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.

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.

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.

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.

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.

Anodic C(sp3)-H Acyloxylation of Indolin-3-ones Enabled by Oxidant-Free Cross-Dehydrogenative C(sp3)-O Coupling.

An efficient anodic C(sp3)-H acyloxylation protocol has been established via intermolecular cross-dehydrogenative C(sp3)-O coupling. The protocol provides various C2-acyloxy indolin-3-ones without the addition of metal catalysts and external oxidants because indolin-3-ones can be directly oxidized at the anode. The effective application of several medical drugs and the realization of the gram-scale experiment have proven the practicality of this protocol.

Synthesis of Substituted Thiophenes through Dehydration and Heterocyclization of Alkynols.

A protocol was described for obtaining a variety of substituted thiophenes with functional potential via metal-free dehydration and sulfur cyclization of alkynols with elemental sulfur (S8) or EtOCS2K in moderate-to-good yields. The method provides the base-free generation of a trisulfur radical anion (S3•-) and its addition to alkynes as an initiator. This research broadens the applications of S3•- in the synthesis of sulfur-containing heterocycles.

Synthetic flavagline derivative 1-chloroacetylrocaglaol promotes apoptosis in K562 erythroleukemia cells through miR-17-92 cluster genes.

Chronic myeloid leukemia accounts for human deaths worldwide and could enhance sevenfold by 2050. Thus, the treatment regimen for this disorder is highly crucial at this time. Flavaglines are a natural class of cyclopentane benzofurans exhibiting various bioactivities like anticancer action. Despite the antiproliferative activity of flavaglines against diverse cancer cells, their roles and mechanism of action in chronic myeloid leukemia (CML) remain poorly understood. Thus, this study examines the antiproliferative effect of a newly synthesized flavagline derivative, 1-chloracetylrocaglaol (A2074), on erythroleukemia K562 cells and the zebrafish xenograft model. The study revealed that A2074 could inhibit proliferation, promote apoptosis, and boost megakaryocyte differentiation of K562 cells. This flavagline downregulated c-MYC and miR-17-92 cluster genes, targeting upregulation of the apoptotic protein Bcl-2-like protein 11 (BIM). The work uncovered a critical role of the c-MYC-miR-17-92-BIM axis in the growth and survival of CML cells.

Cardiac fibroblast miR-27a may function as an endogenous anti-fibrotic by negatively regulating Early Growth Response Protein 3 (EGR3).

Pathological myocardial fibrosis and hypertrophy occur due to chronic cardiac stress. The microRNA-27a (miR-27a) regulates collagen production across diverse cell types and organs to inhibit fibrosis and could constitute an important therapeutic avenue. However, its impact on hypertrophy and cardiac remodelling is less well-known. We employed a transverse aortic constriction (TAC) murine model of left ventricular pressure overload to investigate the in vivo effects of genetic miR-27a knockout, antisense inhibition of miR-27a-5p and fibroblast-specific miR-27a knockdown or overexpression. In silico Venn analysis and reporter assays were used to identify miR-27a-5p's targeting of Early Growth Response Protein 3 (Egr3). We evaluated the effects of miR-27a-5p and Egr3 upon transforming growth factor-beta (Tgf-ß) signalling and secretome of cardiac fibroblasts in vitro. miR-27a-5p attenuated TAC-induced cardiac fibrosis and myofibroblast activation in vivo, without a discernible effect on cardiac myocytes. Molecularly, miR-27a-5p inhibited transforming growth factor-beta (Tgf-ß) signalling and pro-fibrotic protein secretion in cardiac fibroblasts in vitro through suppressing the pro-fibrotic transcription factor Early Growth Response Protein 3 (Egr3). This body of work suggests that cardiac fibroblast miR-27a may function as an endogenous anti-fibrotic by negatively regulating Egr3 expression.

Metal-Free Cascade Formation of Intermolecular C-N Bonds Accessing Substituted Isoindolinones under Cathodic Reduction.

An electrochemical protocol for the construction of substituted isoindolinones via reduction/amidation of 2-carboxybenzaldehydes and amines has been realized. Under metal-free and external-reductant-free electrolytic conditions, the reaction achieves the cascade formation of intermolecular C-N bonds and provides a series of isoindolinones in moderate to good yields. The deuterium-labeling experiment proves that the hydrogen in the methylene of the product is mainly provided by H2O in the system.

Effects of purslane supplementation on C-reactive protein levels and biomarkers of oxidative stress as marks for metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials.

The antioxidant and antiinflammatory properties of purslane (Portulaca oleracea L.) are known in preclinical studies but further examination is needed to expand their potential into the clinical scenario. A systematic review and meta-analysis of randomized controlled trials were performed to elucidate the effects of purslane supplementation on C-reactive protein (CRP) levels and biomarkers of oxidative stress in metabolic syndrome, its related complications, and other diseases. PubMed/MEDLINE, Web of Science, SCOPUS, and Embase were the databases searched. Heterogeneity was examined using the I-squared (I2 ) statistic, in which the source of heterogeneity was determined if the I2 -value was >50%. After all the screening processes, 10 studies met the eligibility criteria and were analyzed. Following purslane supplementation, CRP levels decreased significantly (weighted mean difference [WMD]: -0.33 mg/dl, 95% confidence interval [CI]: -0.66, -0.004, p = .047) but with significant heterogeneity (I2  = 87.4%, p = .001). Purslane supplementation did not significantly change serum levels of malondialdehyde (MDA) (WMD: -0.353 µm/L; 95% CI: -0.920, 0.213; I2  = 50.7%), total antioxidant capacity (TAC) (WMD: 0.090 mm/L, 95% CI: -0.081, 0.262; I2  = 47.1%), and superoxide dismutase (SOD) (WMD: 6.54 U/ml, 95% CI: -22.150, 35.236; I2  = 70.7%). Thus, this meta-analysis showed a positive effect of purslane supplementation as a tool to decrease CRP levels, but not to MDA, TAC, and SOD levels.

Access to Substituted Thiophenes through Xanthate-Mediated Vinyl C(sp2)-Br Bond Cleavage and Heterocyclization of Bromoenynes.

An environmentally sustainable strategy for the chemoselective heterocyclization of bromoenynes through a transition-metal-free sulfuration/cyclization process is reported. Using inexpensive and safe EtOCS2K as a thiol surrogate and tetrabutylphosphonium bromide and H2O as a mixed solvent, the reaction provided a range of substituted thiophenes in moderate to good yields. In addition, 2,3,4,5-tetrasubstituted thiophenes were able to be prepared under mild reaction conditions by electrophilic heterocyclization with NH4I and EtOCS2K in good yields.

Metal-Free Oxidative Esterification of Ketones and Potassium Xanthates: Selective Synthesis of α-Ketoesters and Esters.

A novel and efficient oxidative esterification for the selective synthesis of α-ketoesters and esters has been developed under metal-free conditions. In the protocol, various α-ketoesters and esters are available in high yields from commercially available ketones and potassium xanthates. Mechanistic studies have proven that potassium xanthate not only promotes oxidative esterification but also provides an alkoxy moiety for the reaction, which involves the cleavage and reconstruction of C-O bonds.

Selective synthesis of pyridyl pyridones and oxydipyridines by transition-metal-free hydroxylation and arylation of 2-fluoropyridine derivatives.

An efficient protocol for the construction of various pyridyl pyridone and oxydipyridine derivatives through a hydroxylation and arylation tandem reaction of 2-fluoropyridines is reported. Under simple transition-metal-free conditions, the reaction provided a series of products in good to excellent yields, and their structures were confirmed by crystal diffraction analysis. Furthermore, the controlling effect of 6-position substituents on the highly selective synthesis of pyridone and oxydipyridine was studied.

Direct electrochemical reductive amination between aldehydes and amines with a H/D-donor solvent.

A novel electrochemical synthesis protocol has been achieved for reductive amination between aldehydes and amines in undivided cells at room temperature. Under metal-free and external-reductant-free electrolysis conditions, various important secondary amine products are obtained in moderate-to-high yields. Deuterium-labeling experiments have demonstrated that low-toxicity DMSO acts both as a solvent and a H-donor in the reaction. On this basis, various deuterium-labeled products with good-to-excellent D-incorporation have been synthesized by using DMSO-d6 as a solvent. Furthermore, a molecule with GR-antagonistic activity has been synthesized through further sulfonylation.

Synthesis of N-Biheteroarenes via Acceptorless Dehydrogenative Coupling of Benzocyclic Amines with Indole Derivatives.

Here, via a strategy of in situ capture of partially dehydrogenated cyclic amine motifs, we present an acceptorless dehydrogenative coupling of benzocyclic amines with indole derivatives that enables to access various quinoline-indole linked N-biheteroarenes in an efficient manner. The catalytic transformation is characteristic of operational simplicity, a readily available catalyst system, good substrate and functional compatibility, mild conditions, high atom efficiency, and no need for oxidant and halogenated coupling agents.

NH4I-Promoted and H2O-Controlled Intermolecular Bis-sulfenylation and Hydroxysulfenylation of Alkenes via a Radical Process.

An NH4I-promoted and H2O-controlled intermolecular difunctionalization of alkenes for the synthesis of bis-methylsulfane and ß-hydroxysulfides is presented. Mechanistic investigation revealed the reaction proceeds via methylthiyl radical addition to C═C of alkenes to give a carbon-centered radical and immediately cyclize to a thiiranium ion, followed by combination with H2O to afford ß-hydroxysulfides in 52-89% yields with chemo- and regioselectivities. In the absence of water, 1,2-disulfenylation takes place to give bis-methylsulfane in moderate to good yields.

Electrochemical Synthesis Strategy for Cvinyl-CF3 Compounds through Decarboxylative Trifluoromethylation.

An efficient decarboxylative trifluoromethylation of α,ß-unsaturated carboxylic acids using the Langlois reagent as a trifluoromethyl precursor has been achieved by an electro-oxidative strategy. Under catalyst-free and external oxidant-free electrolysis conditions, a series of Cvinyl-CF3 compounds are obtained with a high regioselectivity in good yields. The successful trapping of the CF3 radical by a scavenger has confirmed that radical processes are involved in this system.

Direct access to bis-S-heterocycles via copper-catalyzed three component tandem cyclization using S8 as a sulfur source.

A novel strategy for constructing sulfur containing bis-S-heterocyclic compounds from oxime esters/vinyl azide, phenylacetylene/aldehydes and elemental sulfur (S8) has been developed. These transformations show good functional group tolerance. Various bis-S-heterocyclic products were efficiently synthesized from easily prepared or widely commercially available starting materials. In this protocol, S8 successfully served as a two-sulfur atom donor for thiophene and thiazole rings, respectively.

Electrochemical vicinal aminotrifluoromethylation of alkenes: high regioselective acquisition of ß-trifluoromethylamines.

A novel vicinal aminotrifluoromethylation of alkenes using CF3SO2Na as a trifluoromethyl precursor and acetonitrile as an N-nucleophile has been achieved by an electrooxidative strategy. The present electrochemical protocol achieves efficient and highly regioselective difunctionalization of C[double bond, length as m-dash]C bonds under metal-free and external oxidant-free electrolysis conditions, leading to a series of ß-trifluoromethylamine compounds with good to excellent yields. It is confirmed that the reaction involves free radical processes since CF3 radicals are trapped by scavengers and the ß-trifluoromethylated radical is trapped by BHT, and the deuterium-labeling experiments prove that the oxygen in the product comes from water.