Benzbromarone Induces Targeted Degradation of HSP47 Protein and Improves Hypertrophic Scar Formation.

Fibrotic diseases are characterized by the abnormal accumulation of collagen in the extracellular matrix, leading to the functional impairment of various organs. In the skin, excessive collagen deposition manifests as hypertrophic scars and keloids, placing a substantial burden on patients and the healthcare system worldwide. HSP47 is essential for proper collagen assembly and contributes to fibrosis. However, identifying clinically applicable HSP47 inhibitors has been a major pharmaceutical challenge. In this study, we identified benzbromarone (BBR) as an HSP47 inhibitor for hypertrophic scarring treatment. BBR inhibited collagen production and secretion in fibroblasts from patients with keloid by binding to HSP47 and inhibiting the interaction between HSP47 and collagen. Interestingly, BBR not only inhibits HSP47 but also acts as a molecular glue degrader that promotes its proteasome-dependent degradation. Through these molecular mechanisms, BBR effectively reduced hypertrophic scarring in mini pigs and rats with burns and/or excisional skin damage. Thus, these findings suggest that BBR can be used to clinically treat hypertrophic scars and, more generally, fibrotic diseases.

Identification and Semi-Synthesis of 3-O-Protocatechuoylceanothic Acid, a Novel and Natural GPR120 Agonist †.

The identification and three step synthesis of 3-O-protocatechuoylceanothic acid, a novel and natural GPR120 agonist, is described. This ceanothane-type triterpenoid was identified from the components of Ziziphus jujuba roots and was found to be a new GPR120 agonist with a novel structure. We synthetically converted ceanothic acid, which does not have GPR120 agonist activity, into 3-O-protocatechuoylceanothic acid in three steps. In addition, we present the corrected NMR spectrum of 3-O-protocatechuoylceanothic acid based on our synthesis.

Involvement of the P2X7 receptor in the migration and metastasis of tamoxifen-resistant breast cancer: effects on small extracellular vesicles production.

Tamoxifen (TAM) is the standard anti-hormonal therapy for estrogen receptor-positive breast cancer. However, long-term TAM therapy can make acquisition of TAM resistance and there are still no solutions to treat TAM-resistant breast cancer. In this study, we found that protein and mRNA expression of the P2X purinoreceptor 7 (P2X7) was higher in tamoxifen resistant MCF-7 (TAMR-MCF-7) cells than in control MCF-7 cells. P2X7 inhibition potently inhibited the migration of TAMR-MCF-7 cells and the liver metastasis burden of TAMR-MCF-7 cells in the spleen-liver metastasis experiment. However, the P2X7 antagonist did not affect protein expression of matrix metalloproteinase (MMP)-2, MMP-9, and epithelial-mesenchymal transition markers. Here our data indicate a link between small extracellular vesicles (sEV) and P2X7, and suggest a new mechanism of metastasis in TAM-resistant breast cancer cells through P2X7 receptors. The migration of TAMR-MCF-7 cells was increased in a concentration-dependent manner by purified sEV treatment. The number of secreted sEVs and the protein levels of CD63 in TAMR-MCF-7 cells were decreased by the P2X7 antagonist, showing that P2X7 influences the production of sEV. Our results suggest that inhibiting the P2X7 could be considered for metastasis prevention in TAM-resistant cancer patients.

Connectivity mapping of angiotensin-PPAR interactions involved in the amelioration of non-alcoholic steatohepatitis by Telmisartan.

Nonalcoholic fatty liver disease (NAFLD) is a global health problem that is associated with various metabolic disorders. Telmisartan is a potential treatment for NAFLD due to its ability to improve insulin sensitivity and decrease hepatic fat accumulation via modulation of PPARγ, and to suppress hepatic fibrosis by blocking angiotensin II receptors. However, the underlying mechanisms of action of telmisartan have yet to be fully elucidated. In the present study, diabetic nonalcoholic steatohepatitis (NASH) mice (STAM mice) received daily administrations of telmisartan for 6 weeks to assess the improvements in NASH. Hepatic transcriptome analyses revealed that the amelioration of NASH likely occurred through the regulation of inflammatory- and fibrosis-related gene responses. An integrated network analysis including transcriptional and non-transcriptional genes regulated by telmisartan showed that the NAFLD pathway is interconnected with the dysregulated RAS-PPAR-NFκB pathways. The downstream targets of PPARα, PPARδ, and RELA in this network significantly overlapped with telmisartan-induced differentially expressed genes (DEGs), which were verified in palmitate-treated Hepa1c1c7 cell line. This transcriptome approach accompanied with cell-based molecular analyses provided the opportunity to understand the fundamental molecular mechanisms underpinning the therapeutic effects of telmisartan, and will contribute to the establishment of a novel pharmacological treatment for NASH patients.

Self-Powered Real-Time Arterial Pulse Monitoring Using Ultrathin Epidermal Piezoelectric Sensors.

Continuous monitoring of an arterial pulse using a pressure sensor attached on the epidermis is an important technology for detecting the early onset of cardiovascular disease and assessing personal health status. Conventional pulse sensors have the capability of detecting human biosignals, but have significant drawbacks of power consumption issues that limit sustainable operation of wearable medical devices. Here, a self-powered piezoelectric pulse sensor is demonstrated to enable in vivo measurement of radial/carotid pulse signals in near-surface arteries. The inorganic piezoelectric sensor on an ultrathin plastic achieves conformal contact with the complex texture of the rugged skin, which allows to respond to the tiny pulse changes arising on the surface of epidermis. Experimental studies provide characteristics of the sensor with a sensitivity (≈0.018 kPa-1 ), response time (≈60 ms), and good mechanical stability. Wireless transmission of detected arterial pressure signals to a smart phone demonstrates the possibility of self-powered and real-time pulse monitoring system.

Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats.

UNLABELLED: We sought to determine the hepatic fibrosis-reversal effects upon simultaneous administration of lithospermate B (LAB), an anti-oxidant, and nivocasan, a caspase inhibitor, to rats compared with each compound alone. Liver fibrosis was induced in Sprague-Dawley rats by thioacetamide (TAA). Rats were treated with TAA and then given LAB and (or) nivocasan. Fibrotic areas were evaluated quantitatively by computerized morphometry. Apoptosis was assessed using a TUNEL assay, and immunohistochemical staining for malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4HNE) was performed to assess oxidative stress levels. Real-time quantitative PCR was used to quantify expression of fibrosis-related genes. The degree of hepatic fibrosis was significantly reduced in rats treated with LAB and nivocasan compared to either treatment alone (P < 0.001). Treatment with each compound significantly decreased expression of fibrosis-related genes, such as type I collagen α1 (col1α1), α-SMA and TGF-ß1 (P < 0.05). Co-treatment with LAB and nivocasan further reduced col1α1 expression compared to treatment with either compound. A TUNEL assay revealed that hepatocyte apoptosis was significantly decreased in the group treated with nivocasan compared to other groups (P < 0.01). Immunohistochemistry showed a decrease in MDA and 4HNE, reflecting amelioration of oxidative stress, when LAB or LAB+nivocasan was administered compared to nivocasan alone (P < 0.01). Nivocasan was found to inhibit caspase-1, -3, -7, -9 and gliotoxin-induced death of rat-derived hepatic stellate cells was inhibited by nivocasan administration without overexpression of α-SMA. CONCLUSIONS: Co-incidental administration of LAB and nivocasan suppressed oxidative stress and apoptosis, resulting in enhanced reversal of hepatic fibrosis in rat.

Role of p38 MAPK in the regulation of apoptosis signaling induced by TNF-alpha in differentiated PC12 cells.

TNF-alpha elicits various responses including apoptosis, proliferation, and differentiation according to cell type. In neuronal PC12 cells, TNF-alpha induces moderate apoptosis while lipopolysarccaharide or trophic factor deprivation can potentiate apoptosis that is induced by TNF-alpha. TNF-alpha initiates various signal transduction pathways leading to the activation of the caspase family, NF-subk;B, Jun N-terminal kinase, and p38 MAPK via the death domain that contains the TNF-alpha receptor. Inhibition of translation using cycloheximide greatly enhanced the apoptotic effect of TNF-alpha. This implies that the induction of anti-apoptotic genes for survival by TNF-alpha may be able to protect PC12 cells from apoptosis. Accordingly, Bcl-2, an anti-apoptotic Bcl-2 family member, was highly expressed in response to TNF-alpha. In this study, we examined the anti-apoptotic role of p38 MAPK that is activated by TNF-alpha in neuronal PC12 cells. The phosphorylation of p38 MAPK in response to TNF-alpha slowly increased and lasted several hours in the PC12 cell and DRG neuron. This prolonged and slow phosphorylation of p38 MAPK was distinct from other non-neuronal cells. The specific inhibitor of p38 MAPK, SB202190, significantly enhanced the apoptosis that was induced by TNF-alpha in PC12 cells. This indicates that the activation of p38 MAPK could protect PC12 cells from apoptosis since there is no known role of p38 MAPK in response to TNF-alpha in neuron. This discovery could be evidence for the neuroprotective role of the p38 MAPK.