Current Medicinal Chemistry - Volume 30, Issue 18, 2023

Background: Cantharidin (CTD) is a highly toxic substance which can be used to treat a variety of cancers. However, the clinical application of CTD is restricted due to the serious side effects. In recent years, screening its analogues, exploring the mechanism of action and using combinatory therapy with certain substances are considered to be feasible methods which can reduce side effects and improve the therapeutic activity of CTD. This review aims to describe SAR (structure-activity relationship) of CTD analogues, CTD induction mechanisms, and combinatory therapy exploration. Methods: We searched for research about CTD by entering the database. Important information was screened and extracted purposefully, including SAR, mechanisms, methods, etc. Finally, these contents were unified into a framework to form a review. Results: Some CTD analogues with imidazolium salt or double bonds at C-5 and C-6 positions demonstrate good anticancer activity. Through introducing methyl and acetoxy groups at the C-1 or C-4 position, the inhibitory effect of PP was weakened or even inactivated. Removing the two methyl groups of C-2 and C-3 can reduce side effects and improve efficacy. Replacing methyl with fluorine can also improve the activity and reduce toxicity. Water solubility and bioavailability could be improved by opening the five fivemembered anhydride ring to form carboxylic acid, salt, amide, and ester derivatives. The anticancer mechanism can be divided into the following aspects, including inhibiting cell invasion and metastasis, inducing apoptosis, regulating cell cycle and enhancing immunity. The proper formulation of CTD and its analogues (liposomes, nanoparticles and micelles) can improve the targeting of liver cancer and reduce toxic and side effects. CTD combined with anti-angiogenic therapeutics (Ginsenoside Rg3, Bevacizumab, Apatinib and Endostar) showed additive anti-pancreatic cancer effects. Conclusion: It was found that the potential mechanism was closely related to multi-channel and multi-target interactions, which provided a guiding direction for the later exploration of new clinical therapeutic applications. However, some detailed mechanisms are still unclear, and more evidence is required to verify. In addition, the new methods to improve the therapeutic potential of CTD and its analogues still need more clinical trials to be tested in the future. This prospect is very broad and worthy of further study.

Several epigenome studies reported the ability of genes to modulate the lipogenic and glucogenic pathways during insulin signaling as well as the other pathways involved in cardiometabolic diseases. Epigenetic plasticity and oxidative stress are interrelated in the pathophysiology of insulin resistance (IR) and cardiometabolic disease conditions. This review aims to ascertain the previous research evidence pertaining to the role of the epigenome and the variations of histone and non-histone proteins during cardiometabolic disease conditions and insulin signaling to develop effective disease-based epigenetic biomarkers and epigenetics-based chromatic therapy. Several public databases, including PubMed, National Library of Medicine, Medline, and google scholar, were searched for the peer-reviewed and published reports. This study delineates the consistent body of evidence regarding the epigenetic alterations of DNA/histone complexes pertinent to oxidative stress, insulin signaling, metabolic cardiomyopathy, and endothelial dysfunction in patients with cardiometabolic diseases. It has been described that both DNA methylation and post-translational histone alterations across visceral and subcutaneous adipose tissue could facilitate gene transcription to modulate inflammation, lipogenesis, and adipogenesis as the complex network of chromatin-modifying enzymatic proteins involved in the defensive insulin signaling across vasculature in patients with cardiometabolic diseases. Resveratrol, vorinostat, trichostatin, and apabetalone are reported to have significant implications as epigenetic modulators. Based on the epigenetic alterations, a wide range of protein/gene markers, such as interleukin-4 (IL-4) and interferon-γ (IFNγ) genes, may be considered as biomarkers in these patients due to their ability to the polarization of immune cells involved in tissue inflammation and atherosclerosis. Hence, it is crucial to unravel the cell-specific epigenetic information to develop individual risk assessment strategies for chromatin-modifying therapies in patients with cardiometabolic diseases.

For several years, blood pressure control and blocking of the renin-angiotensin system (RAS) represented the cornerstones of chronic kidney disease (CKD) treatment. Cardiovascular outcome trials with sodium-glucose co-transporter-2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus (DM) suggested that these agents can effectively delay the progression of CKD in these individuals. A major nephroprotective effect of canagliflozin was also shown in a renal outcome trial in patients with proteinuric diabetic CKD. The Study-to- Evaluate-the-Effect- of-Dapagliflozin-on-Renal-Outcomes-and-Cardiovascular- Mortality-in-Patients-With-Chronic-Kidney-Disease (DAPA-CKD) is a recent milestone in the field, as it included patients with both diabetic and non-diabetic proteinuric CKD and showed impressive reduction in the primary renal outcome of CKD progression, as well as the risk of hospitalization for heart failure and all-cause mortality on top of standard- of-care treatment. These benefits were consistent for patients with diabetic and non-diabetic CKD, including patients with ischemic or hypertensive nephropathy and glomerulonephritides (IgA nephropathy, focal segmental glomerulosclerosis and membranous nephropathy). Based on the above, relevant guidelines should accommodate their recommendations to implement treatment with SGLT-2 inhibitors for CKD patients.

More than 10 million people worldwide have Alzheimer's disease (AD), a degenerative neurological illness and the most prevalent form of dementia. AD's progression in memory loss, cognitive deterioration, and behavioral changes are all symptoms. Amyloid-beta 42 (Aβ42), the hyperphosphorylated forms of microtubule-associated tau protein, and other cellular and systemic alterations are all factors that contribute to cognitive decline in AD. Rather than delivering a possible cure, present therapy strategies focus on reducing disease symptoms. It has long been suggested that various naturally occurring small molecules (plant extract products and microbiological isolates, for example) could be beneficial in preventing or treating disease. Small compounds, such as flavonoids, have attracted much interest recently due to their potential to alleviate cellular stress. Flavonoids have been proven helpful in various ways, including antioxidants, anti-inflammatory agents, and anti-apoptotic agents, but their mechanism remains unknown. The flavonoid therapy of Alzheimer's disease focuses on this review, which includes a comprehensive literature analysis.

Background: Matrix metalloproteinases (MMPs), also known as metalloproteinases, are enzymes that degrade proteins and require the presence of active metal atoms. There are more than 20 types of MMPs, and they promote cell migration through the proteolytic degradation of the extracellular basement. MMPs are upregulated in cancers and inflamed regions. MMPs have three conservation regions: pro-MMP, catalysis, and hemopexin. Through these domains, MMPs cleave matrixes and cell-cell barriers. Consequently, MMPs cleave the whole extracellular matrix (ECM). In other words, they decompose most of the components related to the ECM, in their roles as key enzymes in cellular and pathophysiological events in the body. Introduction: Zn²⁺-containing endo-type peptidases directly degrade and remodel the ECM region in the progression of various diseases. MMPs are frequently found in abnormal disease status of inflammatory responses, periodontal lesion, inflammatory pulmonary lesion, arteriosclerotic smooth muscles, arthritis, and tumor metastasis and invasion. They are also known to participate in aging processes-such as wrinkle formation-by destroying collagen in the dermis. In particular, the onset of diseases via the MMP-dependent inflammatory response is caused by the breakdown of proteins in the ECM and the basement membranous region, which are the supporting structures of cells. Methods: This review describes the developments in the research examining the general and selective inhibitors for MMP associated with various human diseases over the past 20 years in terms of structure remodeling, substrate-recognizing specificities, and pharmacological applicability. Results: Among two similar types of MMPs, MMP-2 is known as gelatinase-A with a 72 kDa, while MMP-9 is termed gelatinase-B with a 92 kDa. Both of these play a key role in this action. Therefore, both enzymatic expression levels coincide during the onset and progression of diseases. Endogenous tissue inhibitors of matrix metalloproteinases (TIMPs) are highly specific for each MMP inhibitor type. The intrinsic factors regulate various MMP types by inhibiting the onset of various diseases mediated by MMP-dependent or independent inflammatory responses. The MMP- 9 and MMP-2 enzyme activity related to the prognosis of diseases associated with the inflammatory response are selectively inhibited by TIMP1 and TIMP2, respectively. The major pathogenesis of MMP-mediated diseases is related to the proliferation of inflammatory cells in various human tissues, which indicates their potential to diagnose or treat these diseases. The discovery of a substance that inhibits MMPs would be very important for preventing and treating various MMP-dependent diseases. Conclusion: Considerable research has examined MMP inhibitors, but most of these have been synthetic compounds. Research using natural products as MMP inhibitors has only recently become a subject of interest. This review intends to discuss recent research trends regarding the physiological properties, functions, and therapeutic agents related to MMPs.

Objective: To evaluate the effectiveness of the Partnership Care Model (PCM) on health-related quality of life (HRQoL) in adults with chronic diseases. Methods Data Sources/Study Setting: Existing literature dealing with the effect of HRQoL on chronic patients according to the HRQoL outcomes based on SF36 questionnaires. Study Design: Systematic review and meta-analysis. Data collection: Medline, PubMed, Scopus, Web of Science, Embase, Cochran database and Persian databases, including SID, Magiran, Iranmedex, and Irandoc, were searched according to the MeSH terms until May 15, 2022. Data analysis was made by using the random effects model and heterogeneity by I² index, and all analyses were made by STATA vers.16 (Stata Corp, College Station, Texas, USA). Principal findings: Three studies were included in the meta-analysis. Computing the common effect size, there was a significant intervention effect in all HRQoL dimensions, physical and mental subscales, as well as HRQoL total score. The results showed that there was significantly moderate to high substantial heterogeneity between studies except for vitality (I²=45.9%, P=0.157) and physical functioning (I²=30.9%, P=0.235) dimensions. Conclusion: According to the results of the study and realizing the efficiency of PCM on the eight dimensions of quality of life of chronic patients, it can be stated that this national model, which is in line with the culture and context of Iran, is effective, simple, efficient and reliable. It can be used in the promotion and improvement of various dimensions of HRQoL in chronic diseases.