Exploration of novel 20S proteasome activators featuring anthraquinone structures and their application in hypoxic cardiomyocyte protection.

Under hypoxic conditions, the accumulation of misfolded proteins primarily relies on the autonomous activity of 20S proteasome for degradation. The buildup of toxic proteins in cardiomyocyte contribute to various cardiovascular diseases. Therefore, enhancing the 20S proteasome degradation capacity and restoring protein homeostasis in myocardial cells with small molecule activators represent a promising therapeutic strategy for the treatment of ischemic cardiomyopathy.

Small molecules as modulators of the proteostasis machinery: Implication in cardiovascular diseases.

With the escalating prevalence of cardiovascular diseases, the substantial socioeconomic burden on healthcare systems is intensifying. Accumulating empirical evidence underscores the pivotal role of the proteostasis network in regulating cardiac homeostasis and function. Disruptions in proteostasis may contribute to the loss of protein function or the acquisition of toxic functions, which are intricately linked to the development of cardiovascular ailments such as atrial fibrillation, heart failure, atherosclerosis, and cardiac aging.

Evaluation of the liver targeting and anti‑liver cancer activity of artesunate‑loaded and glycyrrhetinic acid‑coated nanoparticles.

Globally, liver cancer ranks among the most lethal cancers, with chemotherapy being one of its primary treatments. However, poor selectivity, systemic toxicity, a narrow treatment window, low response rate and multidrug resistance limit its clinical application. Liver-targeted nanoparticles (NPs) exhibit excellent targeted delivery ability and promising effectivity in treating liver cancer.

pH-Responsive and liver-targeting drug delivery system for combination delivery of artesunate with arsenic trioxide prodrug against hepatocellular carcinoma.

Objective: Arsenic trioxide (ATO) exerts therapeutic effects on various solid tumors, and artesunate (ART) synergizes with antitumor drugs. We herein combined ART and an ATO prodrug (ATOP) in pH-responsive and liver-targeting liposomes to improve targeted hepatocellular carcinoma (HCC) treatment.

Methods: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-hydrazone (HYD)-polyethylene glycol (PEG)-glycyrrhetinic acid (GA) (DSPE-HYD-PEG-GA) was synthesized and characterized.

Design, Synthesis and Biological Evaluation of Glycosylated Derivatives of Silibinin as Potential Anti-Tumor Agents.

Objective: Silibinin, a natural product extracted from the seeds of the , is versatile with various pharmacological effects. However, its clinical application was strongly hampered by its low bioavailability and poor water solubility. Herein, a series of glycosylated silibinin derivatives were identified as novel anti-tumor agents.

Exploration of novel dihydroquinoxalinone derivatives as EGFR tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer.

To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFR with an IC value of 0.55 ± 0.

Regulation of Mitochondrial Function by Natural Products for the Treatment of Metabolic Associated Fatty Liver Disease.

Metabolic associated fatty liver disease (MAFLD) is a multifactorial systemic disorder that occurs in the absence of excessive alcohol consumption. The disease is characterized by fatty degeneration and fat accumulation in liver parenchymal cells, the incidence of which is increasing annually, particularly in younger adults. MAFLD is caused by genetic and metabolism related disorders, of which mitochondrial dysfunction is the major contributor.

Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors.

A series of non-covalent piperidine-containing peptidyl derivatives with various substituents at side chains of different residues were designed, synthesized and evaluated as proteasome inhibitors. After proteasome inhibitory evaluations of all the synthesized target compounds, selected ones were tested for their anti-proliferation activities against three multiple myeloma (MM) cell lines. 8 analogues displayed more potent activities than carfilzomib, and the most promising compound 24 showed IC values of 0.

Proteasome, a Promising Therapeutic Target for Multiple Diseases Beyond Cancer.

Proteasome is vital for intracellular protein homeostasis as it eliminates misfolded and damaged protein. Inhibition of proteasome has been validated as a powerful strategy for anti-cancer therapy, and several drugs have been approved for treatment of multiple myeloma. Recent studies indicate that proteasome has potent therapeutic effects on a variety of diseases besides cancer, including parasite infectious diseases, bacterial/fungal infections diseases, neurodegenerative diseases and autoimmune diseases.

Preparation, evaluation, and cytotoxicity studies of artesunate-loaded glycyrrhetinic acid decorated PEG-PLGA nanoparticles.

Objective: The objective of this study was to prepare the liver targeting drug delivery system (TDDS) of artesunate (ART)-loaded polyethylene glycol (PEG)-poly(d,l-lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) modified by glycyrrhetinic acid (GA), and evaluate its cytotoxicity.

Significance: The GA-PEG-PLGA-ART NPs enhanced the cytotoxicity on HCC cell lines. The development of GA-PEG-PLGA NPs will greatly push the clinical applications of ART as a novel anticancer drug.

Protective effect of apigenin magnesium complex on HO-induced oxidative stress and inflammatory responses in rat hepatic stellate cells.

Apigenin displays antioxidant and anti-inflammatory effects. However, effects of apigenin magnesium (AM) complex on these aspects remain unknown. This study investigated the effects of AM complex on oxidative stress and inflammatory responses in hydrogen peroxide (HO)-induced rat hepatic stellate cells (HSCs).

Immunoproteasome-selective inhibitors: An overview of recent developments as potential drugs for hematologic malignancies and autoimmune diseases.

The immunoproteasome, a specialized form of proteasome, is mainly expressed in lymphocytes and monocytes of jawed vertebrates and responsible for the generation of antigenic peptides for cell-mediated immunity. Overexpression of immunoproteasome have been detected in a wide range of diseases including malignancies, autoimmune and inflammatory diseases. Following the successful approval of constitutive proteasome inhibitors bortezomib, carfilzomib and Ixazomib, and with the clarification of immunoproteasome crystal structure and functions, a variety of immunoproteasome inhibitors were discovered or rationally developed.

Design, synthesis, and biological evaluation of novel 3-(thiophen-2-ylthio)pyridine derivatives as potential multitarget anticancer agents.

A series of novel 3-(thiophen-2-ylthio)pyridine derivatives as insulin-like growth factor 1 receptor (IGF-1R) inhibitors was designed and synthesized. IGF-1R kinase inhibitory activities and cytotoxicities against HepG2 and WSU-DLCL2 cell lines were tested. For all of these compounds, potent cancer cell proliferation inhibitory activities were observed, but not through the inhibition of IGR-1R.

-diacetylcystine ameliorates inflammation in experimental non-alcoholic steatohepatitis by regulating nuclear transcription factor kappa B activation.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases worldwide that has been continuously increasing recently. NAFLD embraces a spectrum of liver histological alterations, ranging from simple steatosis (NAFL) to severe non-alcoholic steatohepatitis (NASH), that is characterized by fat accumulation, lobular inflammation, and ballooning degeneration in the hepatocytes in the absence of alcohol abuse. The innate immune system has an important role in NASH pathogenesis.

Identification of novel -acetylcysteine derivatives for the treatment of hepatocellular injury.

New anti-hepatocellular injury drugs with better curative effects and fewer side effects are urgently needed at present. In this study, a series of novel -acetylcysteine (NAC) derivatives were designed, synthesized and biologically evaluated for their anti-hepatocellular injury activities against two different cell models. In the biological evaluation against hydrogen peroxide (HO)-induced LO2 hepatocytes, half of the target compounds exhibited moderate to potent activities in improving the model cell viability, and two compounds ( and ) displayed more potent activities in decreasing malondialdehyde (MDA) levels than the positive control NAC.

Activated carbon N-acetylcysteine microcapsule protects against nonalcoholic fatty liver disease in young rats via activating telomerase and inhibiting apoptosis.

Non-alcoholic fatty liver disease (NAFLD) is becoming one of the world's most common chronic liver diseases in childhood, yet no therapy is available that has been approved by the food and drug administration (FDA). Previous studies have reported that telomere and telomerase are involved the development and progression of NAFLD. This study was designed to investigate the potential beneficial effects of activated carbon N-acetylcysteine (ACNAC) microcapsules on the development of NAFLD in young rats as well as the underlying mechanism(s) involved.

Stimulatory role of interleukin 10 in CD8 T cells through STATs in gastric cancer.

CD8 T cells are considered to be critical in tumor surveillance and elimination. Increased CD8 T cell frequency and function is associated with better prognosis in cancer patients. Interleukin 10 is a cytokine with controversial roles in CD8 T cell-mediated anti-tumor immunity.

Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.

In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile.

Exploration of novel piperazine or piperidine constructed non-covalent peptidyl derivatives as proteasome inhibitors.

A series of novel piperazine or piperidine-containing non-covalent peptidyl derivatives possessing a neopentyl-asparagine residue were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were screened for their 20S proteasome chymotrypsin-like inhibitory activities, and 15 ones displayed more potent activities than carfilzomib with IC values lower than 10 nM. Subsequently, the most potent 10 analogues were tested for their cytotoxic activities against two multiple myeloma (MM) cell lines RPMI-8226 and MM-1S.

Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors.

A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC less than 20nM, and four are more potent than the positive control Carfilzomib.

Upregulation of CD19⁺CD24(hi)CD38(hi) regulatory B cells is associated with a reduced risk of acute lung injury in elderly pneumonia patients.

Acute lung injury (ALI) is a common complication in elderly pneumonia patients who have a rapid progression, and is accompanied by a high mortality rate. Because the treatment options of ALI are limited to supportive care, identifying pneumonia patients who are at higher risk of ALI development is the emphasis of many studies. Here, we approach this problem from an immunological perspective by examining CD19(+)CD24(hi)CD38(hi) B cells, an important participant in acute and chronic inflammation.

N-acetylcysteine protects against liver injure induced by carbon tetrachloride via activation of the Nrf2/HO-1 pathway.

Chronic liver injury is an important clinical problem which eventually leads to cirrhosis, hepatocellular carcinoma and end-stage liver failure. It is well known that cell damage induced by reactive oxygen species (ROS) is an important mechanism of hepatocyte injure. N-acetylcysteine (NAC), a precursor of glutathione (GSH), is well-known role as the antidote to acetaminophen toxicity in clinic.

Protective effects of -acetylcysteine on cisplatin-induced oxidative stress and DNA damage in HepG2 cells.

Hepatocyte injury is a common pathological effect of cisplatin (CDDP) in various solid tumor therapies. Thus, strategies for minimizing CDDP toxicity are of great clinical interest. -acetylcysteine (NAC), a known antioxidant, is often used as an antidote for acetaminophen overdose in the clinic due to its ability to increase the levels of glutathione (GSH).