Lactate Dehydrogenase Inhibition Protects against Hepatic Fibrosis by Regulating Metabolic Reprogramming of Hepatic Stellate Cells.

Hepatic stellate cells (HSCs) activation results in liver fibrosis. When HSCs are activated, metabolism is reprogrammed. However, metabolic alteration in HSCs activation has not been sufficiently addressed.

Recent Advances in Targeted Cancer Therapy: Are PDCs the Next Generation of ADCs?

Antibody-drug conjugates (ADCs) comprise antibodies, cytotoxic payloads, and linkers, which can integrate the advantages of antibodies and small molecule drugs to achieve targeted cancer treatment. However, ADCs also have some shortcomings, such as non-negligible drug resistance, a low therapeutic index, and payload-related toxicity. Many studies have focused on changing the composition of ADCs, and some have even further extended the concept and types of targeted conjugated drugs by replacing the targeted antibodies in ADCs with peptides, revolutionarily introducing peptide-drug conjugates (PDCs).

Inhibition of Carbohydrate Metabolism Potentiated by the Therapeutic Effects of Oxidative Phosphorylation Inhibitors in Colon Cancer Cells.

Cancer cells undergo a significant level of "metabolic reprogramming" or "remodeling" to ensure an adequate supply of ATP and "building blocks" for cell survival and to facilitate accelerated proliferation. Cancer cells preferentially use glycolysis for ATP production (the Warburg effect); however, cancer cells, including colorectal cancer (CRC) cells, also depend on oxidative phosphorylation (OXPHOS) for ATP production, a finding that suggests that both glycolysis and OXPHOS play significant roles in facilitating cancer progression and proliferation. Our prior studies identified a semisynthetic isoflavonoid, DBI-1, that served as an AMPK activator targeting mitochondrial complex I.

Proteomic characterization of hUC-MSC extracellular vesicles and evaluation of its therapeutic potential to treat Alzheimer's disease.

In recent years, human umbilical cord mesenchymal stem cell (hUC-MSC) extracellular vesicles (EVs) have been used as a cell replacement therapy and have been shown to effectively overcome some of the disadvantages of cell therapy. However, the specific mechanism of action of EVs is still unclear, and there is no appropriate system for characterizing the differences in the molecular active substances of EVs produced by cells in different physiological states. We used a data-independent acquisition (DIA) quantitative proteomics method to identify and quantify the protein composition of two generations EVs from three different donors and analysed the function and possible mechanism of action of the proteins in EVs of hUC-MSCs via bioinformatics.

Unveiling the Dual-Enhancing Mechanisms of Kinetically Controlled Silver Nanoparticles on Piezoelectric PVDF Nanofibers for Optimized SERS Performance.

Noble metal nanoparticle (NMP)-based composite substrates have garnered significant attention as a highly promising technique for surface-enhanced Raman scattering (SERS) in diverse scientific disciplines because their remarkable ability to amplify and functionalize Raman signals has positioned them as valuable tools for molecular detection. However, optimizing the size and distribution of NMPs has not received sufficient emphasis because of challenges associated with the precise control of deposition and the modulation of reducing rates during growth. In this research, we achieved the optimized size and spatial patterns of AgNWs on electrospun poly(vinylidene fluoride) (PVDF) nanofibers by utilizing a polydopamine (PDA) layer as a mild and controllable reduction mediator, by which the size and density of the AgNWs could be relatively precisely manipulated, achieving a dense distribution of effective "hot spots".

Peptide-drug conjugates: A new paradigm for targeted cancer therapy.

Peptide-drug conjugates (PDCs) are the new hope for targeted therapy after antibody-drug conjugates (ADCs). Compared with ADCs, the core advantages of PDCs are enhanced tissue penetration, easier chemical synthesis, and lower production costs. Two PDCs have been approved by the US Food and Drug Administration (FDA) for the treatment of cancer.

Screening, Expression and Identification of Nanobody Against Monkeypox Virus A35R.

Introduction: The monkeypox (Mpox) virus epidemic presents a significant risk to global public health security. A35R, a crucial constituent of EEV, plays a pivotal role in virus transmission, serves as a vital target for vaccine development, and has potential for serological detection. Currently, there is a dearth of research on nanobodies targeting A35R.

Mangiferin for the Management of Liver Diseases: A Review.

The liver is a digestive and metabolic organ, and several factors can induce liver damage, which is a severe threat to human health. As a natural polyphenolic compound, mangiferin belongs to xanthone glucoside and mainly exists in many plants, such as mango. It is notorious that mangiferin has remarkable pharmacological activities such as anti-inflammatory, anti-tumor, antioxidative stress, antiviral and so on.

Vitamin D3 affects the gut microbiota in an LPS-stimulated systemic inflammation mouse model.

Although gut dysbiosis contributes to systemic inflammation, the counteractive effect of systemic inflammation on gut microbiota is unknown. Vitamin D may exert anti-inflammatory effects against systemic inflammation, but its regulation of the gut microbiota is poorly understood. In this study, mice were intraperitoneally injected with lipopolysaccharide (LPS) to create a systemic inflammation model and received vitamin D3 treatment orally for 18 continuous days.

Upregulation of Microglial Sirt6 and Inhibition of Microglial Activation by Vitamin D3 in Lipopolysaccharide-stimulated Mice and BV-2 Cells.

Vitamin D3 may suppress microglial activation and neuroinflammation, which play a central role in the pathophysiology of many neurological disorders. Sirt6 can remove histone 3 lysine 9 acetylation (H3K9ac) to repress expression of pathological genes and produce anti-inflammatory effects. However, whether vitamin D3 upregulates microglial Sirt6 to exert its protective effects against microglial activation and neuroinflammation is unclear.

Genomic screening methodology not requiring barcoding: Single nucleotide polymorphism-based, mixed-cell screening (SMICS).

Although high-throughput, cancer cell-line screening is a time-honored, important tool for anti-cancer drug development, this process involves the testing of each, individual drug in each, individual cell-line. Despite the availability of robotic liquid handling systems, this process remains a time-consuming and costly investment. The Broad Institute developed a new method called Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) to screen a mixture of barcoded, tumor cell-lines.

Mangiferin Protects DNase 2 Abundance via Nrf2 Activation to Prevent Cytosolic mtDNA Accumulation during Liver Injury.

Scope: Mitochondrial DNA (mtDNA) released into the cytosol serves as a member of damage-associated molecular patterns to initiate inflammatory responses. Mangiferin is a xanthonoid derivative, usually isolated from plants including mangoes and iris unguicularis. This study aims to investigate whether mangiferin prevents mtDNA accumulation in the cytosol with a focus on deoxyribonuclease 2 (DNase 2) protection from oxidative damage.

Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling.

The deregulation in the Wnt/β-catenin signaling pathway is associated with many human cancers, particularly colorectal cancer (CRC) and, therefore, represents a promising target for drug development. We have screened over 300 semisynthetic and natural compounds using a Wnt reporter assay and identified a family of novel chalcone derivatives (CXs) that inhibited Wnt signaling and CRC cell proliferation. Among them, we selected CX258 for further in vitro and in vivo study to investigate the molecular mechanisms.

Semisynthetic aurones A14 protects against T-cell acute lymphoblastic leukemia via suppressing proliferation and inducing cell cycle arrest with apoptosis.

Background: Acute lymphoblastic leukemia is an aggressive neoplasm and seriously threatens human health. A14 is one kind of semisynthetic aurone that exhibits the capability to inhibit prostate cancer, but little is known about the role of A14 on T-cell acute lymphoblastic leukemia.

Methods: Firstly, the effects of A14 on the ability of leukemia cells to proliferate were measured by Vi-cell counter.

Discovery of genistein derivatives as potential SARS-CoV-2 main protease inhibitors by virtual screening, molecular dynamics simulations and ADMET analysis.

Due to the constant mutation of virus and the lack of specific therapeutic drugs, the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still poses a huge threat to the health of people, especially those with underlying diseases. Therefore, drug discovery against the SARS-CoV-2 remains of great significance. With the main protease of virus as the inhibitor target, 9,614 genistein derivatives were virtually screened by LeDock and AutoDock Vina, and the top 20 compounds with highest normalized scores were obtained.

Diaminobutoxy-substituted Isoflavonoid (DBI-1) Enhances the Therapeutic Efficacy of GLUT1 Inhibitor BAY-876 by Modulating Metabolic Pathways in Colon Cancer Cells.

Cancer cells undergo significant "metabolic remodeling" to provide sufficient ATP to maintain cell survival and to promote rapid growth. In colorectal cancer cells, ATP is produced by mitochondrial oxidative phosphorylation and by substantially elevated cytoplasmic glucose fermentation (i.e.

Potent Synergistic Effect on C-Myc-Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor.

Developing effective treatments for colorectal cancers through combinations of small-molecule approaches and immunotherapies present intriguing possibilities for managing these otherwise intractable cancers. During a broad-based, screening effort against multiple colorectal cancer cell lines, we identified indole-substituted quinolines (ISQ), such as -dimethyl-3-(1-methyl-1-indol-3-yl)quinoline-2,7-diamine (ISQ-1), as potent inhibitors of several cancer cell lines. We found that ISQ-1 inhibited Wnt signaling, a main driver in the pathway governing colorectal cancer development, and ISQ-1 also activated adenosine monophosphate kinase (AMPK), a cellular energy-homeostasis master regulator.

Mangiferin protects against alcoholic liver injury suppression of inflammation-induced adipose hyperlipolysis.

Adipose dysfunction is closely associated with alcoholic liver disease. The impact of mangiferin on ethanol-induced liver injury and the probable underlying molecular mechanism has not been sufficiently addressed. In the present study, mice were subjected to a chronic plus a single binge ethanol feeding to induce liver injury.

Semisynthetic aurones inhibit tubulin polymerization at the colchicine-binding site and repress PC-3 tumor xenografts in nude mice and myc-induced T-ALL in zebrafish.

Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the leading, biologically active analogs were (Z)-2-((2-((1-ethyl-5-methoxy-1H-indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile (5a) and (Z)-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2H)-one (5b) that inhibited in vitro PC-3 prostate cancer cell proliferation with IC values below 100 nM. A xenograft study in nude mice using 10 mg/kg of 5a had no effect on mice weight, and aurone 5a did not inhibit, as desired, the human ether-à-go-go-related (hERG) potassium channel.

Phenylethynyl-substituted Heterocycles Inhibit Cyclin D1 and Induce the Expression of Cyclin-dependent Kinase Inhibitor p21 in Colorectal Cancer Cells.

Fluorinated, phenylethynyl-substituted heterocycles that possessed either an -methylamino or -dimethylamino group attached to heterocycles including pyridines, indoles, 1-indazoles, quinolines, and isoquinolines inhibited the proliferation of LS174T colon cancer cells in which the inhibition of cyclin D1 and induction of the cyclin-dependent kinase inhibitor-1 (., p21) served as a readout for antineoplastic activity at a cellular level. On a molecular level, these agents, particularly 4-((2,6-difluorophenyl)ethynyl)--methylisoquinolin-1-amine and 4-((2,6-difluorophenyl)ethynyl)-,-dimethylisoquinolin-1-amine, bound and inhibited the catalytic subunit of methionine S-adenosyltransferase-2 (MAT2A).

[Establishment of an ErbB3- and ErbB4-specific ligand screening system, and a screen of neuregulin-1 mutants].

Neuregulin-1 (NRG1), now in a phase II clinical trial, has beneficial effects on heart failure patients through the activation of ErbB2/ErbB4 receptor pair. To decrease the side effect of NRG1 on activating ErbB3, a mutation screen was carried out to get NRG1 mutants, which have more specific binding to ErbB2/ErbB4 receptor pair. Two CHO stable cell lines were constructed, which express ErbB2/ErbB3 or ErbB2/ErbB4 receptor pair, respectively.

A recombinant human neuregulin-1 peptide improves preservation of the rodent heart after prolonged hypothermic storage.

Background: Donor hearts are subjected to ischemia-reperfusion injury during transplantation. Recombinant human neuregulin (rhNRG)-1 peptide attenuates myocardial injury in various animal models of cardiomyopathy. Supplementing the organ-storage solution, Celsior (C), with glyceryl trinitrate (GTN) and cariporide improves cardiac preservation after hypothermic storage.

Neuregulin-1/ErbB signaling and chronic heart failure.

Neuregulin-1 (NRG-1), a cardioactive growth factor released from endothelial cells, is indispensable for cardiac development, structural maintenance, and functional integrity of the heart. In recent years, a growing number of studies have focused on NRG-1 and members of the ErbB family that serve as receptors for NRG-1 in order to better understand the role of this signaling pathway in physiology and pathophysiology of the heart. An essential role for NRG-1 and ErbB in heart development and functionality has been suggested by studies in conditional NRG-1/ErbB-deficient mice and by the cardiac-related side effects of anti-ErbB2 antibody therapies used for treatment of breast cancer.

Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses.

Aims: Neuregulin-1 (NRG-1) plays a critical role in the adaptation of the heart to injury, inhibiting apoptosis and inducing cardiomyocyte proliferation. We have shown previously that rhNRG-1 improves cardiac function and survival in animal models of cardiomyopathy. Here we report the first human study aimed at exploring the acute and chronic haemodynamic responses to recombinant human NRG-1 (beta(2a) isoform; rhNRG-1) in patients with stable chronic heart failure (CHF).

Neuregulin 1 sustains the gene regulatory network in both trabecular and nontrabecular myocardium.

Rationale: The cardiac gene regulatory network (GRN) is controlled by transcription factors and signaling inputs, but network logic in development and it unraveling in disease is poorly understood. In development, the membrane-tethered signaling ligand Neuregulin (Nrg)1, expressed in endocardium, is essential for ventricular morphogenesis. In adults, Nrg1 protects against heart failure and can induce cardiomyocytes to divide.