Discovery of APH02174 as a Highly Selective and Orally Bioavailable IRAK4 Degrader for the Treatment of Inflammatory Diseases.

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role as a key regulator in systemic inflammatory diseases, acting as a central mediator in the downstream signaling cascades of Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). Herein, we describe the design and synthesis of novel IRAK4 degraders based on a proteolysis-targeting chimera (PROTAC) strategy. Twenty-one PROTACs -, -, , - and showed strong IRAK4 degradation (DC < 5 nM and > 85%), () was identified as the lead compound exhibiting highly selective IRAK4 degradation and , along with favorable drug metabolism and oral pharmacokinetic properties.

Distinct adipose progenitor cells emerging with age drive active adipogenesis.

Starting at middle age, adults often suffer from visceral adiposity and associated adverse metabolic disorders. Lineage tracing in mice revealed that adipose progenitor cells (APCs) in visceral fat undergo extensive adipogenesis during middle age. Thus, despite the low turnover rate of adipocytes in young adults, adipogenesis is unlocked during middle age.

Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1.

Chimeric antigen receptor CAR T cell therapy faces notable limitations in treatment of solid tumors. The suppressive tumor microenvironment TME, characterized by complex interactions among immune and stromal cells, is gaining recognition in conferring resistance to CAR T cell therapy. Despite the abundance and diversity of macrophages in the TME, their intricate involvement in modulating responses to CAR T cell therapies remains poorly understood.

The Anti-Cancer Role of Pterostilbene in Endometrial Cancer: A Phase II Prospective, Randomized, Window-of-Opportunity Clinical Trial with Megestrol Acetate.

Pterostilbene (3,5-dimethoxy-40-hydroxystilbene) is a potent oral antioxidant with a promising role in anti-cancer treatment. In endometrial cancer (EC), in vitro studies demonstrated a synergistic antiproliferative effect of pterostilbene (PT) with megestrol acetate (MA), a common treatment for EC. This is a randomized phase II clinical trial (NCT03671811) of PT+MA vs.

Mining metagenomes and metatranscriptomes unveils viruses associated with cutaneous squamous cell carcinoma in hematopoietic stem cell transplant recipients.

Unlabelled: We investigated the presence of viral DNA and RNA in cutaneous squamous cell carcinoma (cSCC) tumor and normal tissues from nine individuals with a history of hematopoietic stem cell transplantation (HCT). Microbiome quantification through DNA and RNA sequencing (RNA-seq) revealed the presence of 18 viruses in both tumor and normal tissues. DNA sequencing (DNA-seq) identified , , , , , , and others.

Spectrum-Effect Relationship Between Fingerprints and Anti-Inflammatory and Antitussive Activities of Raw and Processed Mume Fructus Extracts.

Mume Fructus (MF), a representative substance in the field of medicine-food homology, has been extensively utilized in clinical treatments and daily diets for its raw and processed forms. This study aimed to establish the spectrum-effect relationship between ultra-high-performance liquid chromatography coupled with quadrupole tandem time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) fingerprints and anti-inflammatory and antitussive activities of raw and processed MF extracts. In UHPLC-Q-TOF-MS/MS fingerprints, a total of 21 common peaks were identified.

Phase 1 trial of durvalumab (anti-PD-L1) combined with lenalidomide in relapsed/refractory cutaneous T-cell lymphoma.

Selective targeting of the functionally exhausted malignant T cells in cutaneous T-cell lymphoma (CTCL) and distinct cells within the tumor microenvironment (TME) via programmed cell death 1/programmed cell death ligand 1 blockade (durvalumab) may restore an antitumor immune response. The oral immunomodulator lenalidomide, which has activity in CTCL, may enhance durvalumab immune checkpoint blockade. Our phase 1/2 clinical trial of durvalumab and lenalidomide in patients with refractory/advanced CTCL sought to assess the safety and tolerability and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D) of lenalidomide plus fixed-dose durvalumab.

miR-142 deficit in T cells during blast crisis promotes chronic myeloid leukemia immune escape.

We reported that an acquired miR-142 deficit transforms chronic phase (CP) chronic myeloid leukemia (CML) leukemic stem cells (LSCs) into blast crisis (BC) LSCs. Given the role of miR-142 in the development and activity of the immune system, we postulated that this deficit also promotes LSC immune escape. Herein, we report on IL-6-driven miR-142 deficit occurring in T cells during BC transformation.

Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency.

Citrin Deficiency (CD) is caused by inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates carbohydrate response element binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol, and to transcribe key genes of lipogenesis.

Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene.

Background & Aims: Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases.

Comprehensive pharmacokinetic profiling of twelve compounds from Phellinus Igniarius extract in rats by UHPLC-MS/MS.

The medicinal fungus Phellinus Igniarius (P. igniarius) has been demonstrated to possess a variety of pharmacological effects, including anti-oxidant, anti-tumor, blood circulation promotion, anti-diarrheal and sedative properties, etc. In order to gain a deeper understanding of the components in P.

Encapsulation and Delivery of the Kinase Inhibitor PIK-75 by Organic Core High-Density Lipoprotein-Like Nanoparticles Targeting Scavenger Receptor Class B Type 1.

PIK-75 (F7) is a potent multikinase inhibitor that targets p110α, DNA-PK, and p38γ. PIK-75 has shown potential as a therapy in preclinical cancer models, but it has not been used in the clinic, at least in part, due to limited solubility. We therefore developed a nanoparticle to encapsulate PIK-75 and enable targeted cellular delivery.

Sex-dependent differences in hematopoietic stem cell aging and leukemogenic potential.

Sex influences many biological outcomes, but how sex affects hematopoietic stem cell (HSC) aging and hematological disorders is poorly understood. The widespread use of young animal models to study age-related diseases further complicates these matters. Using aged and long-lived BALB/c mouse models, we discovered that aging mice exhibit sex-dependent disparities, mirroring aging humans, in developing myeloid skewing, anemia, and leukemia.

Reduction of myeloid-derived suppressor cells in prostate cancer murine models and patients following white button mushroom treatment.

Background: In a previously reported Phase I trial, we observed therapy-associated declines in circulating myeloid-derived suppressor cells (MDSCs) with the administration of white button mushroom (WBM) tablets in prostate cancer (PCa) patients. These observations led us to hypothesise that WBM could mitigate PCa progression by suppressing MDSCs.

Methods: We performed bidirectional translational research to examine the immunomodulatory effects of WBM consumption in both syngeneic murine PCa models and patients with PCa participating in an ongoing randomised Phase II trial (NCT04519879).

Titanium Dioxide Nanomaterials: Progress in Synthesis and Application in Drug Delivery.

Recent developments in nanotechnology have provided efficient and promising methods for the treatment of diseases to achieve better therapeutic results and lower side effects. Titanium dioxide (TiO) nanomaterials are emerging inorganic nanomaterials with excellent properties such as low toxicity and easy functionalization. TiO with special nanostructures can be used as delivery vehicles for drugs, genes and antigens for various therapeutic options.

Perimenopausal and Menopausal Mammary Glands In A 4-Vinylcyclohexene Diepoxide Mouse Model.

As both perimenopausal and menopausal periods are recognized critical windows of susceptibility for breast carcinogenesis, development of a physiologically relevant model has been warranted. The traditional ovariectomy model causes instant removal of the entire hormonal repertoire produced by the ovary, which does not accurately approximate human natural menopause with gradual transition. Here, we characterized the mammary glands of 4-vinylcyclohexene diepoxide (VCD)-treated animals at different time points, revealing that the model can provide the mammary glands with both perimenopausal and menopausal states.

Trefoil Factor 2 Expressed by the Murine Pancreatic Acinar Cells Is Required for the Development of Islets and for β-Cell Function During Aging.

Exocrine-to-endocrine cross talk in the pancreas is crucial to maintain β-cell function. However, the molecular mechanisms underlying this cross talk are largely undefined. Trefoil factor 2 (Tff2) is a secreted factor known to promote the proliferation of β-cells in vitro, but its physiological role in vivo in the pancreas is unknown.

Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis.

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate.

Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes.

Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up.

Regulation of Enhancers by SUMOylation Through TFAP2C Binding and Recruitment of HDAC Complex to the Chromatin.

Enhancers are fundamental to gene regulation. Post-translational modifications by the small ubiquitin-like modifiers (SUMO) modify chromatin regulation enzymes, including histone acetylases and deacetylases. However, it remains unclear whether SUMOylation regulates enhancer marks, acetylation at the 27th lysine residue of the histone H3 protein (H3K27Ac).

8-Cl-Ado and 8-NH-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia.

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells.

Investigation of the drug-drug interaction and incompatibility mechanism between Aconitum carmichaelii Debx and Pinellia ternata (Thunb.) Breit.

Ethnopharmacological Relevance: The combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible medicaments (EIM), indicating that BX and CW are incompatible. However, the scientific understanding of this incompatibility mechanism, especially the corresponding drug-drug interaction (DDI), remains complex and unclear.

Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity.

Aims/hypothesis: Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly connected 'hub' cells, important for the propagation of intercellular Ca waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes.