NAC1 confines virus-specific memory formation of CD4+ T cells through the ROCK1-mediated pathway.

Nucleus accumbens-associated protein 1 (NAC1), a transcriptional cofactor, has been found to play important roles in regulating regulatory T cells, CD8+ T cells, and antitumor immunity, but little is known about its effects on T-cell memory. In this study, we found that NAC1 expression restricts memory formation of CD4+ T cells during viral infection. Analysis of CD4+ T cells from wild-type (WT) and NAC1-deficient (-/- ) mice showed that NAC1 is essential for T-cell metabolism, including glycolysis and oxidative phosphorylation, and supports CD4+ T-cell survival in vitro. We further demonstrated that a deficiency of NAC1 downregulates glycolysis and correlates with the AMPK-mTOR pathway and causes autophagy defective in CD4+ T cells. Loss of NAC1 reduced the expression of ROCK1 and the phosphorylation and stabilization of BECLIN1. However, a forced expression of ROCK1 in NAC1-/- CD4+ T cells restored autophagy and the activity of the AMPK-mTOR pathway. In animal experiments, adoptively transferred NAC1-/- CD4+ T cells or NAC1-/- mice challenged with VACV showed enhanced formation of VACV-specific CD4+ memory T cells compared to adoptively transferred WT CD4+ T cells or WT mice. This memory T-cell formation enhancement was abrogated by forcing expression of ROCK1. Our study reveals a novel role for NAC1 as a suppressor of CD4+ T-cell memory formation and suggests that targeting NAC1 could be a new approach to promoting memory CD4+ T-cell development, which is critical for an effective immune response against pathogens.

Role and clinical implication of autophagy in COVID-19.

The ongoing coronavirus disease 2019 (COVID-19) pandemic constitutes a serious public health concern worldwide. Currently, more than 6 million deaths have occurred despite drastic containment measures, and this number is still increasing. Currently, no standard therapies for COVID-19 are available, which necessitates identifying effective preventive and therapeutic agents against COVID-19. However, developing new drugs and vaccines is a time-consuming process, and therefore, repurposing the existing drugs or redeveloping related targets seems to be the best strategy to develop effective therapeutics against COVID-19. Autophagy, a multistep lysosomal degradation pathway contributing to nutrient recycling and metabolic adaptation, is involved in the initiation and progression of numerous diseases as a part of an immune response. The key role of autophagy in antiviral immunity has been extensively studied. Moreover, autophagy can directly eliminate intracellular microorganisms by selective autophagy, that is, "xenophagy." However, viruses have acquired diverse strategies to exploit autophagy for their infection and replication. This review aims to trigger the interest in the field of autophagy as an antiviral target for viral pathogens (with an emphasis on COVID-19). We base this hypothesis on summarizing the classification and structure of coronaviruses as well as the process of SARS-CoV-2 infection and replication; providing the common understanding of autophagy; reviewing interactions between the mechanisms of viral entry/replication and the autophagy pathways; and discussing the current state of clinical trials of autophagy-modifying drugs in the treatment of SARS-CoV-2 infection. We anticipate that this review will contribute to the rapid development of therapeutics and vaccines against COVID-19.

Cu(I)-Catalyzed Cross-Coupling Rearrangements of Terminal Alkynes with Tropylium Tetrafluoroborate: Facile Access to Barbaralyl-Substituted Allenyl Acid Esters and 7-Alkynyl Cycloheptatrienes.

Herein, we report a novel strategy for the formation of copper carbene via the cycloisomerization of the π-alkyne-Cu(I) complex from terminal alkynes and tropylium tetrafluoroborate. Mechanistic studies and DFT calculations indicate that the reaction undergoes the intramolecular cycloisomerization process from the π-alkyne-Cu(I) complex to afford the copper carbene intermediate, followed by migratory insertion with the second terminal alkyne to afford the barbaralyl-substituted allenyl acid esters. In addition, we develop a mild and highly efficient Cu(I)-catalyzed cross-coupling protocol to synthesize 7-alkynyl cycloheptatrienes that has a broad functional group tolerance and is applicable to the late-stage functionalization of natural products.

Emerging role of autophagy in anti-tumor immunity: Implications for the modulation of immunotherapy resistance.

Immunotherapies such as CAR-T cell transfer and antibody-targeted therapy have produced promising clinical outcomes in patients with advanced and metastatic cancer that are resistant to conventional therapies. However, with increasing use of cancer immunotherapy in clinical treatment, multiple therapy-resistance mechanisms have gradually emerged. The tumor microenvironment (TME), an integral component of cancer, can significantly influence the therapeutic response. Thus, it is worth exploring the potential of TME in modulating therapy resistance, in the hope to devise novel strategies to reinforcing anti-cancer treatments such as immunotherapy. As a crucial recycling process in the complex TME, the role of autophagy in tumor immunity has been increasingly appreciated. Firstly, autophagy in tumor cells can affect their immune response through modulating MHC-I-antigen complexes, thus modulating immunogenic tumor cell death, changing functions of immune cells via secretory autophagy, reducing the NK- and CTL-mediated cell lysis and degradation of immune checkpoint proteins. Secondly, autophagy is critical for the differentiation, maturation and survival of immune cells in the TME and can significantly affect the immune function of these cells, thereby regulating the anti-tumor immune response. Thirdly, alteration of autophagic activity in stromal cells, especially in fibroblasts, can reconstruct the three-dimensional stromal environment and metabolic reprogramming in the TME. A number of studies have demonstrated that optimal induction or inhibition of autophagy may lead to effective therapeutic regimens when combined with immunotherapy. This review discusses the important roles of autophagy in tumor cells, immune cells and stromal cells in the context of tumor immunity, and the potential of combining the autophagy-based therapy with immunotherapy as novel therapeutic approaches against cancer.

Synthesis of novel 3/5(3,5)-(di)nitropaeonol hydrazone derivatives as nematicidal agents.

Eighteen novel 3/5(3,5)-(di)nitropaeonol hydrazone derivatives were prepared, and their structures well characterized by 1H NMR, HRMS, and mp. Due to the steric hindrance, the substituents on the C = N double bond of all hydrazine compounds (except E/Z = 4/1 for IV-1g, IV-1l, IV-2b, and E/Z = 3/2 for IV-1n, IV-3a) adopted E configuration. Among all compounds, four compounds 2, 4, IV-1j, and IV-1n exhibited potent nematicidal activity than their precursor paeonol, especially 5-nitropaeonol (2) and 3,5-dinitropaeonol (4) displayed the most potent nematicidal activity Heterodera glycines in vivo with LC50 values of 32.3307 and 36.7074 mg/L, respectively.

Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development.

Decreasing the levels of certain proteins has been shown to be important for controlling cancer but it is currently unknown whether proteins could potentially be targeted by the inhibiting of protein synthesis. Under this circumstance, targeting protein translation could preferentially affect certain pathways, which could then be of therapeutic advantage when treating cancer. In this report, eukaryotic elongation factor-2 kinase (EEF2K), which is involved in protein translation, was shown to regulate cholesterol metabolism. Targeting EEF2K inhibited key parts of the cholesterol pathway in cancer cells, which could be rescued by the addition of exogenous cholesterol, suggesting that it is a potentially important pathway modulated by targeting this process. Specifically, targeting EEF2K significantly suppressed tumour cell growth by blocking mRNA translation of the cholesterol biosynthesis transcription factor, sterol regulatory element-binding protein (SREBP) 2, and the proteins it regulates. The process could be rescued by the addition of LDL cholesterol taken into the cells via non-receptor-mediated-uptake, which negated the need for SREBP2 protein. Thus, the levels of SREBP2 needed for cholesterol metabolism in cancer cells are therapeutically vulnerable by targeting protein translation. This is the first report to suggest that targeting EEF2K can be used to modulate cholesterol metabolism to treat cancer.

Autophagy in T-cell differentiation, survival and memory.

Over the past decade, autophagy has emerged as a critical regulatory mechanism of the immune system through critically controlling various aspects of T cell biology and determining the fate of different T cell subsets. Autophagy maintains T cell development and survival by regulating the degradation of organelles and apoptotic proteins. The autophagic process also impacts the formation of memory T cells. Alteration of autophagy in T cells may lead to a variety of pathological conditions such as inflammation, autoimmune diseases and cancer. In this review, we discuss how autophagy impacts T cell differentiation, survival and memory, and its implication in immunotherapy for various diseases.

Synthesis of sulfonate derivatives of carvacrol and thymol as anti-oomycetes agents.

Two series of sulfonate derivatives of carvacrol and thymol were synthesized and screened in vitro for their anti-oomycete activity against Phytophthora capsici, respectively. Among all of 32 derivatives, five compounds 3a, 4a, 4k, 3n, and 4n exhibited more potent anti-oomycete activity against P. capsici with EC50 values of 66.66, 62.94, 68.65, 61.24, and 52.91 mg/L, respectively. This suggested that introduction of different substitutions at the hydroxyl position of 1/2 could have remarkable effect on anti-oomycete activity. Overall, when R1 = isopropyl and R2 = methyl, the anti-oomycete activities of the compounds were higher than that of the corresponding compounds of R1 = methyl and R2 = isopropyl.[Formula: see text].

Synthesis of novel 9R/S-acyloxy derivatives of cinchonidine and cinchonine as insecticidal agents.

Endeavor to discover biorational natural products-based insecticides, two series (27) of novel 9R/S-acyloxy derivatives of cinchonidine and cinchonine were prepared and assessed for their insecticidal activity against Mythimna separata in vivo by the leaf-dipping method at 1 mg/mL. Among all the compounds, especially derivatives 6l and 6o exhibited the best insecticidal activity with final mortality rates of 75.0% and 71.4%, respectively. Overall, a free 9-hydroxyl group is not a prerequisite for insecticidal activity and C9-substitution is well tolerated; the configuration of C8/9 position is important for insecticidal activity, and 9S-configuration is optimal; 6'-OCH3 moiety is not necessary, removal of it is also acceptable. [Formula: see text].

Synthesis, anti-oomycete activity, and SAR studies of paeonol derivatives.

Three series of sulfonate derivatives of paeonol were synthesized and screened in vitro for their anti-oomycete activity against P. capsici, respectively. Among all the compounds, 4m displayed the best promising and pronounced anti-oomycete activity against P. capsici than zoxamide, with the EC50 values of 24.51 and 26.87 mg/L, respectively. The results show that acetyl and 4-OCH3 are two necessary groups. The existence of these two sites is closely related to the anti-oomycete activity. Relatively speaking, hydroxyl group is well tolerated, and the results showed that after modification of hydroxyl group with sulfonyl, the anti-oomycete activity was significantly increased. [Formula: see text].

Enantioselective Alkoxycyclization of 1,6-Enynes with Gold(I)-Cavitands: Total Synthesis of Mafaicheenamine C.

Chiral gold(I)-cavitand complexes have been developed for the enantioselective alkoxycyclization of 1,6-enynes. This enantioselective cyclization has been applied for the first total synthesis of carbazole alkaloid (+)-mafaicheenamine C and its enantiomer, establishing its configuration as R. The cavity effect was also evaluated in the cycloisomerization of dienynes. A combination of experiments and theoretical studies demonstrates that the cavity of the gold(I) complexes forces the enynes to adopt constrained conformations, which results in the high observed regio- and stereoselectivities.

Synthesis of sulfonate derivatives of maltol and their biological activity against Phytophthora capsici and Bursaphelenchus xylophilus in vitro.

Sixteen sulfonate derivatives of maltol were synthesized and screened in vitro for their anti-oomycete and nematicidal activity against Phytophthora capsici and Bursaphelenchus xylophilus, respectively. Among all the compounds, 3e, 3m, and 3p exhibited the most promising and pronounced anti-oomycete activity against P. capsici than zoxamide, and the EC50 values of 25.42, 18.44, 23.69, and 27.99 mg/L, respectively; compounds 3e, 3m, 3n, and 3p exhibited potent nematicidal activity with LC50 values ranging from 1 to 2 mg/L, especially 3m and 3n showed the best promising and pronounced nematicidal activity, with LC50 values of 1.1762 and 1.2384 mg/L, respectively. [Formula: see text].

Synthesis and insecticidal activity of sulfonate derivatives of sesamol against Mythimna separata in vivo.

A series of sulfonate derivatives of sesamol were synthesized and evaluated for their insecticidal activity against a crop-threatening agricultural pest, the pre-third-instar larvae of Mythimna separata in vivo. Among all the target compounds, compounds 3b, 3g, 3h, and 3p exhibited more promising insecticidal activity than sesamol and toosendanin, and the final mortality rates (FMRs) of 3b, 3g, 3h, 3p, 1, and toosendanin were 60.7%/60.7%/67.9%/53.6%/32.1%/50.0%, respectively. Especially compound 3h exhibited the most potent insecticidal activity with FMRs of 67.9%. This suggested that a 4-fluorophenylsulfonyl group introduced at the hydroxyl position of sesamol was necessary for obtaining the most potent compound.[Formula: see text].

Controlled synthesis of N, N-dimethylarylsulfonamide derivatives as nematicidal agents.

Gramine can be intelligently and efficiently supplied with N, N-dimethylamino group and then reacted with the corresponding sulfonyl chlorides to synthesize N, N-dimethylarylsulfonamides. We herein designed and controlled synthesis of N, N-dimethylarylsulfonamide derivatives, and first reported the results of the nematicidal activity of 15 title compounds 3a-o against Meloidogyne incongnita in vitro, respectively. Among all of the title derivatives, compounds 3a, 3c, 3k, and 3o exhibited potent nematicidal activity with median lethal concentration (LC50) values ranging from 0.22 to 0.26 mg/L. Most noteworthy, N, N-dimethyl-4-methoxyphenylsulfonamide (3c) and N, N-dimethyl-8-quinolinesulfonamide (3o) showed the best promising and pronounced nematicidal activity, with LC50 values of 0.2381 and 0.2259 mg/L, respectively.

Tubeimoside-1, a triterpenoid saponin, induces cytoprotective autophagy in human breast cancer cells in vitro via Akt-mediated pathway.

Autophagy, a form of cellular self-digestion by lysosome, is associated with various disease processes including cancers, and modulating autophagy has shown promise in the treatment of various malignancies. A number of natural products display strong antitumor activity, yet their mechanisms of action remain unclear. To gain a better understanding of how traditional Chinese medicine agents exert antitumor effects, we screened 480 natural compounds for their effects on autophagy using a high content screening assay detecting GFP-LC3 puncta in HeLa cells. Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), was identified as a potent activator of autophagy. The activation of autophagy by TBMS1 was evidenced by increased LC3-II amount and GFP-LC3 dots, observation of autophagosomes under electron microscopy, and enhanced autophagic flux. To explore the mechanisms underlying TBMS1-activated autophagy, we performed cheminformatic analyses and surface plasmon resonance (SPR) binding assay that showed a higher likelihood of the binding between Akt protein and TBMS1. In three human breast cancer cell lines, we demonstrated that Akt-mTOR-eEF-2K pathway was involved in TBMS1-induced activation of autophagy, while Akt-mediated downregulations of Mcl-1, Bcl-xl, and Bcl-2 led to the activation of apoptosis of the breast cancer cells. Inhibition of autophagy enhanced the cytotoxic effect of TBMS1 via promoting apoptosis. Our results demonstrate the role and mechanism of TBMS1 in activating autophagy, suggesting that inhibition of cytoprotective autophagy may act as a therapeutic strategy to reinforce the activity of TBMS1 against cancers.

The emerging landscape of circular RNA in cardiovascular diseases.

Circular RNAs (circRNAs), a large novel type of endogenous transcripts, have become a new research hotspot in the field of RNA biology. CircRNAs are mainly generated from exons or introns via multiple mechanisms, and the majority of circRNAs are stable and conserved across different species. Recent studies have revealed that circRNAs can function as miRNA sponges, binding partners of proteins, regulators of transcription, or can even be translated into proteins. Growing evidence has demonstrated that circRNAs play important roles in a wide variety of biological processes such as cell proliferation, apoptosis and senescence, and may serve as potential diagnostic biomarkers or therapeutic targets for various cardiovascular diseases. Here, we review the biogenesis, properties and biological function of circRNAs, and summarize their roles in cardiovascular disorders.

UCH-L1 promotes invasion of breast cancer cells through activating Akt signaling pathway.

As a de-ubiquitin enzyme, ubiquitin C-terminal hydrolase (UCH)-L1 has been shown to be overexpressed in several human cancers. However, the function of UCH-L1 in invasion of breast cancers is still unclear. Here we report that the expression of UCH-L1 is significantly higher in cancer cells with higher invasive ability. While ectopic UCH-L1 expression failed to alter cell proliferation in MCF-7 cells, it caused a significant upregulation of cellular invasion. Furthermore, siRNA mediated knockdown of UCH-L1 led to suppression of invasion in UCH-L1 overexpressing MCF-7 cells. In order to identify molecular mechanisms underlying these observations, a novel in vitro proximity-dependent biotin identification method was developed by fusing UCH-L1 protein with a bacterial biotin ligase (Escherichia coli BirA R118G, BioID). Streptavidin magnetic beads pulldown assay revealed that UCH-L1 can interact with Akt in MCF-7 cells. Pulldown assay with His tagged recombinant UCH-L1 protein and cell lysate from MCF-7 cells further demonstrated that UCH-L1 preferentially binds to Akt2 for Akt activation. Finally, we demonstrated that overexpression of UCH-L1 led to activation of Akt as evidenced by upregulation of phosphorylated Akt. Thus, these findings demonstrated that UCH-L1 promotes invasion of breast cancer cells and might serve as a potential therapeutic target for treatment of human patients with breast cancers.

Co-Catalyzed Synthesis of N-Sulfonylcarboxamides from Carboxylic Acids and Sulfonyl Azides.

A Co-catalyzed effective synthesis of N-sulfonylcarboxamides from the reaction of carboxylic acids and organic azides in the presence of isocyanide has been developed. The protocol has the advantages of short time, low temperature, and being oxidant-free, which provides a new and simple approach for the synthesis of N-sulfonylcarboxamides in good to excellent yields with a broad substrate scope.

Immunotherapy for triple-negative breast cancer: Existing challenges and exciting prospects.

Patients with breast tumors that do not express the estrogen receptor, the progesterone receptor, nor Her-2/neu are hence termed "triple negatives", and generally have a poor prognosis, with high rates of systemic recurrence and refractoriness to conventional therapy regardless of the choice of adjuvant treatment. Thus, more effective therapeutic options are sorely needed for triple-negative breast cancer (TNBC), which occurs in approximately 20% of diagnosed breast cancers. In recent years, exploiting intrinsic mechanisms of the host immune system to eradicate cancer cells has achieved impressive success, and the advances in immunotherapy have yielded potential new therapeutic strategies for the treatment of this devastating subtype of breast cancer. It is anticipated that the responses initiated by immunotherapeutic interventions will explicitly target and annihilate tumor cells, while at the same time spare normal cells. Various immunotherapeutic approaches have been already developed and tested, which include the blockade of immune checkpoints using neutralizing or blocking antibodies, induction of cytotoxic T lymphocytes (CTLs), adoptive cell transfer-based therapy, and modulation of the tumor microenvironment to enhance the activity of CTLs. One of the most important areas of breast cancer research today is understanding the immune features and profiles of TNBC and devising novel immune-modulatory strategies to tackling TNBC, a subtype of breast cancer notorious for its poor prognosis and its imperviousness to conventional treatments. On the optimal side, one can anticipate that novel, effective, and personalized immunotherapy for TNBC will soon achieve more success and impact clinical treatment of this disease which afflicts approximately 20% of patients with breast cancer. In the present review, we highlight the current progress and encouraging developments in cancer immunotherapy, with a goal to discuss the challenges and to provide future perspectives on how to exploit a variety of new immunotherapeutic approaches including checkpoint inhibitors and neoadjuvant immunotherapy for the treatment of patients with TNBC.

Long non-coding RNAs: An emerging powerhouse in the battle between life and death of tumor cells.

Long non-coding RNAs (lncRNAs) represent a class of non-protein coding transcripts longer than 200 nucleotides that have aptitude for regulating gene expression at the transcriptional, post-transcriptional or epigenetic levels. In recent years, lncRNAs, which are believed to be the largest transcript class in the transcriptomes, have emerged as important players in a variety of biological processes. Notably, the identification and characterization of numerous lncRNAs in the past decade has revealed a role for these molecules in the regulation of cancer cell survival and death. It is likely that this class of non-coding RNA constitutes a critical contributor to the assorted known or/and unknown mechanisms of intrinsic or acquired drug resistance. Moreover, the expression of lncRNAs is altered in various patho-physiological conditions, including cancer. Therefore, lncRNAs represent potentially important targets in predicting or altering the sensitivity or resistance of cancer cells to various therapies. Here, we provide an overview on the molecular functions of lncRNAs, and discuss their impact and importance in cancer development, progression, and therapeutic outcome. We also provide a perspective on how lncRNAs may alter the efficacy of cancer therapy and the promise of lncRNAs as novel therapeutic targets for overcoming chemoresistance. A better understanding of the functional roles of lncRNA in cancer can ultimately translate to the development of novel, lncRNA-based intervention strategies for the treatment or prevention of drug-resistant cancer.