Revealing core functional microorganisms in the fermentation process of Qicaipaojiao (Capsicum annuum L.) based on microbial metabolic network.

Paojiao, a typical Chinese traditional fermented pepper, is favored by consumers for its unique flavor profile. Microorganisms, organic acids, amino acids, and volatile compounds are the primary constituents influencing the development of paojiao's flavor. To elucidate the key flavor compounds and core microorganisms of Qicaipaojiao (QCJ), this study conducted a comprehensive analysis of the changes in taste substances (organic acids and amino acids) and volatile flavor compounds during QCJ fermentation. Key flavor substances in QCJ were identified using threshold aroma value and odor activity value and the core microorganisms of QCJ were determined based on the correlation between dominant microorganisms and the key flavor substances. During QCJ fermentation, 16 key taste substances (12 free amino acids and 4 organic acids) and 12 key aroma substances were identified. The fermentation process involved 10 bacteria and 7 fungal genera, including Lactiplantibacillus, Leuconostoc, Klebsiella, Pichia, Wickerhamomyces, and Candida. Correlation analysis revealed that the core functional microorganisms encompassed representatives from 8 genera, including 5 bacterial genera (Lactiplantibacillus, Weissella, Leuconostoc, Klebsiella, and Kluyvera) and 3 fungal genera (Rhodotorula, Phallus, and Pichia). These core functional microorganisms exhibited significant correlations with approximately 70 % of the key flavor substances (P < 0.05). This study contributes to an enhanced understanding of flavor formation mechanisms and offers valuable insight into flavor quality control in food fermentation processes.

Newly identified peptide Nigrocin-OA27 inhibits UVB induced melanin production via the MITF/TYR pathway.

Melasma is a common skin disease induced by an increase in the content of melanin in the skin, which also causes serious physical and mental harm to patients. In this research, a novel peptide (Nigrocin-OA27) from Odorrana andersonii is shown to exert a whitening effect on C57 mice pigmentation model. The peptide also demonstrated non-toxic and antioxidant capacity, and can significantly reduce melanin content in B16 cells. Topical application effectively delivered Nigrocin-OA27 to skin's epidermal and dermal layers and exhibited significant preventive and whitening effects on the UVB-induced ear pigmentation model in C57 mice. The whitening mechanism of Nigrocin-OA27 may be related to reduced levels of the microphthalmia-associated transcription factor and the key enzyme for melanogenesis-tyrosinase (TYR). Nigrocin-OA27 also inhibited the catalytic activity by adhering to the active core of TYR, thereby reducing melanin formation and deposition. In conclusion, Nigrocin-OA27 may be a potentially effective external agent to treat melasma by inhibiting aberrant skin melanin synthesis.

Design, Synthesis, and Anti-Leukemic Evaluation of a Series of Dianilinopyrimidines by Regulating the Ras/Raf/MEK/ERK and STAT3/c-Myc Pathways.

Although the long-term survival rate for leukemia has made significant progress over the years with the development of chemotherapeutics, patients still suffer from relapse, leading to an unsatisfactory outcome. To discover the new effective anti-leukemia compounds, we synthesized a series of dianilinopyrimidines and evaluated the anti-leukemia activities of those compounds by using leukemia cell lines (HEL, Jurkat, and K562). The results showed that the dianilinopyrimidine analog H-120 predominantly displayed the highest cytotoxic potential in HEL cells. It remarkably induced apoptosis of HEL cells by activating the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase (PARP)), increasing apoptosis protein Bad expression, and decreasing the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL). Furthermore, it induced cell cycle arrest in G2/M; concomitantly, we observed the activation of p53 and a reduction in phosphorylated cell division cycle 25C (p-CDC25C) / Cyclin B1 levels in treated cells. Additionally, the mechanism study revealed that H-120 decreased these phosphorylated signal transducers and activators of transcription 3, rat sarcoma, phosphorylated cellular RAF proto-oncogene serine / threonine kinase, phosphorylated mitogen-activated protein kinase kinase, phosphorylated extracellular signal-regulated kinase, and cellular myelocytomatosis oncogene (p-STAT3, Ras, p-C-Raf, p-MEK, p-MRK, and c-Myc) protein levels in HEL cells. Using the cytoplasmic and nuclear proteins isolation assay, we found for the first time that H-120 can inhibit the activation of STAT3 and c-Myc and block STAT3 phosphorylation and dimerization. Moreover, H-120 treatment effectively inhibited the disease progression of erythroleukemia mice by promoting erythroid differentiation into the maturation of erythrocytes and activating the immune cells. Significantly, H-120 also improved liver function in erythroleukemia mice. Therefore, H-120 may be a potential chemotherapeutic drug for leukemia patients.

Peptide OM-LV20 promotes arteriogenesis induced by femoral artery ligature via the miR-29b-3p/VEGFA axis.

BACKGROUND AND AIMS: Therapeutic arteriogenesis is a promising direction for the treatment of ischemic disease caused by atherosclerosis. However, pharmacological or biological approaches to stimulate functional collateral vessels are not yet available. Identifying new drug targets to promote and explore the underlying mechanisms for therapeutic arteriogenesis is necessary. METHODS: Peptide OM-LV20 (20 ng/kg) was administered for 7 consecutive days on rat hindlimb ischemia model, collateral vessel growth was assessed by H&E staining, liquid latex perfusion, and specific immunofluorescence. In vitro, we detected the effect of OM-LV20 on human umbilical vein endothelial cells (HUVEC) proliferation and migration. After transfection, we performed quantitative real-time polymerase chain reaction, in situ-hybridization and dual luciferase reporters to assessed effective miRNAs and target genes. The proteins related to downstream signaling pathways were detected by Western blot. RESULTS: OM-LV20 significantly increased visible collateral vessels and endothelial nitric oxide synthase (eNOS), together with enhanced inflammation cytokine and monocytes/macrophage infiltration in collateral vessels. In vitro, we defined a novel microRNA (miR-29b-3p), and its inhibition enhanced proliferation and migration of HUVEC, as well as the expression of vascular endothelial growth factor A (VEGFA). OM-LV20 also promoted migration and proliferation of HUVEC, and VEGFA expression was mediated via inhibition of miR-29b-3p. Furthermore, OM-LV20 influenced the protein levels of VEGFR2 and phosphatidylinositol3-kinase (PI3K)/AKT and eNOS in vitro and invivo. CONCLUSIONS: Our data indicated that OM-LV20 enhanced arteriogenesis via the miR-29b-3p/VEGFA/VEGFR2-PI3K/AKT/eNOS axis, and highlighte the application potential of exogenous peptide molecular probes through miRNA, which could promote effective therapeutic arteriogenesis in ischemic conditions.

The direct binding of bioactive peptide Andersonin-W1 to TLR4 expedites the healing of diabetic skin wounds.

BACKGROUND: Chronic nonhealing wounds remain a considerable challenge in clinical treatment due to excessive inflammation and impeded reepithelialization and angiogenesis. Therefore, the discovery of novel prohealing agents for chronic skin wounds are urgent and important. Amphibian-derived prohealing peptides, especially immunomodulatory peptides, provide a promising strategy for the treatment of chronic skin trauma. However, the mechanism of immunomodulatory peptides accelerating the skin wound healing remains poorly understood. METHODS: The prohealing ability of peptide Andersonin-W1 (AW1) was assessed by cell scratch, cell proliferation, transwell, and tube formation. Next, full-thickness, deep second-degree burns and diabetic full-thickness skin wounds in mice were performed to detect the therapeutic effects of AW1. Moreover, the tissue regeneration and expression of inflammatory cytokines were evaluated by hematoxylin and eosin (H&E), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry staining. Molecular docking, colocalization, and western blotting were used to explore the mechanism of AW1 in promoting wound healing. RESULTS: We provide solid evidence to display excellent prohealing effects of AW1, identified as a short antimicrobial peptide in our previous report. At relative low concentration of nM, AW1 promoted the proliferation, migration, and scratch repair of keratinocyte, macrophage proliferation, and tube formation of HUVEC. AW1 also facilitated reepithelialization, granulation regeneration, and angiogenesis, thus significantly boosting the healing of full-thickness, deep second-degree burns and diabetic skin wounds in mice. Mechanistically, in macrophages, AW1 directly bound to Toll-like receptor 4 (TLR4) in the extracellular region and regulated the downstream nuclear factor-κB (NF-κB) signaling pathway to facilitate the inflammatory factor secretion and suppress excessive inflammation induced by lipopolysaccharide (LPS). Moreover, AW1 regulated macrophage polarization to promote the transition from the inflammatory to the proliferative phase and then facilitated reepithelialization, granulation regeneration, and angiogenesis, thus exhibiting excellent therapeutic effects on diabetic skin wounds. CONCLUSIONS: AW1 modulates inflammation and the wound healing process by the TLR4/NF-κB molecular axis, thus facilitating reepithelialization, granulation regeneration, and angiogenesis. These findings not only provided a promising multifunctional prohealing drug candidate for chronic nonhealing skin wounds but also highlighted the unique roles of "small" peptides in the elucidation of "big" human disease mechanisms.

Electrochemically Driven para-Selective C(sp2)-H Alkylation Enabled by Activation of Alkyl Halides without Sacrificial Anodes.

With alkyl halides (I, Br, Cl) as a coupling partner, an electrochemically driven strategy for para-selective C(sp2)-H alkylation of electron-deficient arenes (aryl esters, aldehydes, nitriles, and ketones) has been achieved to access diverse alkylated arenes in one step. The reaction enables the activation of alkyl halides in the absence of sacrificial anodes, achieving the formation of C(sp2)-C(sp3) bonds under mild electrolytic conditions. The utility of this protocol is reflected in high site selectivity, broad substrate scope, and scalable.

Potassium xanthate-promoted reductive sulfuration reaction: from aldehydes to thiol, disulfide, and thioester derivatives.

Herein, we developed a synthetic strategy for the direct construction of C-S bonds to obtain biologically active sulfur-containing compounds and a methodology involving the reductive sulfuration of aldehydes or ketones to obtain diverse substituted thiol, disulfide, and thioester derivatives. EtOCS2K is demonstrated as a potential substitute for the Berzelius reagent or Lawesson's reagent for the construction of C-S bonds.

Amphibian-derived peptide RL-RF10 ameliorates paraquat-induced pulmonary fibrosis injury.

Pulmonary fibrosis is the result of dysfunctional repair after lung tissue injury, characterized by fibroblast proliferation and massive extracellular matrix aggregation. Once fibrotic lesions develop, effective treatment is difficult, with few drugs currently available. Here, we identified a short cyclic decapeptide RL-RF10 derived from frog skin secretions as a potential novel lead molecule for the amelioration of pulmonary fibrosis. In vivo experiments indicated that RL-RF10 treatment ameliorated lung histopathological damage and fibrogenesis after paraquat (PQ) induction in a concentration-dependent manner. On day 7, bronchoalveolar lavage fluid assays performed on mice showed that RL-RF10 exerted anti-inflammatory effects by decreasing the expression of inflammation-related factors, including transforming growth factor-ß1 (TGF-ß1) and tumor necrosis factor-α, in lung tissue. In addition, RL-RF10 down-regulated the levels of collagen I, collagen III, and vimentin, while increasing the expression of E-cadherin to inhibit epithelial-mesenchymal transition. Further research demonstrated that the SMAD2/3 signaling pathway, which is strongly linked to TGF-ß1, played a critical function in enhancing the pulmonary fibrosis relief achieved by RL-RF10. Both in vivo and in vitro assays showed that RL-RF10 treatment led to a significant reduction in the phosphorylation levels of SMAD2 and SMAD3 following PQ induction. Overall, we investigated the protective effects and underlying mechanisms of the RL-RF10 peptide against pulmonary fibrosis and demonstrated its potential as a novel therapeutic drug candidate for the treatment of pulmonary fibrotic diseases.

Synergistic combination of isogarcinol isolated from edible fruits of Garcinia multiflora and dexamethasone to overcome leukemia glucocorticoid resistance.

Isogarcinol (ISO), a cytotoxic polycyclic polyprenylated acylphloroglucinol isolated from the edible fruits of Garcinia multiflora. However, synergistic combination of ISO and dexamethasone (DEX) to overcome leukemia glucocorticoid resistance has never been investigated. Therefore, in this study, the effects of ISO in combination with DEX was conducted on leukemia in vivo and glucocorticoid resistance in vitro. As a result, the combination of the two compounds could efficiently inhibit leukemia progression in mice and reverse DEX resistance in acute lymphoblastic leukemia (ALL) Jurkat cells. Significantly, our findings indicated that c-Myc may be a potential target of ISO, as it is involved in cell cycle arrest and apoptosis by the combination of ISO and DEX in Jurkat cells. Furthermore, western blot analysis revealed that ISO and DEX inhibits the PI3K/Akt/mTOR signaling pathway and promotes the nuclear translocation of glucocorticoid receptor (GR), which activates target genes NR3C1 and TSC22D3, leading to apoptosis in Jurkat cells. Hence, our results suggest that ISO, as a safe and effective food-derived agent, can enhance the anti-leukemia effects of DEX.

Glucosylation endows nanoparticles with TLR4 agonist capability to trigger macrophage polarization and augment antitumor immunity.

Carbohydrates have emerged as promising candidates for immunomodulation, however, how to present them to immune cells and achieve potent immunostimulatory efficacy remains challenging. Here, we proposed and established an effective way of designing unique glyconanoparticles that can amplify macrophage-mediated immune responses through structural mimicry and multiple stimulation. We demonstrate that surface modification with glucose can greatly augment the immunostimulatory efficacy of nanoparticles, comparing to mannose and galactose. In vitro studies show that glucosylation improved the pro-inflammatory efficacy of iron oxide nanoparticles (IONPs) by up to 300-fold, with the immunostimulatory activity of glucosylated IONPs even surpassing that of LPS under certain conditions. In vivo investigation show that glucosylated IONPs elicited increased antitumor immunity and achieved favorable therapeutic outcomes in multiple murine tumor models. Mechanistically, we proposed that glucosylation potentiated the immunostimulatory effect of IONPs by amplifying toll-like receptors 4 (TLR4) activation. Specifically, glucosylated IONPs directly interacted with the TLR4-MD2 complex, resulting in M1 macrophage polarization and enhanced antitumor immunity via activation of NF-κB, MAPK, and STAT1 signaling pathways. Our work provides a simple modification strategy to endow nanoparticles with potent TLR4 agonist effects, which may shed new light on the development of artificial immune modulators for cancer immunotherapy.

Electrochemically Driven C4-Selective Decyanoalkylation of Cyanopyridines with Unactivated Alkyl Bromides Enabling C(sp3)-C(sp2) Coupling.

With cyanopyridines and alkyl bromides as coupling partners, an electrochemically driven C4-selective decyanoalkylation has been established to access diverse 4-alkylpyridines in one step. The reaction proceeds through the single electron reduction/radical-radical coupling tandem process under mild electrolytic conditions, achieving the cleavage of the C(sp2)-CN bond and the formation of C(sp3)-C(sp2). The practicality of this protocol is illustrated by no sacrificial anodes, a broad substrate scope, and gram-scale synthesis.

Hemoglobin albumin lymphocyte and platelet score and all-cause mortality in coronary heart disease: a retrospective cohort study of NHANES database.

Aim: Anemia, inflammatory status, and malnutrition are all important factors in the prognosis of cardiovascular disease (CVD), and their interactions are also noteworthy. A recent scoring system, the hemoglobin albumin lymphocyte and platelet (HALP) score, combining multi-dimensional metrics, has been used in the prognoses of many diseases except coronary heart disease (CHD). Herein, this study aims to explore the association between HALP score and all-cause mortality in patients with CHD. Methods: Demographic and clinical data of adult patients with CHD were extracted from the National Health and Nutrition Examination Surveys (NHANES) database from 2003 to 2018 in this retrospective cohort study. Weighted univariate and multivariate COX proportional hazard models were used for covariates screening and exploration of the association between HALP score and all-cause mortality. The evaluation indexes were hazard ratios (ORs) and 95% confidence intervals (CIs). Kaplan-Meier (KM) curve and the receiver operator characteristic (ROC) curve were used to assess the predictive performance of HALP on CHD prognosis. In addition, subgroup analyses of age and congestive heart failure (CHF) were also performed. Results: Among the eligible patients, 657 died of all-cause mortality. After adjusting for the covariates including age, education level, PIR, marital status, smoking, physical activity, total energy intake, CHF, stroke, hypertension, DM, CKD, cancer or malignancy, monocyte, drug for CVD, treatment for anemia, anticoagulants drug, and adrenal cortical steroids, we found that HALP score was negatively associated with the risk of all-cause mortality [HR = 0.83, 95% CI: (0.74-0.93)]. Compared with patients with high HALP scores, those who had lower HALP scores seemed to have a higher risk of all-cause mortality (all P < 0.05). HALP score has a potential predictive value on CHD prognosis with an area under the curve (AUC) of 0.61. Furthermore, in patients aged <65 years, with or without CHF, a lower HALP score was also associated with a higher risk of all-cause mortality (all P < 0.05). Conclusions: HALP score has a potential predictive value on CHD prognosis; however, the causal association between HALP score and mortality in patients with CHD needs further exploration.

A frog peptide provides new strategies for the intervention against skin wound healing.

BACKGROUND: Amphibian derived pro-healing peptides as molecular probes might provide a promising strategy for development of drug candidates and elucidation of cellular and molecular mechanisms of skin wound healing. A novel skin amphibian peptide, OA-RD17, was tested for modulation of cellular and molecular mechanisms associated with skin wound healing. METHODS: Cell scratch, cell proliferation, trans-well, and colony formation assays were used to explore the pro-healing ability of peptide OA-RD17 and microRNA-632 (miR-632). Then, the therapeutic effects of OA-RD17 and miR-632 were assessed in mice, diabetic patient ex vivo skin wounds and SD rats. Moreover, hematoxylin and eosin (H&E), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and immunofluorescence staining were performed to detect skin wound tissue regeneration, inflammatory factors expression, and macrophage polarization. Finally, RNA sequencing, molecular docking, co-localization, dual luciferase reporter, real-time quantitative reverse transcription PCR (RT-qPCR), and Western blotting were used to explore the mechanism of OA-RD17 and miR-632 on facilitating skin wound healing. RESULTS: The non-toxic peptide (OA-RD17) promoted macrophage proliferation and migration by activating MAPK and suppressed inflammation by inhibiting NF-κB. In keratinocytes, OA-RD17 inhibited excessive inflammation, and activated MAPK via the Toll-like receptor 4 (TLR4) to promote proliferation and migration, as well as up-regulate the expression of miR-632, which targeted GSK3ß to activate Wnt/ß-catenin to boost proliferation and migration in a positive feedback manner. Notably, OA-RD17 promoted transition from the inflammatory to proliferative stage, accelerated epidermal and granulation regeneration, and exhibited therapeutic effects on mouse and diabetic patient ex vivo skin wounds. MiR-632 activated Wnt/ß-catenin to promote full-thickness skin wound healing in rats. CONCLUSIONS: OA-RD17 exhibited promising therapeutic effects on mice (full-thickness, deep second-degree burns), and ex vivo skin wounds in diabetic patients by regulating macrophages proliferation, migration, and polarization (MAPK, NF-κB), and keratinocytes proliferation and migration (TLR4/MAPK/miR-632/Wnt/ß-catenin molecular axis). Moreover, miR-632 also activated Wnt/ß-catenin to promote full-thickness skin wound healing in rats. Notably, our results indicate that OA-RD17 and miR-632 are promising pro-healing drug candidates.

Pannexin1 Channel-Mediated Inflammation in Acute Ischemic Stroke.

Emerging evidence suggests that inflammation mediated by the pannexin1 channel contributes significantly to acute ischemic stroke. It is believed that the pannexin1 channel is key in initiating central system inflammation during the early stages of acute ischemic stroke. Moreover, the pannexin1 channel is involved in the inflammatory cascade to maintain the inflammation levels. Specifically, the interaction of pannexin1 channels with ATP-sensitive P2X7 purinoceptors or promotion of potassium efflux mediates the activation of the NLRP3 inflammasome, triggering the release of pro-inflammatory factors such as IL-1 and IL-18, exacerbating and sustaining inflammation of brain. Also, increased release of ATP induced by cerebrovascular injury activates pannexin1 in vascular endothelial cells. This signal directs peripheral leukocytes to migrate into ischemic brain tissue, leading to an expansion of the inflammatory zone. Intervention strategies targeting pannexin1 channels may greatly alleviate inflammation after acute ischemic stroke to improve this patient population's clinical outcomes. In this review, we sought to summarize relevant studies on inflammation mediated by the pannexin1 channel in acute ischemic stroke and discussed the possibility of using brain organoid-on-a-chip technology to screen miRNAs that exclusively target the pannexin1 channel to provide new therapeutic measures for targeted regulation of pannexin1 channel to reduce inflammation in acute ischemic stroke.

N6-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice.

Bacteria-triggered sepsis is characterized by systemic, uncontrolled inflammation in affected individuals. Controlling the excessive production of pro-inflammatory cytokines and subsequent organ dysfunction in sepsis remains challenging. Here, we demonstrate that Spi2a upregulation in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages reduces the production of pro-inflammatory cytokines and myocardial impairment. In addition, exposure to LPS upregulates the lysine acetyltransferase, KAT2B, to promote METTL14 protein stability through acetylation at K398, leading to the increased m6A methylation of Spi2a in macrophages. m6A-methylated Spi2a directly binds to IKKß to impair IKK complex formation and inactivate the NF-κB pathway. The loss of m6A methylation in macrophages aggravates cytokine production and myocardial damage in mice under septic conditions, whereas forced expression of Spi2a reverses this phenotype. In septic patients, the mRNA expression levels of the human orthologue SERPINA3 negatively correlates with those of the cytokines, TNF, IL-6, IL-1ß and IFNγ. Altogether, these findings suggest that m6A methylation of Spi2a negatively regulates macrophage activation in the context of sepsis.

Peptide RL-QN15 promotes regeneration of epidermal nerve fibers and recovery of sensory function in diabetic skin wounds.

Epidermal nerve fiber regeneration and sensory function are severely impaired in skin wounds of diabetic patients. To date, however, research on post-traumatic nerve regeneration and sensory reconstruction remains scarce, and effective clinical therapeutics are lacking. In the current study, localized treatment with RL-QN15, considered as a drug candidate for intervention in skin wounds in our previous research, accelerated the healing of full-thickness dorsal skin wounds in diabetic mice and footpad skin wounds in diabetic rats. Interestingly, nerve density and axonal plasticity in the skin wounds of diabetic rats and mice, as well as plantar sensitivity in diabetic rats, were markedly enhanced by RL-QN15 treatment. Furthermore, RL-QN15 promoted the proliferation, migration, and axonal length of neuron-like PC12 cells, which was likely associated with activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) signaling pathway. The therapeutic effects of RL-QN15 were partially reduced by blocking the PI3K/Akt signaling pathway with the inhibitor LY294002. Thus, RL-QN15 showed positive therapeutic effects on the distribution of epidermal nerve fibers and stimulated the recovery of sensory function after cutaneous injury. This study lays a solid foundation for the development of RL-QN15 peptide-based therapeutics against diabetic skin wounds.

An integrated study of hormone-related sarcopenia for modeling and comparative transcriptome in rats.

Sarcopenia is a senile disease with high morbidity, serious complications and limited clinical treatments. Menopause increases the risk of sarcopenia in females, while the exact pathogenesis remains unclear. To systematically investigate the development of hormone-related sarcopenia, we established a model of sarcopenia by ovariectomy and recorded successive characteristic changes. Furthermore, we performed the transcriptome RNA sequencing and bioinformatics analysis on this model to explore the underlying mechanism. In our study, we identified an integrated model combining obesity, osteoporosis and sarcopenia. Functional enrichment analyses showed that most of the significantly enriched pathways were down-regulated and closely correlated with endocrine and metabolism, muscle dysfunction, cognitive impairment and multiple important signaling pathways. We finally selected eight candidate genes to verify their expression levels. These findings confirmed the importance of estrogen in the maintenance of skeletal muscle function and homeostasis, and provided potential targets for further study on hormone-related sarcopenia.

Novel ammonia-responsive carboxymethyl cellulose/Co-MOF multifunctional films for real-time visual monitoring of seafood freshness.

Nowadays, ammonia-responsive biopolymer-based intelligent active films are of great interest for their huge potential in maintaining and monitoring the freshness of seafood. However, it is still a challenge to create biopolymer-based intelligent active films with favorable color stability, antibacterial and visual freshness indication functions. Herein, cobalt-based metal-organic framework (Co-MOF) nanosheets with ammonia-sensitive and antibacterial functions were successfully synthesized and then embedded into carboxymethyl cellulose (CMC) matrix to develop high performance and multifunctional CMC-based intelligent active films. The influence of Co-MOF addition on the structure, physical and functional characters of CMC film was comprehensively studied. The results showed that the Co-MOF nanofillers were homogeneously embedded within the CMC matrix, bringing about remarkable promotion on tensile strength (from 45.3 to 62.2 MPa), toughness (from 0.7 to 2.3 MJ/m3), water barrier and UV-blocking performance of CMC film. Notably, the obtained CMC/Co-MOF nanocomposite films also presented excellent long-term color stability, antibacterial activity (with the bacteriostatic efficiency of 99.6 % and 99.3 % against Escherichia coli and Staphylococcus aureus), and ammonia-sensitive discoloration performance. Finally, the CMC/Co-MOF nanocomposite films were successfully applied for real-time visual monitoring of shrimp freshness. The above results demonstrate that the CMC/Co-MOF nanocomposite films possess huge potential applications in intelligent active packaging.

FAAH served a key membrane-anchoring and stabilizing role for NLRP3 protein independently of the endocannabinoid system.

NLRP3, the sensor protein of the NLRP3 inflammasome, plays central roles in innate immunity. Over-activation of NLRP3 inflammasome contributes to the pathogenesis of a variety of inflammatory diseases, while gain-of-function mutations of NLRP3 cause cryopyrin-associated periodic syndromes (CAPS). NLRP3 inhibitors, particularly those that inhibit inflammasome assembly and activation, are being intensively pursued, but alternative approaches for targeting NLRP3 would be highly desirable. During priming NLRP3 protein is synthesized on demand and becomes attached to the membranes of ER and mitochondria. Here, we show that fatty acid amide hydrolase (FAAH), the key integral membrane enzyme in the endocannabinoid system, unexpectedly served the critical membrane-anchoring and stabilizing role for NLRP3. The specific interaction between NLRP3 and FAAH, mediated by the NACHT and LRR domains of NLRP3 and the amidase signature sequence of FAAH, was essential for preventing CHIP- and NBR1-mediated selective autophagy of NLRP3. Heterozygous knockout of FAAH, resulting in ~50% reduction in both FAAH and NLRP3 expression, was sufficient to substantially inhibit the auto-inflammatory phenotypes of the NLRP3-R258W knock-in mice, while homozygous FAAH loss almost completely abrogates these phenotypes. Interestingly, select FAAH inhibitors, in particular URB597 and PF-04457845, disrupted NLRP3-FAAH interaction and induced autophagic NLRP3 degradation, leading to diminished inflammasome activation in mouse macrophage cells as well as in peripheral blood mononuclear cells isolated from CAPS patients. Our results unraveled a novel NLRP3-stabilizing mechanism and pinpointed NLRP3-FAAH interaction as a potential drug target for CAPS and other NLRP3-driven diseases.

Cathodic Carbonyl Alkylation of Aryl Ketones or Aldehydes with Unactivated Alkyl Halides.

An efficient cathodic carbonyl alkylation of aryl ketones or aldehydes with unactivated alkyl halides has been realized through the electrochemical activation of iron. The protocol is believed to include a radical-radical coupling or nucleophilic addition process, and the formation of ketyl radicals and alkyl radicals has been demonstrated. The protocol provides various tertiary or secondary alcohols by the formation of intermolecular C-C bonds under safe and mild conditions, is scalable, consumes little energy, and exhibits a broad substrate scope.