly reduced proinflammatory cytokines in allografts compared with control group. ST2825 combined with anti-CD154 induced long-term skin allograft acceptance in about one-third of recipients (>100 days). 'Skin-tolerant' recipients showed attenuated donor-specific IFN-γ responses, intact IL-4 responses, and compromised alloantibody responses. We conclude that MyD88 inhibitor ST2825 attenuates acute cardiac rejection and promotes donor-specific hyporesponsiveness in stringent skin transplant models. The direct evidence suggests that pharmacological inhibition of MyD88 hold promising potential for transplant rejection.

Nitrogen microplasma generated in chip-based ingroove glow discharge device for detection of organic fragments by optical emission spectrometry.

In this study, nitrogen was successfully used to maintain the microplasma discharge to excite and detect organic compounds for the first time. A new nitrogen glow discharge microplasma-generated in-chip-based ingroove device was developed and applied as the excitation source for optical emission spectrometry. The unique ingroove design of the discharge chamber can provide good stability and sensitivity for nitrogen microplasma to detect trace organic samples. Unlike argon/helium microplasmas, the nitrogen microplasma has a strict demand on the material of electrodes, especially cathodes. We tested the effects of four common electrode materials from various aspects and obtained the most appropriate material for nitrogen glow discharge, namely, platinum. We also studied the excitation and detection mechanism of organic compounds in nitrogen microplasma and confirmed that the main means of excitation in nitrogen plasma was through energy transfer rather than penning ionization. Several organic compounds were directly injected and detected in the optimized working conditions with the limits of detection at the hundreds of picograms level. Because of the portable nitrogen generators handily and commercially available, this detection system with nitrogen as the discharge gas can overcome the limitation of noble gas supply. In addition, the advantages of small size, low energy consumption, good stability, and reproducibility demonstrate that the nitrogen ingroove microplasma source can be applied in a portable detector for on-site and real-time spectrometry detection.

Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition.

BACKGROUND: The hypoxia-activated prodrug TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Here, we have explored the effect of Chk1 inhibition on TH-302-mediated pharmacological activities. METHODS: We employed in vitro cell viability, DNA damage, cellular signaling assays and the in vivo HT29 human tumor xenograft model to study the effect of Chk1inhibition on TH-302 antitumor activities. RESULTS: TH-302 cytotoxicity is greatly enhanced by Chk1 inhibition in p53-deficient but not in p53-proficient human cancer cell lines. Chk1 inhibitors reduced TH-302-induced cell cycle arrest via blocking TH-302-induced decrease of phosphorylation of histone H3 and increasing Cdc2-Y15 phosphorylation. Employing the single-cell gel electrophoresis (comet) assay, we observed a potentiation of the TH-302 dependent tail moment. TH-302 induced γH2AX and apoptosis were also increased upon the addition of Chk1 inhibitor. Potentiation of TH-302 cytotoxicity by Chk1 inhibitor was only observed in cell lines proficient in, but not deficient in homology-directed DNA repair. We also show that combination treatment led to lowering of Rad51 expression levels as compared to either agent alone. In vivo data demonstrate that Chk1 inhibitor enhances TH-302 anti-tumor activity in p53 mutant HT-29 human tumor xenografts, supporting the hypothesis that these in vitro results can translate to enhanced in vivo efficacy of the combination. CONCLUSIONS: TH-302-mediated in vitro and in vivo anti-tumor activities were greatly enhanced by the addition of Chk1 inhibitors. The preclinical data presented in this study support a new approach for the treatment of p53-deficient hypoxic cancers by combining Chk1 inhibitors with the hypoxia-activated prodrug TH-302.

Possible benefit of splenectomy in liver transplantation for autoimmune hepatitis.

Liver transplantation for autoimmune hepatitis (AIH) is usually successful with excellent long-term outcomes, but primary disease may recur. The recurrence of AIH is a significant cause of graft loss. This study was to analyze the effect of splenectomy in preventing AIH relapse. The clinical courses of 12 patients who had transplantation for AIH were analyzed retrospectively. All patients were subjected to transplantation for end-stage liver disease caused by chronic AIH. Based on the duration of immunosuppressive treatment before liver transplantation, simultaneous splenectomy was performed in ten patients. Two patients underwent liver transplantation without splenectomy, one of them developed recurrent AIH and died from graft failure caused by AIH relapse. However, no episode of AIH recurrence was observed in patients who had undergone simultaneous splenectomy. Splenectomy might be an option to prevent AIH relapse in some patients with high risk factors.

Acute high-intensity interval exercise improves food-related cognition in young adults with obesity: An ERP study.

Purpose Cognitive function, particularly food-related cognition, is critical for maintaining a healthy weight and preventing the acceleration of obesity. High-Intensity Interval Exercise (HIIE) is an increasingly popular form of exercise and has been shown to improve physical fitness and cognitive function. However, there is limited research on the effects and underlying mechanisms of HIIE on general and food-related cognition among adults with obesity. The aim of the current study was to examine the influence of a single bout of HIIE on food-related cognition among young adults with obesity. Methods Fifteen young men with obesity (BMI = 33.88 ± 4.22, age = 24.60 ± 5.29 years) were recruited. Participants took part in a HIIE condition consisting of 30 minutes of stationary cycle exercise (5-min warm-up, 20-min HIIE and 5-min cool down), and a control session consisting of a time and attention-matched period of sedentary rest in a counterbalanced order. Behavioral (reaction time and accuracy) and event-related potential measures (P3 and the late positive potential, LPP) elicited during a food-related Flanker task were measured after the HIIE and control session. Results Shorter response times were observed following HIIE, regardless of congruency or picture type, with no change in accuracy. Increased P3 and LPP amplitudes were observed following HIIE relative to the control session. Conclusion The findings suggest a single bout of HIIE has a beneficial effect on general and food-related cognition among young adults with obesity, with increased recruitment of cognitive resources to support cognitive control. Future research is warranted to examine the dose-response relationship between acute bouts or longer participation in HIIE on food-related cognition in obesity.

PIII/PV-Catalyzed Beckmann Reaction and Sequential [2,3]-Sigmatropic Rearrangement to Construct 2-Amidopyridines.

An organophosphorus catalytic method for the synthesis of substituted 2-amidopyridines is reported. The method employs a small-ring organophosphorus-based catalyst and a hydrosilane reductant to drive the conversion of ketoximes and pyridine-N-oxides into 2-amidopyridines through sequential Beckmann rearrangement followed by [2,3]-sigmatropic rearrangement. The readily available ketoximes could be activated to nitrilium ions in PIII/PV redox catalysis and could efficiently participate in the domino reaction of pyridine-N-oxides, thus providing various substituted 2-amidopyridines in moderate to excellent yields. This presented strategy features excellent functional group tolerance and a broad substrate scope.

Food-related inhibitory control deficits in young male adults with obesity: Behavioral and ERP evidence from a food-related go/no-go task.

PURPOSE: Obesity poses a pervasive challenge to global public health, which is linked to adverse physical health outcomes and cognitive decline. Cognitive function, particularly food-related cognitive function, plays a critical role in sustaining a healthy weight and mitigating the progression of obesity. The aim of this study was to investigate the behavioral and neuroelectronic aspects of food-related inhibitory functions in young adult males with obesity. METHODS: Forty-nine participants with obesity and healthy-weight were recruited (BMI = 35.83 ± 5.06 kg/m2 vs. 22.55 ± 1.73 kg/m2, age = 24.23 ± 4.55 years vs. 26.00 ± 3.97 years). A food-related Go/No-go task which included 6 distinct blocks in a randomized order was conducted to investigate the general and food-related inhibitory control. 180 stimulus images from the Food Picture Database encompassing high-calorie food, low-calorie food, and neutral images were selected. Behavioral (Go RT, Go ACC, No-go ACC) and event-related potential measures (N2 and P3 amplitude) during the food-related Go/No-go task were measured. RESULTS: The main findings indicated that the group with obesity exhibited lower No-go accuracy, slower go reaction times, and smaller P3 amplitudes in high-calorie, low-calorie foods, and neutral picture, compared to the normal-weight group, but with no group difference in N2. Additionally, high-calorie food induced larger N2 and P3 amplitude than the neutral stimuli. CONCLUSIONS: Young male adults with obesity exhibit poorer inhibitory control in both food and non-food domains, specifically in slower reaction time and reduced accuracy, featuring difficulties in neural resource recruitment during the inhibitory control process. Additionally, the P3 component could serve as sensitive indicators to reveal the neural mechanisms of inhibitory control deficits in obesity, while the N2 and P3 components may differentiate the neural differences between high-calorie foods and non-foods in inhibitory control processing. Food, especially high-calorie food, induces more neural resources and may exacerbate the poor inhibitory ability towards food in obesity. Targeted interventions such as exercise interventions, cognitive training as well as neuromodulation interventions are warranted in the future to improve impaired general and food-related inhibitory functions in the obese populations, offering both theoretical and practical frameworks for obesity prevention and treatment.

Discovery of a brain-permeable bromodomain and extra terminal domain (BET) inhibitor with selectivity for BD1 for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease and lacks effective therapeutic agents. Dysregulation of transcription mediated by bromodomain and extra-terminal domain (BET) proteins containing two different bromodomains (BD1 and BD2) is an important factor in multiple diseases, including MS. Herein, we identified a series of BD1-biased inhibitors, in which compound 16 showed nanomolar potency for BD1 (Kd = 230 nM) and a 60-fold selectivity for BRD4 BD1 over BD2. The co-crystal structure of BRD4 BD1 with 16 indicated that the hydrogen bond interaction of 16 with BD1-specific Asp145 is important for BD1 selectivity. 16 showed favorable brain distribution in mice and PK properties in rats. 16 was able to inhibit microglia activation and had significant therapeutic effects on EAE mice including improvement of spinal cord inflammatory conditions and demyelination protection. Overall, these results suggest that brain-permeable BD1 inhibitors have the potential to be further investigated as therapeutic agents for MS.

Proteomic analysis of differential proteins related to anti-nociceptive effect of electroacupuncture in the hypothalamus following neuropathic pain in rats.

Increasing evidence has been accumulated for the effectiveness of acupuncture therapy in relieving pain. However, there are limited data on regulation of protein expression after electroacupuncture (EA) intervention. Thus, the present study is designed to determine changes in protein expression following EA stimulation in rats with sciatic nerve chronic constrictive injury (CCI) induced neuropathic pain. Sixty Wistar rats were equally randomized into normal control group, CCI group, and CCI with EA stimulation (EA) group. The CCI model was established by ligature of the left sciatic nerve. EA stimulation was applied at Zusanli (ST36) and Yanglingquan (GB34) in the EA group. Differentially expressed hypothalamic proteins in the three groups were identified by 2-D gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry. The functional clustering and pathway of the identified proteins were analyzed by Mascot software. Results showed that, after CCI, the thermal pain threshold of the affected hind footpad was decreased and was reversed gradually by 12 sessions of EA treatment. Following EA intervention, there were 17 hypothalamic proteins identified with significant changes in the expression (>twofold). Three gene-ontologies (oxidoreductase activity, oxidation reduction, and protein binding) were enriched, while there was a significant regulation of glycolysis/gluconeogenesis/hexose metabolism pathway. These data demonstrate that EA intervention can attenuate pain via regulation of expression of multiple proteins in the hypothalamus. Further, hypothalamic glucose metabolism may be important in supporting energy and neurotransmitter homeostasis in the effects of EA intervention.

Effects of the synbiotic composed of mangiferin and Lactobacillus reuteri 1-12 on type 2 diabetes mellitus rats.

Many synbiotics are effective for the prevention and treatment of type 2 diabetes mellitus (T2DM). In the treatment of T2DM, synbiotics often regulate the composition of intestinal flora, which autoinducer-2 (AI-2) may play an important role. Whether the changes of intestinal flora are related to AI-2 during synbiotics treatment of T2DM is a topic worth studying. We elucidated the effects of synbiotic composed of mangiferin and Lactobacillus reuteri 1-12 (SML) on T2DM rats. Male Spraque-Dawley rats were injected intraperitoneally with streptozotocin (STZ) and randomly grouped. After that, biochemical parameters, intestinal flora, fecal AI-2, and intestinal colonization of L. reuteri were detected. The results showed that SML had a hypoglycemic effect and mitigated the organ lesions of the liver and pancreas. Also, SML regulated biochemical parameters such as short chain fatty acids (SCFAs), lipopolysaccharides (LPS), intercellular cell adhesion molecule-1 (ICAM-1), and tumor necrosis factor-α (TNF-α). On the other hand, the proportion of probiotics, such as Lactobacillus acidophilus, L. reuteri, Bifidobacterium pseudolongum, Lactobacillus murinus, and Lactobacillus johnsonii, were elevated by the treatment of SML. In addition, SML promoted the colonization and proliferation of L. reuteri in the gut. Another thing to consider was that AI-2 was positively correlated with the total number of OTUs sequences and SML boosted AI-2 in the gut. Taken together, these results supported that SML may modulate intestinal flora through AI-2 to treat T2DM. This study provided a novel alternative strategy for the treatment of T2DM in future.

Protective effect and mechanism of Polygonatum kingianum against hypoxia-induced injury.

Background: Hypoxia is an essential cause of fatigue and aging, and is associated with the occurrence and development of many diseases. Polygonatum kingianum (PK) is a deficiency-nourishing Chinese herbal medicine utilized as both medicine and food, and it has long been used to ameliorate human conditions associated with fatigue and aging over 2000 years in China. PK is an important genuine-medicinal-materials cultivated in Yunnan, China, and is used by the Bai, Wa, and Zhuang nationalities as a traditional medicine for enhancing immunity, anti-fatigue, and anti-aging, while the preventive effect of PK on hypoxia-induced injury and the underlying mechanism are indefinite. Aim of the study: The present study aimed to evaluate the anti-hypoxia efficacy and understand the corresponding mechanism of PK water extract. Materials and methods: The main active ingredients and targets of PK were predicted using network pharmacology, and the anti-hypoxia activities of Gracillin and Liquiritigenin were verified by in vitro experiments. The pharmacodynamic experiments were conducted to evaluate the major signal pathways of PK for detecting anti-hypoxia activity. Results: Fifty active ingredients and 371 potential targets were screened by network pharmacology, then, we confirmed that Gracillin and Liquiritigenin were the main active components of PK to exert anti-hypoxia effect in vitro. The pharmacodynamic experiments revealed that PK enhanced the extension rate of the survival time (ERST) and regulated the targets-related biochemical parameters of rats under hypoxia, showing significant anti-hypoxia effects on rats. Conclusion: The network pharmacology results suggested that PK exerts its anti-hypoxia effect through a multi-component and multi-target manner. Simultaneously, we also observed that Gracillin (saponins) and Liquiritigenin (flavonoids) are the main active components of PK to play a role in anti-hypoxia. The anti-hypoxia effect of PK could be associated with scavenging excess free radicals, maintaining the activities of antioxidant enzymes, and inhibiting oxidative stress due to lipid peroxidation. These findings provide insight into the Polygonatum kingianum as promising medicines or healthcare products for preventing and treating hypoxia.

A JAK tyrosine kinase and pseudokinase Co-inhibition strategy combines enhanced potency and on-demand activation.

Janus tyrosine kinase (JAK) inhibitors have been on the market for several years, but their use is limited by drug resistance and intolerable side effects. Herein, we propose a novel strategy of JAK tyrosine kinase (TK) and pseudokinase (PK) domain co-inhibition system to consolidate robust JAK inhibition and on-demand activation. A photoexcited prodrug PAT-SIL-TG-1&AT exhibits the synergy effects of TK-PK co-inhibition and enable the spatiotemporal control of JAK2 signaling. The hypoxia-activated prodrug HAT-SIL-TG-1&AT significantly inhibited HEL cells proliferation and downregulated phosphorylated STAT3/5 under hypoxic conditions. Importantly, HAT-SIL-TG-1&AT showed synergistic antitumor effects and selectively inhibited the JAK-STAT signaling in tumor tissues in vivo. This work demonstrates a viable solution to achieve superior JAK2 inhibition, and provides an inspiration for other kinases containing PK domain.