ITGB1/FERMT1 mechanoactivation enhances CD44 characteristic stemness in oral squamous cell carcinoma via ubiquitin-dependent CK1α degradation.

Cancer stem cells (CSCs) contribute to chemotherapy resistance and poor prognosis, posing significant challenges in the treatment of oral squamous cell carcinoma. The extracellular matrix (ECM)-constructed microenvironment remodels the niche of CSCs. Yet mechanisms by which biophysical properties of ECM relate to CSCs remain undefined.

Calcium-sensing receptor- and ADAM10-mediated klotho shedding is regulated by tetraspanin 5.

Soluble, circulating Klotho (sKlotho) is essential for normal health and renal function. sKlotho is shed from the renal distal convoluted tubule (DCT), its primary source, via enzymatic cleavage. However, the physiologic mechanisms that control sKlotho production, trafficking, and shedding are not fully defined.

Targeted Elimination of the Oral Pathogen to Overcome Chemoresistance of Oral Squamous Cell Carcinoma by Biologically Derived Nanotherapeutics.

Local oral microbiota are closely related to the tumorigenesis and therapeutic response of oral cancer. In this study, we have validated that oral commensal () is highly responsible for chemoresistance and contributes to the poor therapeutic outcome of traditional chemotherapy. Accordingly, the biologically derived nanovesicles from ginger (GDNVs) with excellent elimination ability are explored to transport the clinically used drug paclitaxel (PTX) for potentiating the therapeutic efficiency.

Carrier-Free Nanoagent Interfering with Cancer-Associated Fibroblasts' Metabolism to Promote Tumor Penetration for Boosted Chemotherapy.

Elevated production of extracellular matrix (ECM) in tumor stroma is a critical obstacle for drug penetration. Here we demonstrate that ATP-citrate lyase (ACLY) is significantly upregulated in cancer-associated fibroblasts (CAFs) to produce tumor ECM. Using a self-assembling nanoparticle-design approach, a carrier-free nanoagent (CFNA) is fabricated by simply assembling NDI-091143, a specific ACLY inhibitor, and doxorubicin (DOX) or paclitaxel (PTX), the first-line chemotherapeutic drug, via multiple noncovalent interactions.

Glomerular Elasticity and Gene Expression Patterns Define Two Phases of Alport Nephropathy.

Objectives: To understand the early stages if Alport nephropathy, we characterize the structural, functional, and biophysical properties of glomerular capillaries and podocytes in mice, analyze kidney cortex transcriptional profiles at three time points, and investigate the effects of the ER stress mitigation by TUDCA on these parameters. We use human FSGS associated genes to identify molecular pathways rescued by TUDCA.

Findings: We define a disease progression timeline in mice.

Enhanced lipid biosynthesis in oral squamous cell carcinoma cancer-associated fibroblasts contributes to tumor progression: Role of IL8/AKT/p-ACLY axis.

Lipid metabolic reprogramming of tumor cells has been proven to play a critical role in tumor initiation and development. However, lipid metabolism in cancer-associated fibroblasts (CAFs) has rarely been studied, particularly in CAFs of oral squamous cell carcinoma (OSCC). Additionally, the molecular mechanism by which tumor cells regulate lipid metabolism in fibroblasts is unclear.

Mitophagy-Mediated Tumor Dormancy Protects Cancer Cells from Chemotherapy.

Despite obvious tumor shrinkage, relapse after chemotherapy remains a main cause of cancer-related mortality, indicating that a subpopulation of cancer cells acquires chemoresistance and lingers after treatment. However, the mechanism involved in the emergence of chemoresistant cells remains largely unknown. Here, we demonstrate that the degradation of mitochondria via autophagy leads to a dormant state in a subpopulation of cancer cells and confers on them resistance to lethal cisplatin (DDP) exposure.

miR-21 Expressed by Dermal Fibroblasts Enhances Skin Wound Healing Through the Regulation of Inflammatory Cytokine Expression.

The management of skin wound healing is still a challenge. MicroRNA-21 (miR-21) has been reported to play important roles in wound repair; however, the underlying mechanism needs to be further clarified. The present study aimed to study the direct role of miR-21 in skin wound healing in miR-21 KO mice and to investigate the role of miR-21 in controlling the migration and proliferation of primary human skin cells and its underlying mechanism(s).

FNIII14 Peptide-Enriched Membrane Nanocarrier to Disrupt Stromal Barriers through Reversing CAFs for Augmenting Drug Penetration in Tumors.

Given the key roles of cancer associated fibroblasts (CAFs) in shaping tumor stroma, this study shows a CAF-associated ITGB1-inactivating peptide-enriched membrane nanodelivery system (designated as PMNPs-D) to simultaneously target CAFs and tumor cells for boosted chemotherapy through promoted drug perfusion. In the structure of PMNPs-D, the PLGA-based inner core is loaded with the chemotherapeutic drug doxorubicin, and the outer surface is cloaked by hybrid biomembranes with the insertion of integrin β1 (ITGB1) inhibiting peptide (i.e.

Myosin light chain phosphatase catalytic subunit dephosphorylates cardiac myosin via mechanisms dependent and independent of the MYPT regulatory subunits.

Cardiac muscle myosin regulatory light chain (RLC) is constitutively phosphorylated at ∼0.4 mol phosphate/mol RLC in normal hearts, and phosphorylation is maintained by balanced activities of dedicated cardiac muscle-specific myosin light chain kinase and myosin light chain phosphatase (MLCP). Previously, the identity of the cardiac-MLCP was biochemically shown to be similar to the smooth muscle MLCP, which is a well-characterized trimeric protein comprising the regulatory subunit (MYPT1), catalytic subunit PP1cβ, and accessory subunit M20.

Resistance of Acta2 mice to aortic disease is associated with defective release of mutant smooth muscle α-actin from the chaperonin-containing TCP1 folding complex.

Pathogenic variants of the gene for smooth muscle α-actin (ACTA2), which encodes smooth muscle (SM) α-actin, predispose to heritable thoracic aortic disease. The ACTA2 variant p.Arg149Cys (R149C) is the most common alteration; however, only 60% of carriers have a dissection or undergo repair of an aneurysm by 70 years of age.

Physiologic Regulation of Systemic Klotho Levels by Renal CaSR Signaling in Response to CaSR Ligands and pH o.

Background: The kidney is the source of sKlotho and kidney-specific loss of Klotho leads to a phenotype resembling the premature multiorgan failure phenotype in Klotho-hypomorphic mice ( kl/kl mice). Klotho and the Ca-sensing receptor (CaSR) are highly expressed in the distal convoluted tubule (DCT). The physiologic mechanisms that regulate sKlotho levels are unknown.

Potential targets identified in adenoid cystic carcinoma point out new directions for further research.

Adenoid cystic carcinoma (AdCC) of the head and neck originates from salivary glands, with high risks of recurrence and metastasis that account for the poor prognosis of patients. The purpose of this research was to identify key genes related to AdCC for further investigation of their diagnostic and prognostic significance. In our study, the AdCC sample datasets GSE36820, GSE59702 and GSE88804 from the Gene Expression Omnibus (GEO) database were used to explore the abnormal coexpression of genes in AdCC compared with their expression in normal tissue.

Control of Podocyte and Glomerular Capillary Wall Structure and Elasticity by WNK1 Kinase.

Cytoskeletal structure and its regulation are essential for maintenance of the differentiated state of specific types of cells and their adaptation to physiologic and pathophysiologic conditions. Renal glomerular capillaries, composed of podocytes, endothelial cells, and the glomerular basement membrane, have distinct structural and biophysical properties and are the site of injury in many glomerular diseases. Calcineurin inhibitors, immunosuppressant drugs used for organ transplantation and auto-immune diseases, can protect podocytes and glomerular capillaries from injury by preserving podocyte cytoskeletal structure.

Actin R256 Mono-methylation Is a Conserved Post-translational Modification Involved in Transcription.

Nuclear actin has been elusive due to the lack of knowledge about molecular mechanisms. From actin-containing chromatin remodeling complexes, we discovered an arginine mono-methylation mark on an evolutionarily conserved R256 residue of actin (R256me1). Actin R256 mutations in yeast affect nuclear functions and cause diseases in human.

A Simplified and Efficient Method to Isolate Primary Human Keratinocytes from Adult Skin Tissue.

Primary human keratinocytes isolated from fresh skin tissues and their expansion in vitro have been widely used for laboratory research and for clinical applications. The conventional isolation method of human keratinocytes involves a two-step sequential enzymatic digestion procedure, which has been proven to be inefficient in generating primary cells from adult tissues due to the low cell recovery rate and reduced cell viability. We recently reported an advanced method to isolate human primary epidermal progenitor cells from skin tissues that utilizes the Rho kinase inhibitor Y-27632 in the medium.

The dominant protein phosphatase PP1c isoform in smooth muscle cells, PP1cβ, is essential for smooth muscle contraction.

Contractile force development of smooth muscle is controlled by balanced kinase and phosphatase activities toward the myosin regulatory light chain (RLC). Numerous biochemical and pharmacological studies have investigated the specificity and regulatory activity of smooth muscle myosin light-chain phosphatase (MLCP) bound to myosin filaments and comprised of the regulatory myosin phosphatase target subunit 1 (MYPT1) and catalytic protein phosphatase 1cβ (PP1cβ) subunits. Recent physiological and biochemical evidence obtained with smooth muscle tissues from a conditional MYPT1 knockout suggests that a soluble, MYPT1-unbound form of PP1cβ may additionally contribute to myosin RLC dephosphorylation and relaxation of smooth muscle.

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts.

The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) α-actin encoded by We focus here on R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM α-actin-R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells.

The different roles of myosin IIA and myosin IIB in contraction of 3D collagen matrices by human fibroblasts.

Contraction of 3D collagen matrices by fibroblasts frequently is used as an in vitro model of wound closure. Different iterations of the model - all conventionally referred to as "contraction" - involve different morphological patterns. During floating matrix contraction, cells initially are round without stress fibers and subsequently undergo spreading.

Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing.

Myocardin-related transcription factors (MRTFs) regulate cellular contractility and motility by associating with serum response factor (SRF) and activating genes involved in cytoskeletal dynamics. We reported previously that MRTF-A contributes to pathological cardiac remodeling by promoting differentiation of fibroblasts to myofibroblasts following myocardial infarction. Here, we show that forced expression of MRTF-A in dermal fibroblasts stimulates contraction of a collagen matrix, whereas contractility of MRTF-A null fibroblasts is impaired under basal conditions and in response to TGF-β1 stimulation.

Distinct roles for non-muscle myosin II isoforms in mouse hepatic stellate cells.

Background & Aims: Upon liver injury, hepatic stellate cells (HSCs) undergo dramatic morphological and functional changes including migration and contraction. In the present study, we investigated the role of myosin II isoforms in the development of the contractile phenotype of mouse HSCs, which are considered therapeutic targets to decrease portal hypertension and fibrosis.

Methods: We characterized the expression of myosin IIA and IIB in primary mouse HSCs and addressed their function by gene knock-down using isoform-specific siRNAs.

Blebbistatin inhibits contraction and accelerates migration in mouse hepatic stellate cells.

Background And Purpose: Blebbistatin, an inhibitor of myosin-II-specific ATPase, has been used to inhibit contraction of invertebrate and mammalian muscle preparations containing non-muscle myosin. Activated hepatic stellate cells have contractile properties and play an important role in the pathophysiology of liver fibrosis and portal hypertension. Therefore, hepatic stellate cells are considered as therapeutic target cells.

SHIP2 controls PtdIns(3,4,5)P(3) levels and PKB activity in response to oxidative stress.

Reactive oxygen species (ROS) are known to be involved in redox signalling pathways that may contribute to normal cell function as well as disease progression. The tumour suppressor PTEN and the inositol 5-phosphatase SHIP2 are critical enzymes in the control of PtdIns(3,4,5)P(3) level. It has been reported that oxidants, including those produced in cells such as macrophages, can activate downstream signalling via the inactivation of PTEN.