Current Medicinal Chemistry - Volume 28, Issue 14, 2021

A few decades ago, the incidence of colorectal cancer (CRC) was low and is now the fourth in the list of deadly cancers producing nearly a million deaths annually. A population that is aging along with risk factors such as smoking, obesity, sedentary lifestyle with little or no physical activity, and non-healthy food habits of developed countries can increase the risk of colorectal cancer. The balance in gut microbiota and the metabolites produced during bacterial fermentation within the host plays a significant role in regulating intestinal diseases as well as colorectal cancer development. Recent progress in the understanding of illness resulted in multiple treatment options such as surgery, radiation, and chemotherapy, including targeted therapy and multitherapies. The treatment plan for CRC depends on the location, stage and grade of cancer as well as genomic biomarker tests. Despite all the advancements made in the genetic and molecular aspects of the disease, the knowledge seems inadequate as the drug action as well as the wide variation in drug response did not appear strongly correlated with the individual molecular and genetic characteristics, which suggests the requirement of comprehensive molecular understanding of this complex heterogeneous disease. Furthermore, multitherapies or a broad spectrum approach, which is an amalgamation of the various promising as well as effective therapeutic strategies that can tackle heterogeneity and act on several targets of the disease, need to be validated in clinical studies. The latest treatment options have significantly increased the survival of up to three years in the case of advanced disease. The fact that colorectal cancer is developed from a polypoid precursor, as well as the symptoms of the disease that occur at an advanced stage, underlines how screening programs can help early detection and decrease mortality as well as morbidity from CRC.

Drugs have to overcome numerous barriers to reach their desired therapeutic targets. In several cases, drugs, especially the highly lipophilic molecules, suffer from low solubility and bioavailability and therefore their desired targeting is hampered. In addition, undesired metabolic products might be produced or off-targets could be recognized. Along these lines, nanopharmacology has provided new technological platforms, to overcome these boundaries. Specifically, numerous vehicle platforms such as cyclodextrins and calixarenes have been widely utilized to host lipophilic drugs such as antagonists of the angiotensin II AT1 receptor (AT1R), as well as quercetin and silibinin. The encapsulation of these drugs in supramolecules or other systems refines their solubility and metabolic stability, increases their selectivity and therefore decreases their effective dose and improves their therapeutic index. In this mini review we report on the formulations of silibinin and AT1R antagonist candesartan in a 2-HP-β-cyclodextrin host molecule, which displayed enhanced cytotoxicity and increased silibinin’s and candesartan’s stability, respectively. Moreover, we describe the encapsulation of quercetin in gold nanoparticles bearing a calixarene supramolecular host. Also, the encapsulation of temozolomide in a calixarene nanocapsule has been described. Finally, we report on the activity enhancement that has been achieved upon using these formulations as well as the analytical and computational methods we used to characterize these formulations and explore the molecular interactions between the host and quest molecules.

Wilson's disease is a congenital disorder of copper metabolism whose pathogenesis remains, at least in part, unknown. Subjects carrying the same genotype may show completely different phenotypes, differing for the age at illness onset or for the hepatic, neurologic or psychiatric clinical presentation. The inability to find a unequivocal correlation between the type of mutation in the ATPase copper transporting beta (ATP7B) gene and the phenotypic manifestation, has encouraged many authors to look for epigenetic factors interacting with the genetic changes. Here, the evidences regarding the ability of copper overload to change the global DNA methylation status are discussed.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes and one of the leading causes of end-stage renal disease. Tubular damage is an early change and characteristic of DN, and mitochondrial dysfunction plays an important role in the development of DN. Therefore, the timely removal of damaged mitochondria in tubular cells is an effective treatment strategy for DN. Mitophagy is a type of selective autophagy that ensures the timely elimination of damaged mitochondria to protect cells from oxidative stress. In this review, we summarize our understanding of mitochondrial dysfunction and dynamic disorders in tubular cells in DN and the molecular mechanism of mitophagy. Finally, the role of mitophagy in DN and its feasibility as a therapeutic target for DN are discussed.

Background: NMR spectroscopy is one of the most powerful tools to study the structure and interaction properties of peptides and proteins from a dynamic perspective. Knowing the bioactive conformations of peptides is crucial in the drug discovery field to design more efficient analogue ligands and inhibitors of protein-protein interactions targeting therapeutically relevant systems. Objective: This review provides a toolkit to investigate peptide conformational properties by NMR. Methods: Articles cited herein, related to NMR studies of peptides and proteins were mainly searched through PubMed and the web. More recent and old books on NMR spectroscopy written by eminent scientists in the field were consulted as well. Results: The review is mainly focused on NMR tools to gain the 3D structure of small unlabeled peptides. It is more application-oriented as it is beyond its goal to deliver a profound theoretical background. However, the basic principles of 2D homonuclear and heteronuclear experiments are briefly described. Protocols to obtain isotopically labeled peptides and principal triple resonance experiments needed to study them, are discussed as well. Conclusion: NMR is a leading technique in the study of conformational preferences of small flexible peptides whose structure can be often only described by an ensemble of conformations. Although NMR studies of peptides can be easily and fast performed by canonical protocols established a few decades ago, more recently we have assisted to tremendous improvements of NMR spectroscopy to investigate instead large systems and overcome its molecular weight limit.

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the gene that encodes a critical cell regulatory protein, huntingtin (Htt). The expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats causes improper folding of functional proteins and is an initial trigger of pathological changes in the brain. Recent research has indicated that the functional dysregulation of many transcription factors underlies the neurodegenerative processes that accompany HD. These disturbances are caused not only by the loss of wild-type Htt (WT Htt) function but also by the occurrence of abnormalities that result from the action of mutant Htt (mHtt). In this review, we aim to describe the role of transcription factors that are currently thought to be strongly associated with HD pathogenesis, namely, RE1-silencing transcription factor, also known as neuron-restrictive silencer factor (REST/NRSF), forkhead box proteins (FOXPs), peroxisome proliferator-activated receptor gamma coactivator-1a (PGC1α), heat shock transcription factor 1 (HSF1), and nuclear factor Κ light-chain-enhancer of activated B cells (NF- ΚB). We also take into account the role of these factors in the phenotype of HD as well as potential pharmacological interventions targeting the analyzed proteins. Furthermore, we considered whether molecular manipulation resulting in changes in transcription factor function may have clinical potency for treating HD.

Tanshinones are an important type of natural products isolated from Salvia miltiorrhiza Bunge with various bioactivities. Tanshinone IIa, cryptotanshinone and tanshinone I are three kinds of tanshinones which have been widely investigated. Particularly, sodium tanshinone IIa sulfonate is a water-soluble derivative of tanshinone IIa and it is used in clinical in China for treating cardiovascular diseases. In recent years, there are increasing interests in the investigation of tanshinones derivatives in various diseases. This article presents a review of the anti-atherosclerotic effects, cardioprotective effects, anticancer activities, antibacterial activities and antiviral activities of tanshinones and structural modification work in recent years.

Magnetic particles play an important role in current technology, and this field of technology extends to a broader progression. The term magnetic particles typically cover the paramagnetic particles and super-paramagnetic particles. Various materials like iron oxide are common, but other materials are available as well; a survey of such materials has been included in this work. They can serve for technological purposes like separation and isolation of chemical products or toxic waste, their use in the diagnosis of pathologies, drug delivery and other similar applications. In this review, biosensors, bioanalytical devices and bioassays, have been discussed. Materials for magnetic particles preparation, methods of assay, biosensors and bioassays working in stationary as well as flow-through arrangements are described here. A survey of actual literature has been provided as well.

Low circulating high-density lipoproteins (HDL) are not only defining criteria for metabolic syndrome, but are more generally associated with atherosclerotic cardiovascular disease (ASCVD) and other chronic diseases. Oxidative stress, a hallmark of cardio-metabolic disease, further influences HDL activity by suppressing their function. Especially the leukocyte- derived enzyme myeloperoxidase (MPO) has recently attracted great interest as it catalyzes the formation of oxidizing reactive species that modify the structure and function of HDL, ultimately increasing cardiovascular risk. Contrariwise, paraoxonase-1 (PON1) is an HDL-associated enzyme that protects HDL from lipid oxidation and then acts as a protective factor against ASCVD. It is noteworthy that recent studies have demonstrated how MPO, PON1 and HDL form a functional complex in which PON1 partially inhibits the MPO activity, while MPO in turn partially inactivates PON1.In line with that, a high MPO/PON1 ratio characterizes patients with ASCVD and metabolic syndrome and has been suggested as a potential marker of dysfunctional HDL as well as a predictor of ASCVD. In this review, we summarize the evidence on the interactions between MPO and PON1 with regard to their structure, function and interaction with HDL activity. We also provide an overview of in vitro and experimental animal models, finally focusing on clinical evidence from a cohort of patients with ASCVD and metabolic syndrome.