Design, Synthesis, and Biological Activity of Novel Phenyltriazolinone PPO Inhibitors Containing Five-Membered Heterocycles.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX, which is a key step in the synthesis of porphyrins in vivo. PPO inhibitors use protoporphyrinogen oxidase as the target and block the biosynthesis process of porphyrin by inhibiting the activity of the enzyme, eventually leading to plant death. In this paper, phenyl triazolinone was used as the parent structure, and the five-membered heterocycle with good herbicidal activity was introduced by using the principle of substructure splicing. According to the principle of bioisosterism, the sulfur atoms on the thiophene ring were replaced with oxygen atoms. Finally, 33 phenyl triazolinones and their derivatives were designed and synthesized, and their characterizations and biological activities were investigated. The in vitro PPO inhibitory activity and greenhouse herbicidal activity of 33 target compounds were determined, and compound D4 with better activity was screened out. The crop safety determination, field weeding effect determination, weeding spectrum determination, and crop metabolism study were carried out. The results showed that compound D4 showed good safety to corn, soybean, wheat, and peanut but poor selectivity to cotton. The field weeding effect of this compound is comparable to that of the commercial herbicide sulfentrazone. The herbicidal spectrum experiment showed that compound D4 had a wide herbicidal spectrum and a good growth inhibition effect on dicotyledonous weeds. Molecular docking results showed that compound D4 forms a hydrogen bond with amino acid residue Arg-98 in the tobacco mitochondria (mtPPO)-active pocket and forms two π-π stacking interactions with Phe-392. This indicates that compound D4 has stronger PPO inhibitory activity. This indicates that compound D4 has wide prospects for development.

Design, Synthesis, and Biological Activity Determination of Novel Phenylpyrazole Protoporphyrinogen Oxidase Inhibitor Herbicides Containing Five-Membered Heterocycles.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitor herbicides have attracted widespread attention in recent years as ideal herbicides due to their high efficiency, low toxicity, and low pollution. In this article, 30 phenylpyrazole derivatives containing five-membered heterocycles were designed and synthesized according to the principle of bioelectronic isoarrangement and active substructure splicing. A series of structural characterizations were performed on the synthesized compounds. The herbicide activity in greenhouse was evaluated to determine their growth inhibition effect on weeds, their IC50 value through in vitro PPO enzyme activity measurement was calculated, and target compounds 2i and 3j that have herbicide effects comparable to pyraflufen-ethyl were selected. Crop safety experiments have shown that when the spraying concentration is 300 g of ai/ha, gramineous crops such as wheat, corn, and rice are more tolerant to compound 2i, with wheat exhibiting high tolerance, which is equivalent to the crop safety of pyraflufen-ethyl. Compound 2i can be used as a candidate herbicide for wheat, corn, and paddy fields, and the results are consistent with the cumulative concentration experiment. Molecular docking results showed that compound 2i interacted with the amino acid residue ARG-98 by forming two hydrogen bonds and interacted with the amino acid residue PHE-392 by forming two π-π stacking interactions, indicating that compound 2i has more excellent herbicidal activity than pyraflufen-ethyl and is expected to become a potential lead compound of phenylpyrazole PPO inhibitor herbicides.

Protective effects and regulatory mechanisms of Shen-shuai-yi recipe on renal fibrosis in unilateral ureteral obstruction-induced mice.

Renal fibrosis (RF) is a common pathological feature of chronic kidney disease (CKD), which remains a major public health problem. As now, there is still lack of chemical or biological drugs to reverse RF. Shen-shuai-yi Recipe (SSYR) is a classical Chinese herbal formula for the treatment of CKD. However, the effects and mechanisms of SSYR in treating RF are still not clear. In this study, the active constituents SSYR for treating RF were explored by UHPLC-Q-Orbitrap HRMS. Bioinformatics analyses were employed to analyze the key pharmacological targets and the core active constituents of SSYR in the treatment of RF. In experimental validation, vehicle or SSYR at doses of 2.12 g/kg/d and 4.25 g/kg/d were given by orally to unilateral ureteric obstruction (UUO) mice. 13 days after treatment, we detected the severity of renal fibrosis, extracellular collagen deposition and pre-fibrotic signaling pathways. Bioinformatics analysis suggested that signal transducer and activator of transcription 3 (STAT3) was the core target and lenticin, luteolin-7-O-rutinoside, hesperidin, kaempferol-3-O-rutinoside, and 3,5,6,7,8,3',4'-heptamethoxyflavone were the key constituents in SSYR for treating RF. SSYR significantly reduced the expressions of fibronectin (FN), α-smooth muscle actin (α-SMA), collagen-I and alleviated renal interstitial collagen deposition in UUO kidneys. In mechanism, SSYR potently blocked the phosphorylation of STAT3 and Smad3 and suppressed the expression of connective tissue growth factor (CTGF). Collectively, SSYR can ameliorate RF via inhibiting the phosphorylation of STAT3 and its downstream and reducing the collagen deposition, suggesting that SSYR can be developed as a novel medicine for treating RF.

Chlorocholine Perchlorate is an Organic Ferroelectric with Two-Step Ladder-like Dielectric, Second Harmonic Generation Effects, and Ferroelectricity.

The organic salt chlorocholine perchlorate [ClCH2 CH2 N(CH3 )3 ⋅ClO4 ] (CCP) is found to be a molecular ferroelectric with a high theoretical spontaneous polarization (Ps) value up to 17.09 µC cm-2 . CCP exhibits two successive order-disorder phase transition at 332 and 365 K with space groups changing from Cc to Cmc21 and then P63 /mmc, accompanied by unusual two-step ladder-like dielectric, SHG signal with obvious "on/off" contrasts. These findingings provides a further instance of exploring successive thermal-stimuli multi-responsive switching materials applied as switches and sensors.

A novel isophorone-based fluorescent probe for recognition of Al3+ and its bioimaging in cells and plants.

In this work, a novel isophorone-based fluorescent probe H-1 was designed and synthesized. The probe H-1 could achieve highly selective detection of Al3+ through forming a 1:1 complex, with a recognition mechanism based on intramolecular charge transfer (ICT). The detection limit of the probe H-1 for Al3+ is as low as 8.25 × 10-8 M which was determined by fluorescent titration. It is confirmed that H-1 could be used not only for fluorescence spectrometry to detect Al3+ ions in actual water samples, but also for biological imaging to detect Al3+ ions in cells and plants.

Screening for Wilson's disease in acute liver failure: A new scoring system in children.

Background: Wilson's disease (WD) is a rare cause of acute liver failure (ALF) and has a high fatality rate. Rapid and accurate diagnosis is important for ALF because of WD (ALF-WD). Our objective was to establish a simple, rapid, and accurate diagnostic test to distinguish ALF-WD from non-WD ALF (NWDALF) in children. Materials and methods: The data from all cases with pediatric ALF were retrospectively collected and analyzed. We performed receiver operator characteristics curve (ROC) analysis and confirmed the optimum cut-off points. Results: Fifty-eight patients with pediatric ALF (12 with WD, 46 with other etiologies) were included. Older age was observed in ALF-WD compared to NWDALF (11.16 ± 2.51 years vs. 3.34 ± 3.81 years, p < 0.001). An analysis based on routine biochemical testings revealed that total bilirubin (TBil), direct bilirubin, indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST:ALT ratio, alkaline phosphatase (ALP), ALP:TBil ratio, serum albumin, gamma-glutamyl transferase, cholinesterase, hemoglobin, and platelet were statistically significant between the ALF-WD and NWDALF groups. The optimum cut-off points were obtained through ROC analysis. A scoring system was formed by assigning a score of 1 or 0 to patients who met the 13 cut-off points. Using ROC analysis, we determined a cut-off point of ≥ 6.5 for ALF-WD with 91.7% sensitivity and 97.8% specificity (p < 0.0001). In addition, a best cut-off point of ≥ 1.5 based on only five variables (ALT, AST, AST:ALT ratio, ALP, and ALP:TBil ratio), had 100% sensitivity and 91.3% specificity for ALF-WD (p < 0.0001). Based on this, when age was calculated as the sixth indicator, the best cut-off value of ≥ 2.5 had 100% sensitivity and 97.8% specificity (p < 00.0001). Conclusion: Our study developed a new scoring system that consists of simple laboratory tests with good sensitivity and specificity and can be used by clinicians to quickly distinguish ALF-WD from NWDALF in children.

SNS-032 attenuates liver fibrosis by anti-active hepatic stellate cells via inhibition of cyclin dependent kinase 9.

Liver fibrosis is a common pathological process of all chronic liver diseases. Hepatic stellate cells (HSCs) play a central role in the development of liver fibrosis. Cyclin-dependent kinase 9 (CDK9) is a cell cycle kinase that regulates mRNA transcription and elongation. A CDK9 inhibitor SNS-032 has been reported to have good effects in anti-tumor. However, the role of SNS-032 in the development of liver fibrosis is unclear. In this study, SNS-032 was found to alleviate hepatic fibrosis by inhibiting the activation and inducing the apoptosis of active HSCs in carbon tetrachloride-induced model mice. In vitro, SNS-032 inhibited the activation and proliferation of active HSCs and induced the apoptosis of active HSCs by downregulating the expression of CDK9 and its downstream signal transductors, such phosphorylated RNA polymerase II and Bcl-2. CDK9 short hairpin RNA was transfected into active HSCs to further elucidate the mechanism of the above effects. Similar results were observed in active HSCs after CDK9 knockdown. In active HSCs with CDK9 knockdown, the expression levels of CDK9, phosphorylated RNA polymerase II, XIAP, Bcl-2, Mcl-1, and ɑ-SMA significantly decreased, whereas those of cleaved-PARP1 and Bax decreased prominently. These results indicated that SNS-032 is a potential drug and CDK9 might be a new prospective target for the treatment of liver fibrosis.

Cornuside ameliorates cognitive impairments in scopolamine induced AD mice: Involvement of neurotransmitter and oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis Sieb. et Zucc., traditional Chinese medicine, has been widely used in the treatment of dementia. Cornel iridoid glycosides of Cornus officinalis is therapeutic to Alzheimer's disease (AD), while its pharmacodynamic material basis is not clear. Cornuside, an iridoid glycoside extracted from of Cornus officinalis Sieb. et Zucc, might be a potential anti-AD candidate. AIM OF THE STUDY: Cornuside was evaluated for its effect on scopolamine induced AD mice, and its action mechanisms were explored. MATERIALS AND METHODS: ICR mice were administered with 1 mg/kg scopolamine intraperitoneally to induce amnesia. The therapeutic effect of cornuside of cognitive function was evaluated via series of behavioral tests, including Morris water maze test, step-through test and step-down test. In addition, specific enzyme reaction tests were used to detect the content of acetylcholine (ACh) and malondialdehyde (MDA), as well as the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), choline acetyltransferase (ChAT), superoxide dismutase (SOD), catalase (CAT), monoamine oxidase (MAO) in the brain. The levels of monoamine neurotransmitters were detected by high performance liquid chromatography-electrochemical detection (HPLC-ECD). RESULTS: Cornuside ameliorated the spatial memory impairment in Morris water maze test and cognitive disruption in step-through and step-down test. Furthermore, cornuside improved the level of ACh by reducing the activities of AChE and BuChE, and increasing the activity of ChAT in hippocampus. Cornuside also increased the levels of monoamine neurotransmitters by inhibiting MAO activity in hippocampus and cortex. In addition, cornuside attenuated MDA by enhancing the activities of SOD and CAT in hippocampus and cortex. CONCLUSION: Cornuside improved cognitive dysfunction induced by scopolamine in behavioral tests. The mechanisms of cornuside were further investigated from the aspects of neurotransmitters and oxidative stress. Cornuside could inhibit oxidative stress and neurotransmitter hydrolases, increase ACh and monoamine neurotransmitters, which finally contributed to its therapeutic effect on scopolamine induced amnesia.

Secoiridoid dimers and their biogenetic precursors from the fruits of Cornus officinalis with potential therapeutic effects on type 2 diabetes.

Cornusdiridoid A-F (1-6), six unusual cornuside-morroniside secoiridoid dimers, and their possible new biogenetic precursor, 3″,5″-dehydroxycornuside (7), together with four known secoiridoids (8-11), were obtained from the fruits of Cornus officinalis. Their structures were elucidated on the basis of various spectroscopic and chemical methods. A plausible biosynthetic pathway of compounds 1-11 was proposed. The α-glucosidase inhibitory, antioxidant and anti-inflammatory activities of these isolates were evaluated. Some of them emerged out as potent antidiabetic, anti-inflammatory and free radical scavenging agents. Molecular docking was also carried out for antidiabetic target α-glucosidase to investigate the possible binding modes of the most potent α-glucosidase inhibitor, vincosamide (9). These results revealed that the secoiridoids from C. officinalis fruits may be served as new potential antidiabetic agents to prevent and treat type 2 diabetes.

Causes of severe neonatal hyperbilirubinemia: a multicenter study of three regions in China.

BACKGROUND: Available evidence suggests that our country bear great burden of severe hyperbilirubinemia. However, the causes have not been explored recently in different regions of China to guide necessary clinical and public health interventions. METHODS: This was a prospective, observational study conducted from March 1, 2018, to February 28, 2019. Four hospitals in three regions of China participated in the survey. Data from infants with a gestational age ≥ 35 weeks, birth weight ≥ 2000 g, and total serum bilirubin (TSB) level ≥ 17 mg/dL (342 µmol/L) were prospectively collected. RESULTS: A total of 783 cases were reported. Causes were identified in 259 cases. The major causes were ABO incompatibility (n = 101), glucose-6-phosphate dehydrogenase deficiency (n = 76), and intracranial hemorrhage (n = 70). All infants with glucose-6-phosphate dehydrogenase deficiency were from the central south region. Those from the central south region had much higher peak total bilirubin levels [mean, 404 µmol/L; standard deviation (SD), 75 µmol/L] than those from the other regions (mean, 373 µmol/L; SD, 35 µmol/L) (P < 0.001). CONCLUSIONS: ABO incompatibility was the leading cause in the east and northwest regions, but cases in the central south region were mainly caused by both ABO incompatibility and glucose-6-phosphate dehydrogenase deficiency, and infants in this region had a much higher peak total bilirubin level. Intracranial hemorrhage may be another common cause. More thorough assessments and rigorous bilirubin follow-up strategies are needed in the central south region.

[Survey of Online Outpatient Clinic Usage Experiences and Analysis of Factors Influencing Retreatment].

BACKGROUND: Because of the COVID-19 epidemic, people are mostly isolated at home and must seek medical advice over the internet. In addition, government authorities are currently investing greater efforts in developing internet hospitals. PURPOSE: The purpose of this essay was to assess how outpatients feel about online outpatient clinics and to analyze the factors that affect their satisfaction and willingness to return to these clinics. The results provide advice regarding how to more effectively encourage patients to use online outpatient clinics. METHODS: A self-developed questionnaire was used to survey 191 patients who had visited the online outpatient clinic of a tertiary hospital in Sichuan Province from January to July 2019. A descriptive analysis was conducted on the collected data, and factors influencing satisfaction were identified. RESULTS: The majority of the surveyed patients were young or middle-aged (92.7%) and 42.9% held a college degree or higher. Nearly three-quarters (72.2%) expressed feeling satisfied or better with the online outpatient clinic, with 31.4% of these expressing feeling very satisfied. Nearly all (91.1%) expressed the opinion that the online outpatient clinic had improved their awareness of health self-management . Furthermore, 176 (92.1%) were willing to use the online outpatient clinic again. The results of univariate analysis showed that the main factors negatively influencing re-use of the online outpatient clinic were: failure to solve the problem in a timely manner (χ2 = 8.603, p = .045), the complicated process of online registration (χ2 = 8.322, p = .016), the failure of the online physical examination (χ2 = 8.958, p = .015), and unreliable quality (χ2 = 15.373, p = .004). CONCLUSIONS: The participants surveyed in this study reported a lower satisfaction for their online outpatient clinic experience than reported in similar surveys of traditional outpatient services. However, many reported that their health-related self-management awareness had improved after use, indicating that they feel better about the online outpatient clinic. The factors that affected willingness to reuse to the online outpatient clinic related mainly to imperfections related to the clinic and its inability to adequately meet patient needs. Online outpatient clinics should simplify the process of registration, improve functions, and increase service functions such as online examination appointments and follow-up visits to improve patient satisfaction.

Waardenburg syndrome type II in a Chinese pedigree caused by frameshift mutation in the SOX10 gene.

Waardenburg syndrome (WS) is a congenital hereditary disease, attributed to the most common symptoms of sensorineural deafness and iris hypopigmentation. It is also known as the hearing-pigmentation deficient syndrome. Mutations on SOXl0 gene often lead to congenital deafness and has been shown to play an important role in the pathogenesis of WS. We investigated one family of five members, with four patients exhibiting the classic form of WS2, whose DNA samples were analyzed by the technique of Whole-exome sequencing (WES). From analysis of WES data, we found that both the mother and all three children in the family have a heterozygous mutation on the Sex Determining Region Y - Box 10 (SOX10) gene. The mutation was c.298_300delinsGG in exon 2 of SOX10 (NM_006941), which leads to a frameshift of nine nucleotides, hence the amino acids (p. S100Rfs*9) are altered and the protein translation may be terminated prematurely. Further flow cytometry confirmed significant down-regulation of SOX10 protein, which indicated the SOX10 gene mutation was responsible for the pathogenesis of WS2 patients. In addition, we speculated that some other mutated genes might be related to disease phenotype in this family, which might also participate in promoting the progression of WS2.

Efficacy and Mechanism of a Chinese Classic Prescription of Yueju in Treating Nonalcoholic Steatohepatitis and Protecting Hepatocytes from Apoptosis.

Yueju, a famous classic Chinese prescription, has been extensively used in treating depression syndromes for hundreds of years. Recent studies have reported that Yueju showed good effects in treating metabolic diseases, such as obesity and hyperlipidemia. Nonalcoholic steatohepatitis (NASH), which leads to cirrhosis and severe cardiovascular diseases, is closely linked to obesity and abnormal lipid metabolism. In this study, Yueju could decrease the levels of alanine aminotransferase, aspartate transaminase, triglyceride, cholesterol, and low-density lipoprotein-C but increase the high-density lipoprotein-C in the serum of the NASH rat model induced by high-fat and high-cholesterol diet. Yueju could alleviate hepatosteatosis by increasing the phosphorylation of acetyl-CoA carboxylase and inhibiting the expression of fatty acid synthase and stearoyl-CoA desaturase 1. Yueju downregulated the expression of α-smooth muscle actin and collagen type 1A1, ameliorating the liver fibrilization. Yueju could also protect the hepatocytes from apoptosis by upregulating antiapoptosis protein Bcl-2 and X-linked inhibitor of apoptosis protein and downregulating apoptotic proteins Bax and cleaved poly ADP-ribose polymerase. Thus, Yueju could improve liver function, regulate lipid metabolism, alleviate hepatosteatosis and fibrosis, and protect hepatocytes from apoptosis against NASH. Yueju may be used as an alternative effective medicine for NASH treatment.

Undescribed morroniside-like secoiridoid diglycosides with α-glucosidase inhibitory activity from Corni Fructus.

Corni Fructus, also known as the fruit of Cornus officinalis Sieb. et Zucc., has long been used as a traditional Chinese medicine and is widely consumed as a nutritional food in the form of function drink and wine. Recently, Corni Fructus has attracted considerable interest because of its anti-diabetic effects. A systematic phytochemical investigation of Corni Fructus was performed to find anti-diabetic components, which led to the isolation of 10 unreported iridoid glycosides, cornusdiglycosides A-J (1-8, 9a/9b and 10a/10b). Their chemical structures were determined through spectroscopic analysis (ultraviolet [UV], infrared [IR], high-resolution electrospray ionisation mass spectroscopy [HRESIMS], one-dimensional [1D] and two-dimensional [2D] nuclear magnetic resonance [NMR]). Such morroniside-type diglycosides were first reported from natural sources, and all isolates were evaluated for α-glucosidase inhibitory activity. The results showed that all compounds (1-10) exhibited α-glucosidase (from Saccharomyces cerevisiae) inhibitory activities with IC50 values ranging from 78.9 ± 4.09 to 162.2 ± 9.17 µM, whereas acarbose, the positive control, displayed α-glucosidase inhibitory activity with IC50 value of 118.9 ± 7.89 µM.

Overexpression of MiR482c in Tomato Induces Enhanced Susceptibility to Late Blight.

Tomato is the highest-value fruit/vegetable crop worldwide. However, the quality and yield of tomatoes are severely affected by late blight. MicroRNA482s (miR482s) are involved in the plant's immune system. In this study, miR482c was transiently and stably overexpressed in tomatoes in transgenic plants to explore its mechanism in tomato resistance against late blight. Transgenic tomato plants with transiently overexpressed miR482c displayed a larger lesion area than the control plants upon infection. Furthermore, compared with wild-type (WT) tomato plants, the transgenic tomato plants stably overexpressing miR482c displayed a decreased expression of target genes accompanied by lower peroxidase (POD), superoxide dismutase (SOD), and phenylalanine ammonia-lyase (PAL) activity activities and higher malondialdehyde (MDA) content, thereby leading to a decline in reactive oxygen species (ROS) scavenging ability and aggravating the damage of lipid peroxidation product accumulation on the cell membrane, eventually enhancing plant susceptibility. This finding indicates that miR482c may act as a negative regulator in tomato resistance by regulating nucleotide binding sites and leucine-rich repeat (NBS-LRR) expression levels and ROS levels.

The identification and isolation of anti-inflammatory ingredients of ethno medicine Breynia fruticosa.

ETHNOPHARMACOLOGICAL RELEVANCE: Breynia fruticosa is a folk medicine in China, traditionally used to treat gastroenteritis, sore throat, eczema and arthritis. However, the bioactive ingredients are unknown. AIM OF THE STUDY: To identify and isolate the anti-inflammatory ingredients of B. fruticosa. MATERIALS AND METHODS: B. fruticosa extracts were fractioned by Amberchrom CG161M and Toyopearl HW40C resins. Acetic acid-induced capillary permeability mice model was used to evaluate the anti-inflammation activities of fractions. The anti-inflammatory ingredients were identified by high performance liquid chromatography/mass spectroscopy (HPLC-MS). On-line two dimensional liquid chromatography system was constructed to remove the tannins and enrich the breynins. The breynins were purified by preparative HPLC and evaluated for their anti-arthritis activities using complete Freund's adjuvant (CFA) induced arthritis rats model. RESULTS: The anti-inflammatory ingredients of B. fruticosa are sulfur containing sesquiterpenoids (breynins). The on-line two dimensional preparative liquid chromatography system can effectively remove the tannins and enrich the bioactive ingredients in large scale within 1 h. Four major breynins were purified, and their structures were elucidated by analysis of MS and NMR data. Breynins can significantly prevent the rats' arthritis deterioration, with inhibition ratio 50% at dose 0.2 mg kg-1, comparable with that of indomethacin at dose 2 mg kg-1. CONCLUSION: The breynins have strong anti-arthritis activities, which is responsible to the anti-inflammatory effects of B. fruticosa. However, breynins are also toxic components of B. fruticosa.

Solanum lycopersicum microRNA1916 targets multiple target genes and negatively regulates the immune response in tomato.

MicroRNA1916 (miR1916) is one of the nonconserved miRNAs that respond to various stresses in plants, but little has been known at present about its mechanisms in biotic stresses. In this study, the expression of Solanum lycopersicum (sly)-miR1916 in tomato was found to be down-regulated after infection with Phytophthora infestans or Botrytis cinerea. Tomato plants that overexpressed sly-miR1916 displayed significant enhancement in susceptibility to P. infestans and B. cinerea infection, as well as increased tendency to produce reactive oxygen species. Silencing of sly-miR1916 by short tandem target mimic and artificial microRNA strategies caused the tomato plants to become more tolerant to adverse conditions. In addition, lower sly-miR1916 expression could up-regulate the expression of strictosidine synthase (STR-2), UDP-glycosyltransferases (UGTs), late blight resistance protein homolog R1B-16, disease resistance protein RPP13-like, and MYB transcription factor (MYB12), which ultimately resulted in the accumulation of α-tomatine and anthocyanins via STR-2, UGT, and MYB12. Furthermore, ectopic expression of sly-miR1916/STR-2 significantly changed the tolerance of tobacco to B. cinerea. Taken together, the results demonstrated that sly-miR1916 might regulate the expression of STR-2, UGT, and MYB12 in tomato plant, conferring sensitivity to biotic stress via modulating α-tomatine and anthocyanins.

Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new Wnt/ß-catenin signalling pathway agonists.

Phenanthridine derivativeHLY78 has previously been identified as the first Wnt/ß-catenin signalling pathway agonist that targets the DAX domain of axin. However, due to the relatively weak activation on the Wnt/ß-catenin signalling pathway, HLY78 is insufficient for further pharmacological study. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships (SARs) of HLY78-derived phenanthridine derivatives as agonists of the Wnt/ß-catenin signalling pathway are presented. In this work, 36 derivatives were designed and synthesized with some derivatives exhibiting stronger Wnt activity than the activity of HLY78. In particular, one of them, 8-((1,3-dimethy-pyrazol-5-yl)methoxy)-5-ethyl-4-methyl-5,6-dihydro-phenanthridin-9-ol, exhibited strong Wnt active activity and is 10 times more potent than HLY78. The following SAR analysis suggests that a pyrazole group, especially at the C-8 position, is important for Wnt activation; a methyl group at the C-4position seems to be more beneficial for Wnt activation than ethyl; and oxidation of the C-6 position reduces the Wnt activation.

Connexin 43 C-terminus directly inhibits the hyperphosphorylation of Akt/ERK through protein-protein interactions in glioblastoma.

Although the deregulation of epidermal growth factor receptor (EGFR) is one of the most common molecular mechanisms of glioblastoma (GBM) pathogenesis, the efficacy of anti-EGFR therapy is limited. Additionally, response to anti-EGFR therapy is not solely dependent on EGFR expression and is more promising in patients with reduced activity of EGFR downstream signaling pathways. Thus, there is considerable interest in identifying the compensatory regulatory factors of the EGFR signaling pathway to improve the efficacy of anti-EGFR therapies for GBM. In this study, we confirmed the low efficacy of EGFR inhibitors in GBM patients by meta-analysis. We then identified a negative correlation between connexin 43 (Cx43) expression and Akt/ERK activation, which was caused by the direct interactions between Akt/ERK and Cx43. By comparing the interactions between Akt/ERK and Cx43 using a series of truncated and mutated Cx43 variants, we revealed that the residues T286/A305/Q308/Y313 and S272/S273 at the carboxy terminus of Cx43 are critical for its binding with Akt and ERK, respectively. In addition, Kaplan-Meier survival analysis using data from The Cancer Genome Atlas datasets indicated that the expression of Cx43 significantly improved the prognosis of GBM patients who express EGFR. Together, our results suggested that Cx43 acts as an inhibitory regulator of the activation of growth factor receptor downstream signaling pathways, indicating the potential of Cx43 as a marker for predicting the efficacy of EGFR inhibitor treatments for GBM. Targeting the interaction between the carboxy terminus of Cx43 and Akt/ERK could be an effective therapeutic strategy against GBM.

[Predictors of Long-term Mortality and Health Related Quality of Life for Elderly Patients with Sepsis].

OBJECTIVE: To explore the predictors of long-term mortality and healthy related quality of life (HR-QoL) for elderly patients with sepsis. METHODS: Two hundred and thirty-eight septic patients older than 60 years old admitted to intensive care unit (ICU) were enrolled in the study,and were followed up by telephone interview one year after ICU discharge. The hospital mortality and cumulative one-year mortality were analyzed,single and multiple factors analysis were used to for the risk factors of 1-year mortality. Quality of life (QoL) was evaluated by the Euro QoL-5 Dimensions (EQ5D) questionnaire,and the influential factors of long-term QoL were also analyzed. RESULTS: A total of 238 patients were enrolled,58 patients of them(24.4%) died during hospitalization and one-year accumulative mortality was 59.7% (142 cases). Single factor analysis showed that acute physiology and chronic health evaluation (APACHE Ⅱ),continuous renal replacement therapy (CRRT),fungal infection,sepsis,tracheal extubation and use of vasopressor within 24 h,the length of mechanical ventilation were correlated with one-year mortality. Multivariate regression analysis showed that APACHE Ⅱscore,CRRT and fungal infection were independent risk factors for one-year mortality,while tracheal extubation within 24 h and shorter length of ICU stay were related to better quality of life. CONCLUSION: One-year mortality of elderly patients with sepsis was high. Tracheal extubation in 24 h and length of hospital stay were predictor of long-term QoL.