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. It is widely acknowledged that the proteostasis network encompasses molecular chaperones, autophagy, and the ubiquitin proteasome system (UPS). Consequently, the proteostasis network emerges as an appealing target for therapeutic interventions in cardiovascular diseases. Numerous small molecules, acting as modulators of the proteostasis machinery, have exhibited therapeutic efficacy in managing cardiovascular diseases. This review centers on elucidating the role of the proteostasis network in various cardiovascular diseases and explores the potential of small molecules as therapeutic agents.

Association Between Plasma Levels of ANGPTL3, 4, 8 and the Most Common Additional Cardiovascular Risk Factors in Patients with Hypertension.

Background: ANGPTL3, 4 and 8 have been reported to be involved in the regulation of lipid and glucose metabolism. The aim of this study was to investigate the expression of ANGPTL3, 4, 8 in hypertensive patients with or without overweight/obesity, T2D, and hyperlipidemia, and the possible association between their expression and the status of the aforementioned comorbidities. Methods: Plasma levels of ANGPTL3, 4, and 8 in 87 hospitalized patients with hypertension were measured using ELISA kits. Associations between circulating ANGPTLs levels and the most common additional cardiovascular risk factors were assessed using multivariate linear regression analyses. Pearson's correlation analysis was used to examine the association between ANGPTLs and clinical parameters. Results: In the context of hypertension, (1) although not statistically significant, circulating ANGPTL3 levels were higher in the overweight/obese group than in the normal weight group; (2) circulating levels of ANGPTL3 and ANGPTL8 were significantly lower in patients with T2D than in non-diabetic patients; (3) circulating ANGPTL3 levels were significantly higher in the hyperlipidemic group than in the non-hyperlipidemic group. ANGPTL3 was associated with T2D and hyperlipidemia status, whereas ANGPTL8 was independently associated with T2D status. In addition, circulating ANGPTL3 levels were positively correlated with TC, TG, LDL-C, HCY, and ANGPTL8, and circulating ANGPTL4 levels were positively correlated with UACR and BNP. Conclusion: Changes in circulating ANGPTL3 and ANGPTL8 levels have been observed in hypertensive patients with the most common additional cardiovascular risk factors, suggesting a role in the common comorbidities of hypertension and cardiovascular disease. Hypertensive patients with overweight/obesity or hyperlipidemia may benefit from therapies targeting ANGPTL3.

A peptide encoded by lncRNA MIR7-3 host gene (MIR7-3HG) alleviates dexamethasone-induced dysfunction in pancreatic ß-cells through the PI3K/AKT signaling pathway.

BACKGROUND: Dysfunction of pancreatic ß-cells induced by glucocorticoids contributes to diabetes mellitus development. Long noncoding RNAs (lncRNAs) have been recognized to contain short open reading frames (ORFs) that can be translated into functional small peptides. Here, we investigated whether the short peptide encoded by the lncRNA MIR7-3 host gene (MIR7-3HG) can affect dexamethasone (DEX)-induced ß-cell dysfunction. METHODS: Bioinformatics analysis was used for selection of MIR7-3HG and prediction of its protein encoding potential. The small peptide was identified by a western blot method. The cell-permeable TAT was fused into MIR7-3HG ORF to produce the cell-permeable fusion peptide (TAT-MIR7-3HG-ORF). The effects of TAT-MIR7-3HG-ORF on DEX-induced ß-cell dysfunction were evaluated by examining cell viability, apoptosis, insulin secretion, and reactive oxygen species (ROS) generation. RESULTS: DEX induced ß-TC6 cell dysfunction by impairing cell viability, insulin secretion and promoting cell apoptosis and ROS generation. The MIR7-3HG ORF could encode a 125-amino-acid-long short peptide. TAT-MIR7-3HG-ORF effectively transduced into ß-TC6 cells and attenuated DEX-induced dysfunction in ß-TC6 cells. Moreover, transduced TAT-MIR7-3HG-ORF reversed DEX-mediated inhibition of the activation of the PI3K/AKT signaling pathway. The inhibitor of the PI3K/AKT pathway partially abolished the alleviative effect of transduced TAT-MIR7-3HG-ORF on DEX-induced ß-TC6 cell dysfunction. CONCLUSION: The lncRNA MIR7-3HG encodes a short peptide, which can protect pancreatic ß-cells from DEX-induced dysfunction by activating the PI3K/AKT pathway. Our study broadens the diversity and breadth of lncRNAs in human disorders.

Purification, structural characterization, and biological activities of degraded polysaccharides from Porphyra yezoensis.

The degraded polysaccharides from Porphyra yezoensis (DPPY) prepared using the H2 O2 -Vc method under optimized conditions were isolated and purified by DEAE Cellulose-52, and Sephadex G-100, providing four pure components, namely, DPPY-0, DPPY-0.1, DPPY-0.3, and DPPY-0.5. Their relative molecular weights were measured to be 10.8, 10.7, 18.7, and 35.5 kDa, respectively. GC-MS analysis revealed that all the four fractions were mainly composed of galactose, together with a small portion of glucose, mannose, xylose, and rhamnose. Structural analysis revealed that the purified polysaccharides mainly possess a backbone of (1 â†’ 3)-ß-D-galactose (1 â†’ 4)-3,6-anhydro-α-L-galactopyranose (G-A) units and (1 â†’ 3)-ß-D-galactose (1 â†’ 4)-α-L-galactose-6-sulfate (G-L6S) units. They were found to promote the proliferation of RAW264.7 macrophages and enhance phagocytosis of the RAW264.7 cells. Antioxidant assays indicated that DPPY-0.5 possessed the most potent reducing power and free radical scavenging ability among the four purified polysaccharides. High sulfate content and proper molecular weight of these fractions are favorable to their immunomodulatory and antioxidant activities. PRACTICAL APPLICATIONS: Porphyra yezoensis, common economic red algae widely distributed in East Asian countries, contains a high content of polysaccharides with a variety of biological activities. However, P. yezoensis polysaccharide (PPY) has not been well utilized due to the relatively low biological activities and lack of understanding of its structure-activity relationship. Thus, it is necessary to improve the bioactivities and elucidate the structure-activity relationship of this polysaccharide for its practical use. In the present work, four purified fractions (DPPY-0, DPPY-0.1, DPPY-0.3, and DPPY-0.5) were isolated from the degraded P. yezoensis polysaccharide, and were investigated for their antioxidant and immunoregulatory activities. The results of the present work will lay a foundation for the application of the degraded P. yezoensis polysaccharide in the food industry as a functional food ingredient.

On-ward participation of clinical pharmacists in a Chinese intensive care unit for patients with COVID-19: A retrospective, observational study.

BACKGROUND: The practical experiences of active pharmacists involved in managing critically ill patients with coronavirus disease 2019 (COVID-19) have been rarely reported. OBJECTIVE: This work aimed to share professional experiences on medication optimization and provide a feasible reference for the pharmaceutical care of critically ill patients with COVID-19. METHODS: This study was conducted in a COVID-19-designated hospital in China. A group of dedicated clinical pharmacists participated in multidisciplinary rounds to optimize the treatments for critically ill patients with COVID-19. Consensus on medication recommendations was reached by a multidisciplinary team through bi-daily discussion. Related drug, classification, cause, and adjustment content for recommendations were recorded and reviewed. RESULTS: A total of 111 medication recommendations were supplied for 22 out of 33 (56.7%) critically ill patients from 1 February 2020 to 18 March 2020, and 106 (95.5%) of these were accepted. Among these recommendations, 64 (67.7%), 32 (28.8%), and 15 (13.5%) were related to antibiotics and antifungals, antiviral agents, and other drugs, respectively. Recommendation types significantly differed for different anti-infectives (p < 0.05). For antibiotics and antifungals, treatment effectiveness accounted for 60.9% of recommendation types, with 15 (38.5%) cases related to untreated infections. For antiviral agents, adverse drug events were the most common recommendation types (84.4%), with 20 (74.1%) cases related to liver function dysfunction. Discontinuation of suspected antiviral agents (66.7%) was usually recommended after the occurrence of adverse events that may progress and bring poor outcomes. CONCLUSION: Forceful and extensive on-ward participation is recommended for clinical pharmacists in managing critically ill patients. Our experiences highlight the need for special attention toward untreated infections and adverse events related to antiviral agents.

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. In this review, recent developments of proteasome inhibitors for various diseases and related structure activity relationships are going to be summarized.

Pharmacist-driven multidisciplinary initiative continuously improves postoperative nausea and vomiting in female patients undergoing abdominal surgery.

WHAT IS KNOWN AND OBJECTIVE: The incorrect or insufficient prophylaxis of postoperative nausea and vomiting (PONV) is common in practice. A clinical pharmacist-led guidance team (CPGT) was established and included in general surgery teams. OBJECTIVE: This study aimed to evaluate the effects of the CPGT on the improvement of PONV and prophylaxis administration. METHODS: A prospective before-after study was conducted on 156 female patients undergoing abdominal surgery at a Chinese tertiary teaching hospital from December 2016 to December 2017. A total of 82 patients were enrolled in the preintervention period, and 74 patients were included in the post-intervention period. The CPGT established the evidence-based criteria for prophylactic anti-emetic administration and conducted interventions, including a review of medical records, provision of feedback, educational outreach, and dedicated support. Primary outcomes included the incidence of PONV within 24 hours of surgery, administered number of prophylactic anti-emetics, and accuracy of the timing for prophylactic anti-emetics. Outcomes were analysed by logistic regression or multivariable linear regression. RESULTS AND DISCUSSION: After intervention, patients reported significantly less PONV (33.78% vs 56.10%; odds ratio [OR]: 0.29; numbers needed to treat [NNT]: 3.47), vomiting (29.73% vs 45.12%; OR: 0.42; NNT: 5.16) and nausea (31.08% vs 56.10%; OR: 0.24; NNT: 3.19) within 24 hours of surgery. The accuracy of the timing for prophylactic anti-emetics significantly increased (OR: 3.66; P: .003). Anaesthesiologists administered increased numbers of prophylactic anti-emetics (OR: 5.82; P < .001). The improvement of PONV did not decrease during the four-month period after intervention (P: .639). WHAT IS NEW AND CONCLUSION: The CPGT is a valuable service model to continuously improve PONV and optimize prophylaxis administration.

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. Not only the inhibitory activities, the selectivities for immunoproteasome over constitutive proteasome are essential for the clinical potential of these analogues, which has been validated by the clinical evaluation of immunoproteasome-selective inhibitor KZR-616 for the treatment of systemic lupus erythematosus. In this review, structure, function as well as the current developments of various inhibitors against immunoproteasome are going to be summarized, which help to fully understand the target for drug discovery.

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. Selected compounds were further screened against various kinases. Typical compound 22 (50% inhibitory concentration [IC50 ] values, HepG2: 2.98 ± 1.11 µM and WSU-DLCL2: 4.34 ± 0.84 µM) exhibited good inhibitory activities against fibroblast growth factor receptor-2 (FGFR2), FGFR3, epidermal growth factor receptor, Janus kinase, and RON (receptor originated from Nantes), with IC50 values ranging from 2.14 to 12.20 µM. Additionally, the cell-cycle analysis showed that compound 22 could arrest HepG2 cells in the G1/G0 phase. Taken together, all the experiments confirmed that the compounds in this series were multitarget anticancer agents worth further optimizing.

The Role of the Sodium-taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) in Related Liver Disease.

BACKGROUND: Sodium Taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) play significant roles as membrane transporters because of their presence in the enterohepatic circulation of bile salts. They have emerged as promising drug targets in related liver disease. METHODS: We reviewed the literature published over the last 20 years with a focus on NTCP and BSEP. RESULTS: This review summarizes the current perception about structure, function, genetic variation, and regulation of NTCP and BSEP, highlights the effects of their defects in some hepatic disorders, and discusses the application prospect of new transcriptional activators in liver diseases. CONCLUSION: NTCP and BSEP are important proteins for transportation and homeostasis maintenance of bile acids. Further research is needed to develop new models for determining the structure-function relationship of bile acid transporters and screening for substrates and inhibitors, as well as to gain more information about the regulatory genetic mechanisms involved in the processes of liver injury.

[Research progress on selective immunoproteasome inhibitors].

Immunoproteasome is associated with various diseases such as hematologic malignancies, inflammatory, autoimmune and central nervous system diseases, and over expression of immunoproteasome is observed in all of these diseases. Immunoproteasome inhibitors can reduce the expression of immunoproteasome by inhibiting the production of related cell-inducing factors and the activity of T lymphocyte for treating related diseases. In order to achieve good efficacy and reduce the toxic effects, key for development of selective immunoproteasome inhibitors is the high selectivity and potent activity of the three active subunits of the proteasome. This review summarizes the structure and functions of immunoproteasome and the associated diseases. Besides, structure, activity and status of selective immunoproteasome inhibitors are also been highlighted.

Antioxidant and antimicrobial evaluation of carboxymethylated and hydroxamated degraded polysaccharides from Sargassum fusiforme.

In order to improve the bioactivity of the polysaccharide from Sargassum fusiforme (PSF), the degraded polysaccharide (DPSF) was modified by carboxymethylation, yielding carboxymethylated degraded polysaccharides (CDPSF), which were further modified to generate hydroxamated derivatives (HCDPSF). Both CDPSF and HCDPSF were characterized by Fourier transform infrared spectroscopy. The molecular weight of CDPSF and HCDPSF was found to be 354 kDa and 375 kDa, respectively. The in vitro antioxidant activity of CDPSF and HCDPSF was evaluated by determining the radical scavenging ability and total antioxidant activity. The results indicated that the antioxidant activity of CDPSF and HCDPSF was significantly improved when compared to those of DPSF. Antimicrobial assays indicated that both CDPSF and HCDPSF possessed a marked antimicrobial ability, while DPSF did not exhibit such effects under the same conditions. Such polysaccharide derivatives have potentials in the pharmaceutical and food industries.

Synthesis, iron binding and antimicrobial properties of hexadentate 3-hydroxypyridinones-terminated dendrimers.

Macromolecular chelators have potential applications in the medical area, for instance, in treatment of iron overload-related disorders and in the treatment of external infections. In this investigation, several novel iron(III)-selective hydroxypyridinone hexadentate-terminated first and second generation dendrimeric chelators were synthesized using a convergent strategy. Their iron chelating ability was demonstrated by UV/Visible spectrometry and high resolution mass spectrometry (HRMS). The iron binding affinities were also investigated by the competition with a fluorescent iron chelator CP691. The result indicated that these dendrimers possesses a high affinity for iron with a very high pFe3+ value, which is close to that of an isolated hexadentate unit. These dendrimeric chelators were found to exhibit inhibitory effect on the growth of both Gram-positive and Gram-negative bacteria.

Preparation, characterization and catalytic behavior of pectinase covalently immobilized onto sodium alginate/graphene oxide composite beads.

Pectinase was immobilized onto sodium alginate/graphene oxide beads via amide bonds by using N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide as the activating agent. The immobilized pectinase was characterized by Fourier transform infrared spectra and scanning electron microscopy analyses. Immobilization conditions were optimized by Box-Behnken design and the response surface method. The activity of the immobilized pectinase prepared under optimal conditions reached 1236.86 ±â€¯40.21 U/g, with an enzyme activity recovery of 83.5%. The optimal pH of free pectinase was 4.5, while that of immobilized pectinase was shifted to 4.0. The optimal temperature of immobilized pectinase was increased to 60 °C, which was 10 °C higher than that of free form. Furthermore, the immobilized pectinase possessed a superior thermal stability and storage stability to those of free pectinase. Reusability studies indicated that the immobilized pectinase retained 73% of initial activity after six times cycles. Due to these good properties, such immobilized pectinase may find application in food industry.

Novel hydroxypyridinone derivatives containing an oxime ether moiety: Synthesis, inhibition on mushroom tyrosinase and application in anti-browning of fresh-cut apples.

A range of hydroxypyridinone derivatives were synthesized starting from kojic acid. Among them, 10 and 11 were found to possess the strongest inhibitory effect on monophenolase activity of mushroom tyrosinase, having IC50 values of 2.04 and 1.60µM, respectively. The IC50 values of 10 and 11 for the inhibition of diphenolase activity of mushroom tyrosinase were determined as 13.89 and 7.99µM, respectively. Investigation of the inhibitory mechanism of these two compounds indicated that the inhibition was reversible and of a competitive-uncompetitive mixed type. The KI and KIS values of 10 were determined to be 24.84 and 32.54µM, respectively, and the corresponding values for 11 being 18.07 and 21.34µM, respectively. The effect of 11 on the browning process of fresh-cut apples was evaluated by measuring the color change and browning index. The results indicated that 11 had a significant effect on controlling the browning of fresh-cut apple slices.

Preparation, antioxidant and antimicrobial evaluation of hydroxamated degraded polysaccharides from Enteromorpha prolifera.

In order to improve the antioxidant and antimicrobial abilities, hydroxamated degraded polysaccharides from Enteromorpha prolifera (HCDPE) were prepared from the corresponding carboxymethylated degraded polysaccharides (CDPE). HCDPE was characterized by FT-IR. The weight-average molecular weight of HCDPE was determined as 55.4kDa. The in vitro antioxidant activity of HCDPE was evaluated by determining the radical (1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl and superoxide anion radicals) scavenging abilities and total antioxidant activity. It was found that DPPH radical scavenging ability and total antioxidant activity of HCDPE were significantly improved compared to those of CDPE. The inhibitory effects of polysaccharides against the five bacterial strains (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella spp.) were also evaluated by bacterial inhibition zone and minimum inhibitory concentration (MIC) assays. The results indicated that CDPE and HCDPE possess marked antimicrobial ability, while such an effect was not observed for the crude polysaccharides (PE) and the degraded polysaccharides (DPE).

Identification of novel N-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 N-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 (H2O2)-induced LO2 hepatocytes, half of the target compounds exhibited moderate to potent activities in improving the model cell viability, and two compounds (6a and 6b) displayed more potent activities in decreasing malondialdehyde (MDA) levels than the positive control NAC. In further 4-acetamidophenol (APAP)-induced LO2 cell experiment, compounds 6a and 6b could not only improve the cell viability but also significantly reduce the secretion of MDA. Additionally, compound 6a displayed excellent Caco-2 permeability and oral bioavailability in rats. All these experimental results suggested that compounds 6a and 6b could serve as potential lead molecules for further development of anti-hepatocellular injury drugs.