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Developing methods to directly transform C(sp 3 ) -H bonds is crucial in synthetic chemistry due to their prevalence in various organic compounds. While conventional protocols have largely relied on transition metal catalysis, recent advancements in organocatalysis, particularly with radical NHC catalysis have sparked interest in the direct functionalization of "inert" C(sp 3 ) -H bonds for cross C-C coupling with carbonyl moieties. This strategy involves selective cleavage of C(sp 3 ) -H bonds to generate key carbon radicals, often achieved via hydrogen atom transfer (HAT) processes. By leveraging the bond dissociation energy (BDE) and polarity effects, HAT enables the rapid functionalization of diverse C(sp 3 )-H substrates, such as ethers, amines, and alkanes. This mini-review summarizes the progress in carbene organocatalytic functionalization of inert C(sp 3 )-H bonds enabled by HAT processes, categorizing them into two sections: 1) C-H functionalization involving acyl azolium intermediates; and 2) functionalization of C-H bonds via reductive Breslow intermediates., (© 2024 Wiley-VCH GmbH.)

Macrolactones exhibit distinct conformational and configurational properties and are widely found in natural products, medicines, and agrochemicals. Up to now, the major effort for macrolactonization is directed toward identifying suitable carboxylic acid/alcohol coupling reagents to address the challenges associated with macrocyclization, wherein the stereochemistry of products is usually controlled by the substrate's inherent chirality. It remains largely unexplored in using catalysts to govern both macrolactone formation and stereochemical control. Here, we disclose a non-enzymatic organocatalytic approach to construct macrolactones bearing chiral planes from achiral substrates. Our strategy utilizes N-heterocyclic carbene (NHC) as a potent acylation catalyst that simultaneously mediates the macrocyclization and controls planar chirality during the catalytic process. Macrolactones varying in ring sizes from sixteen to twenty members are obtained with good-to-excellent yields and enantiomeric ratios. Our study shall open new avenues in accessing macrolactones with various stereogenic elements and ring structures by using readily available small-molecule catalysts., (© 2024. The Author(s).)

The direct functionalization of inert C(sp 3 )-H bonds to form carbon-carbon and carbon-heteroatom bonds offers vast potential for chemical synthesis and therefore receives increasing attention. At present, most successes come from strategies using metal catalysts/reagents or photo/electrochemical processes. The use of organocatalysis for this purpose remains scarce, especially when dealing with challenging C-H bonds such as those from simple alkanes. Here we disclose the first organocatalytic direct functionalization/acylation of inert C(sp 3 )-H bonds of completely unfunctionalized alkanes. Our approach involves N-heterocyclic carbene catalyst-mediated carbonyl radical intermediate generation and coupling with simple alkanes (through the corresponding alkyl radical intermediates generated via a hydrogen atom transfer process). Unreactive C-H bonds are widely present in fossil fuel feedstocks, commercially important organic polymers, and complex molecules such as natural products. Our present study shall inspire a new avenue for quick functionalization of these molecules under the light- and metal-free catalytic conditions., (© 2023 Wiley-VCH GmbH.)

The gene mutations of LRRK2, which encodes leucine-rich repeat kinase 2 (LRRK2), are associated with one of the most prevalent monogenic forms of Parkinson's disease (PD). However, the potential effectors of the Gly2019Ser (G2019S) mutation remain unknown. In this study, the authors investigate the effects of LRRK2 G2019S on endoplasmic reticulum (ER) stress in induced pluripotent stem cell (iPSC)-induced dopamine neurons and explore potential therapeutic targets in mice model. These findings demonstrate that LRRK2 G2019S significantly promotes ER stress in neurons and mice. Interestingly, inhibiting LRRK2 activity can ameliorate ER stress induced by the mutation. Moreover, LRRK2 mutation can induce ER stress by directly interacting with thrombospondin-1/transforming growth factor beta1 (THBS1/TGF-β1). Inhibition of LRRK2 kinase activity can effectively suppress ER stress and the expression of THBS1/TGF-β1. Knocking down THBS1 can rescue ER stress by interacting with TGF-β1 and behavior burden caused by the LRRK2 mutation, while suppression of TGF-β1 has a similar effect. Overall, it is demonstrated that the LRRK2 mutation promotes ER stress by directly interacting with THBS1/TGF-β1, leading to neural death in PD. These findings provide valuable insights into the pathogenesis of PD, highlighting potential diagnostic markers and therapeutic targets., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The development of catalyst-controlled methods for direct functionalization of two distinct C-H bonds represents an appealing approach for C-C formations in synthetic chemistry. Herein, we describe an organocatalytic approach for straightforward acylation of C(sp 3 )-H bonds employing readily available aldehyde as "acyl source" involving dehydrogenative coupling of aldehydes with ether, amine, or benzylic C(sp 3 )-H bonds. The developed method affords a broad range of ketones under mild conditions. Mechanistically, simple ortho-cyanoiodobenzene is essential in the oxidative radical N-heterocyclic carbene catalysis to give a ketyl radical and C(sp 3 ) radical through a rarely explored intermolecular hydrogen atom transfer pathway, rendering the acylative C-C formations in high efficiency under a metal- and light-free catalytic conditions. Moreover, the prepared products show promising anti-bacterial activities that shall encourage further investigations on novel agrochemical development., (© 2023 Wiley-VCH GmbH.)

Facial nerve, the 7th cranial nerve, is a mixed nerve composed of sensory and motor fibers, and its main branch is situated in the cerebellopontine angle. Facial nerve dysfunction is a debilitating phenomenon that can occur in skullbase tumors and Bell's pals. Recovery of the facial nerve dysfunction after surgery for skullbase tumors can be disappointing, but is usually favorable in Bell's palsy. Advances in magnetic resonance imaging (MRI) allow to visualize the facial nerve and its course in the cerebellopontine angle, also when a large tumor is present and compresses the nerve. Here, we describe the anatomical, neurochemical and clinical aspects of the facial nerve and highlight the recent progress in visualizing the facial nerve with MRI., (© 2023. The Author(s).)

The pathogenesis of Parkinson's disease remains unclear that there is no cure for Parkinson's disease yet. The abnormal expressions of certain miRNA are closely related to the occurrence and progression of Parkinson's disease. Here, we demonstrate that miR-9-5p inhibits the dopaminergic neuron apoptosis via the regulation of β -catenin signaling which directly targets SCRIB, a tumor suppressor gene. Besides, miR-9-5p improved the motor function of mice with Parkinson's disease. The results of this study suggest that miR-9-5p might be a potential therapeutic target against Parkinson's disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhenyong Xiao et al.)

Glioma is one of the most frequent intracranial malignant tumors. Abnormal expression of microRNAs usually contributes to the development and progression of glioma. In the current study, we explored the role and underlying mechanism of miR-497 in glioma. We revealed that miR-497 expression was significantly down-regulated in glioma tissues and cell lines. Reduced expression of miR-497 was associated with poor disease-free and over-all survival rate. Restoration of miR-497 decreased glioma cell growth and invasion both in vitro and in vivo. The oncogene Wnt3a was identified as a downstream target of miR-497 by using luciferase and western blot assays. Knockdown of Wnt3a mimicked the effect of miR-497 in glioma cells. In summary, our study demonstrated that miR-497 may function as a tumor suppressor in glioma and suggested that miR-497 is a potential therapeutic target for glioma patients., (Copyright © 2018. Published by Elsevier B.V.)

The role of microglial-mediated sustained neuroinflammation in the onset and progression of Parkinson's disease (PD) is well established, but the mechanisms contributing to microglial activation remain unclear. LincRNA-p21, a well studied long intergenic noncoding RNA (lincRNA), plays pivotal roles in diverse biological processes and diseases. Its role in microglial activation and inflammation-induced neurotoxicity, however, has not yet been fully elucidated. Here, we report that lincRNA-p21 promotes microglial activation through a p53-dependent transcriptional pathway. We further demonstrate that lincRNA-p21 competitively binds to the miR-181 family and induces microglial activation through the miR-181/PKC-δ pathway. Moreover, PKC-δ induction further increases the expression of p53/lincRNA-p21 and thus forms a circuit. Taken together, our results suggest that p53/lincRNA-p21, together with miR-181/PKC-δ, form a double-negative feedback loop that facilitates sustained microglial activation and the deterioration of neurodegeneration.

Background: Parkinson's disease (PD) is the most prevalent neurodegenerative disorder that is characterised by selective loss of midbrain dopaminergic (DA) neurons. Chronic inflammation of the central nervous system is mediated by microglial cells and plays a critical role in the pathological progression of PD. Brain-specific microRNA-124 (miR-124) expression is significantly downregulated in lipopolysaccharide (LPS)-treated BV2 cells and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. However, whether abnormal miR-124 expression could regulate the activation of microglia remains poorly understood., Methods: BV2 cells were activated by exposure to LPS, and the expression levels of miR-124, mitogen-activated protein kinase kinase kinase 3 (MEKK3), and the nuclear factor of kappaB (NF-κB) p-p65 were analysed. Over-expression and knockdown studies of miR-124 were performed to observe the effects on MEKK3/NF-κB signalling pathways, and the induction of pro-inflammatory and neurotoxic factors was assessed. In addition, a luciferase reporter assay was conducted to confirm whether MEKK3 is a direct target of miR-124. Meanwhile, production of miR-124, MEKK3, and p-p65; midbrain DA neuronal death; or activation of microglia were analysed when treated with or without miR-124 in the MPTP-induced model of PD., Results: We found that the knockdown of MEKK3 could inhibit the activation of microglia by regulating NF-κB expression. Over-expression of miR-124 could effectively attenuate the LPS-induced expression of pro-inflammatory cytokines and promote the secretion of neuroprotective factors. We also first identified a unique role of miR-124 in mediating the microglial inflammatory response by targeting MEKK3/NF-κB signalling pathways. In the microglial culture supernatant (MCS) transfer model, over-expression of the miR-124 or knockdown of MEKK3 in BV2 cells prevented SH-SY5Y from apoptosis and death. Moreover, MEKK3 and p-p65 were abundantly expressed in the midbrain. Furthermore, their expression levels increased and microglial activation was observed in the MPTP-induced model of PD. In addition, exogenous delivery of miR-124 could suppress MEKK3 and p-p65 expression and attenuate the activation of microglia in the substantia nigra pars compacta of MPTP-treated mice. miR-124 also could prevent MPTP-dependent apoptotic midbrain DA cell death in a MPTP-induced PD model., Conclusions: Taken together, our data suggest that miR-124 can inhibit neuroinflammation in the development of PD by regulating the MEKK3/NF-κB signalling pathways and implicate miR-124 as a potential therapeutic target for regulating the inflammatory response in PD.

MicroRNAs (miRNAs), a kind of endogenous non-coding RNAs, regulate gene expression through binding to the 3'-untranslational region (UTR) of target messenger RNAs (mRNAs) and act as endogenous agents of RNA interference, resulting in either mRNA degradation or translational repression. MiR-31 has been demonstrated to be associated with the development and progression of glioma. However, the underlying molecular mechanism remains largely unclear. In the present study, we demonstrated that miR-31 only inhibited the cell migration and invasion, as well as the expression of a known miR-31 target oncogene radixin, in U251 glioma cells that expressed low level of p21; however, miR-31 showed no above effects on glioma SHG44 cells that highly expressed p21. Moreover, upregulation of p21 in U251 cells reversed the suppressive effects of miR-31 on the cell migration and invasion, suggesting that low p21 level is necessary for the miR-31-mediated inhibitory effects on glioma. Furthermore, analysis for 35 glioma specimens showed that the expression of radixin was negatively correlated with the miR-31 level in glioma tissues with low p21 expression; however, no such correlation was found in glioma tissues with high p21 level, further supporting that the low p21 level is necessary for the suppressive effect of miR-31 on the expression of its target oncogenes. In summary, our study demonstrates that the suppressive effect of miR-31 on glioma cell migration and invasion is p21-dependent, and suggests that miR-31 may be used for the treatment of patients with p21-deficent glioma.

Parkinson's disease (PD) is the most prevalent movement disorder characterized by selective loss of midbrain dopaminergic (DA) neurons. MicroRNA-124 (miR-124) is abundantly expressed in the DA neurons and its expression level decreases in the 1-methyl-4-pheny-1, 2, 3, 6-tetrahydropyridine (MPTP) model of PD. However, whether the upregulation of miR-124 could attenuate neurodegeneration remains unknown. Here, we employed miR-124 agomir and miR-124 mimics to upregulate miR-124 expression in MPTP-treated mice and MPP(+) -intoxicated SH-SY5Y cells, respectively. We found that loss of DA neurons and striatal dopamine in MPTP-treated mice was significantly reduced by upregulating miR-124. In addition, we identified a target of miR-124, Bim that mediated the neuroprotection of miR-124. Indeed, treatment of miR-124 agomir in MPTP-treated mice inhibited Bim expression, thus suppressing Bax translocation to mitochondria. Moreover, impaired autophagy process in MPTP-treated mice and MPP(+) -intoxicated SH-SY5Y cells characterized as autophagosomes (AP) accumulation and lysosomal depletion were alleviated by the upregulation of miR-124. Taken together, these results indicate that upregulation of miR-124 could regulate apoptosis and impaired autophagy process in the MPTP model of PD, thus reducing the loss of DA neurons., (© 2015 International Society of Neuropathology.)