Flavokavains A- and B-Free Kava Enhances Resilience against the Adverse Health Effects of Tobacco Smoke in Mice.

Tobacco smoke remains a serious global issue, resulting in serious health complications, contributing to the onset of numerous preventive diseases and imposing significant health burdens. Despite regulatory policies and cessation measures aimed at curbing its usage, novel interventions are urgently needed for effective damage reduction. Our preclinical and pilot clinical studies showed that AB-free kava has the potential to reduce tobacco-smoking-induced lung cancer risk, mitigate tobacco dependence, and reduce tobacco use.

Proteolysis targeting chimera extracellular vesicles for therapeutic development treating triple negative breast cancer.

Proteolysis targeting chimeras (PROTACs) are an emerging targeted cancer therapy approach, but wide-spread clinical use of PROTAC is limited due to poor cell targeting and penetration, and instability in vivo. To overcome such issues and enhance the in vivo efficacy of PROTAC drugs, microfluidic droplet-based electroporation (µDES) was developed as a novel extracellular vesicle (EVs) transfection system, which enables the high-efficient PROTAC loading and effective delivery in vivo. Our previously developed YX968 PROTAC drug had shown the selectively degradation of HDAC3 and 8, which effectively suppresses the growth of breast tumor cell lines, including MDA-MB-231 triple negative breast cancer (TNBC) line, via dual degradation without provoking a global histone hyperacetylation.

ANGPTL4 Suppresses Clear Cell Renal Cell Carcinoma via Inhibition of Lysosomal Acid Lipase.

Unlabelled: Renal cell carcinoma (RCC), the most common form of kidney cancer, is a heterogeneous disease with clear cell RCC (ccRCC) being the most prevalent and aggressive subtype. While most ccRCC tumors have elevated expression of angiopoietin-like4 (ANGPTL4), in our study we identified a significant subset of patients whose cancers show no increase in ANGPTL4 expression. These patients have a worse prognosis compared to the patients with high expression of ANGPTL4.

KDM6A regulates immune response genes in multiple myeloma.

The histone H3 at lysine 27 (H3K27) demethylase lysine demethylase 6A (KDM6A) is a tumor suppressor in multiple cancers, including multiple myeloma (MM). We created isogenic MM cells disrupted for KDM6A and tagged the endogenous protein to facilitate genome-wide studies. KDM6A binds genes associated with immune recognition and cytokine signaling.

AB-free kava enhances resilience against the adverse health effects of tobacco smoke in mice.

Tobacco smoke remains a serious global issue, resulting in serious health complications, contributing to the onsets of numerous preventive diseases, and imposing significant financial burdens. Despite regulatory policies and cessation measures aimed at curbing its usage, novel interventions are urgently needed for effective damage reduction. Our preclinical and pilot clinical studies showed that AB-free kava has the potential to reduce tobacco smoke-induced lung cancer risk, mitigate tobacco dependence, and reduce tobacco use.

Single-cell transcriptomics unveil profiles and interplay of immune subsets in rare autoimmune childhood Sjögren's disease.

Childhood Sjögren's disease represents critically unmet medical needs due to a complete lack of immunological and molecular characterizations. This study presents key immune cell subsets and their interactions in the periphery in childhood Sjögren's disease. Here we show that single-cell RNA sequencing identifies the subsets of IFN gene-enriched monocytes, CD4 T effector memory, and XCL1 NK cells as potential key players in childhood Sjögren's disease, and especially in those with recurrent parotitis, which is the chief symptom prompting clinical visits from young children.

KDM6A Regulates Immune Response Genes in Multiple Myeloma.

Unlabelled: The histone H3K27 demethylase KDM6A is a tumor suppressor in multiple cancers, including multiple myeloma (MM). We created isogenic MM cells disrupted for KDM6A and tagged the endogenous protein to facilitate genome wide studies. KDM6A binds genes associated with immune recognition and cytokine signaling.

Targeting intracellular proteins with cell type-specific functions for cancer immunotherapy.

Immune checkpoint inhibitors (ICIs) use antibodies that block cell surface immune checkpoint proteins with great efficacy in treating immunogenic or "immune hot" tumors such as melanoma, kidney, and lung adenocarcinoma. ICIs have limited response rates to other non-immunogenic cancers. The tumor microenvironment (TME) consists of many cell types that collectively promote tumor progression.

Co-targeting BCL-X and MCL-1 with DT2216 and AZD8055 synergistically inhibit small-cell lung cancer growth without causing on-target toxicities in mice.

Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. The dismal prognosis in SCLC is in part associated with an upregulation of BCL-2 family anti-apoptotic proteins, including BCL-X and MCL-1. Unfortunately, the currently available inhibitors of BCL-2 family anti-apoptotic proteins, except BCL-2 inhibitors, are not clinically relevant because of various on-target toxicities.

CD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells.

Regulatory T (Treg) cells are one of the major immunosuppressive cell types in cancer and a potential target for immunotherapy, but targeting tumor-infiltrating (TI) Treg cells has been challenging. Here, using single-cell RNA sequencing of immune cells from renal clear cell carcinoma (ccRCC) patients, we identify two distinct transcriptional fates for TI Treg cells, Fate-1 and Fate-2. The Fate-1 signature is associated with a poorer prognosis in ccRCC and several other solid cancers.

Proteolysis-targeting chimera against BCL-X destroys tumor-infiltrating regulatory T cells.

Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis and, within tumors, their upregulation is common and promotes an immunosuppressive microenvironment. Therapeutic strategies that can eliminate Tregs in the tumor (i.e.

Plumbagin from a tropical pitcher plant (Nepenthes alata Blanco) induces apoptotic cell death via a p53-dependent pathway in MCF-7 human breast cancer cells.

Plumbagin (5-hydroxy-2-methyl-1,4-naphthaquinone) has displayed antitumor activity in vitro and in animal models; however, the underlying molecular mechanisms have not been fully explored. The aim of this study was to investigate the anticancer effects of plumbagin isolated from Nepenthes alata against MCF-7 breast cancer cells. We examined the cytotoxicity, cell cycle regulation, apoptotic cell death, and generation of intracellular reactive oxygen species (ROS) in MCF-7 cells.

Alkyl chain-modified cyclometalated iridium complexes as tunable anticancer and imaging agents.

Five mononuclear cyclometalated iridium complexes [1](PF6)-[5](PF6) were prepared using imidazole-based ligands of varying alkyl chain length. The complexes were characterised by various analytical techniques. The single crystal X-ray structures of [2](PF6), [3](PF6) and [4](PF6) revealed the expected distorted Oh structures around the metal centre; however, the chain length was found to play a crucial role in deciding the overall geometry.

A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation.

We previously discovered a novel sirtuin (SIRT) inhibitor, MHY2256, that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. We investigated the anticancer activity of MHY2256 against hormone-related cancer, an endometrial cancer with a poor prognosis. The IC values of MHY2256 were shown to be much lower than those of salermide, a well-known SIRT inhibitor.

Novel therapeutic roles of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways.

Current clinical trials of new anticancer therapies against metastatic renal cell carcinoma (RCC), including molecular-targeted therapies, have not shown promise. The purpose of this study was to preclinically assess the antitumor effects of MC-4, a partially purified material of Artemisia annua L., as a monotherapy or in combination with the known mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, everolimus, against Caki-1 (Von Hippel-Lindau (VHL)+/+) and 786-O (VHL-/-) human RCC cells.

Detoxifying effect of pyridoxine on acetaminophen-induced hepatotoxicity via suppressing oxidative stress injury.

The detoxifying effect of pyridoxine against acetaminophen (APAP)-induced hepatotoxicity was investigated. HepG2 cells were co-treated with APAP and pyridoxine to compare with betaine or methionine for 24 h. LDH, ALT and AST activities were measured to determine direct cells damage in vitro and in vivo.

Rhodium-Catalyzed [3 + 2] Annulation of Cyclic N-Acyl Ketimines with Activated Olefins: Anticancer Activity of Spiroisoindolinones.

The rhodium(III)-catalyzed redox-neutral coupling reaction of N-acyl ketimines generated in situ from 3-hydroxyisoindolinones with various activated olefins is described. This approach leads to the synthesis of bioactive spiroisoindolinone derivatives in moderate to high yields. In the case of internal olefins such as maleimides, maleates, fumarates, and cinnamates, spiroindanes were obtained by the [3 + 2] annulations reaction.

Anticancer Effects of a New SIRT Inhibitor, MHY2256, against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding.

The sirtuins (SIRTs), a family of NAD-dependent class III histone deacetylase, are involved in various biological processes including cell survival, division, senescence, and metabolism via activation of the stress-response pathway. Recently, inhibition of SIRTs has been considered a promising anticancer strategy, but their precise mechanisms of action are not well understood. In particular, the relevance of p53 to SIRT-induced effects has not been fully elucidated.

Synthesis of Succinimide-Containing Chromones, Naphthoquinones, and Xanthones under Rh(III) Catalysis: Evaluation of Anticancer Activity.

The weakly coordinating ketone group directed C-H functionalizations of chromones, 1,4-naphthoquinones, and xanthones with various maleimides under rhodium(III) catalysis are described. These protocols efficiently provide a range of succinimide-containing chromones, naphthoquinones, and xanthones with excellent site selectivity and functional group compatibility. All synthetic compounds were screened for in vitro anticancer activity against human breast adenocarcinoma cell lines (MCF-7).

Cyclometallated iridium complexes inducing paraptotic cell death like natural products: synthesis, structure and mechanistic aspects.

Six mononuclear Ir complexes (1-6) using polypyridyl-pyrazine based ligands (L1 and L2) and {[cp*IrCl(μ-Cl)] and [(ppy)Ir(μ-Cl)]} precursors have been synthesised and characterised. Complexes 1-5 have shown potent anticancer activity against various human cancer cell lines (MCF-7, LNCap, Ishikawa, DU145, PC3 and SKOV3) while complex 6 is found to be inactive. Flow cytometry studies have established that cellular accumulation of the complexes lies in the order 2 > 1 > 5 > 4 > 3 > 6 which is in accordance with their observed cytotoxicity.

Rh(III)-Catalyzed C-H Functionalization of Indolines with Readily Accessible Amidating Reagent: Synthesis and Anticancer Evaluation.

The rhodium(III)-catalyzed direct C-H functionalization of various indolines with 1,4,2-dioxazol-5-ones as new amidating agents is described. This transformation provides efficient preparation of C7-amidated indolines known to display potent anticancer activity. The synthetic compounds were evaluated for in vitro anticancer activity against human prostate adenocarcinoma cells (LNCaP), human endometrial adenocarcinoma cells (Ishikawa), and human ovarian carcinoma cells (SKOV3).

A New Histone Deacetylase Inhibitor, MHY219, Inhibits the Migration of Human Prostate Cancer Cells via HDAC1.

Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration.

Ru(II)-catalyzed selective C-H amination of xanthones and chromones with sulfonyl azides: synthesis and anticancer evaluation.

A ketone-assisted ruthenium-catalyzed selective amination of xanthones and chromones C-H bonds with sulfonyl azides is described. The reactions proceed efficiently with a broad range of substrates with excellent functional group compatibility. This protocol provides direct access to 1-aminoxanthones, 5-aminochromones, and 5-aminoflavonoid derivatives known to exhibit potent anticancer activity.

Dinuclear [{(p-cym)RuCl}2(μ-phpy)](PF6)2 and heterodinuclear [(ppy)2Ir(μ-phpy)Ru(p-cym)Cl](PF6)2 complexes: synthesis, structure and anticancer activity.

Phpy bridged homodinuclear Ru-Ru () and heterodinuclear Ir-Ru complexes () have been developed. Complex induces autophagy towards the cisplatin resistant human breast cancer (MCF7) cell line, whereas is inactive.