Mini Reviews in Medicinal Chemistry - Volume 22, Issue 20, 2022

Oral administration is a commonly used, safe, and patient-compliant method of drug delivery. However, due to the multiple absorption barriers in the gastrointestinal tract (GIT), the oral bioavailability of many drugs is low, resulting in a limited range of applications for oral drug delivery. Nanodrug delivery systems have unique advantages in overcoming the multiple barriers to oral absorption and improving the oral bioavailability of encapsulated drugs. Metal-organic frameworks (MOFs) are composed of metal ions and organic linkers assembled by coordination chemistry. Unlike other nanomaterials, nanoscale metal-organic frameworks (nano-MOFs, NMOFs) are increasingly popular for drug delivery systems (DDSs) due to their tunable pore size and easily modified surfaces. This paper summarizes the literature on MOFs in pharmaceutics included in SCI for the past ten years. Then, the GIT structure and oral drug delivery systems are reviewed, and the advantages, challenges, and solution strategies possessed by oral drug delivery systems are discussed. Importantly, two major classes of MOFs suitable for oral drug delivery systems are summarized, and various representative MOFs as oral drug carriers are evaluated in the context of oral drug delivery systems. Finally, the challenges faced by DDSs in the development of MOFs, such as biostability, biosafety, and toxicity, are examined.

Background: Pancreatic cancer is a fatal malignant neoplasm with infrequent signs and symptoms until a progressive stage. In 2020, GLOBOCAN reported that pancreatic cancer accounts for 4.7% of all cancer deaths. Despite the availability of standard chemotherapy regimens for treatment, the survival benefits are not guaranteed because tumor cells become chemoresistant even due to the development of chemoresistance in tumor cells even with a short treatment course, where apoptosis and autophagy play critical roles. Objective: This review compiled essential information on the regulatory mechanisms and roles of apoptosis and autophagy in pancreatic cancer, as well as drug-like molecules that target different pathways in pancreatic cancer eradication, with an aim to provide ideas to the scientific communities in discovering novel and specific drugs to treat pancreatic cancer, specifically PDAC. Method: Electronic databases that were searched for research articles for this review were Scopus, Science Direct, PubMed, Springer Link, and Google Scholar. The published studies were identified and retrieved using selected keywords. Discussion/Conclusion: Many small-molecule anticancer agents have been developed to regulate autophagy and apoptosis associated with pancreatic cancer treatment, where most of them target apoptosis directly through EGFR/Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. The cancer drugs that regulate autophagy in treating cancer can be categorized into three groups: i) direct autophagy inducers (e.g., rapamycin), ii) indirect autophagy inducers (e.g., resveratrol), and iii) autophagy inhibitors. Resveratrol persuades both apoptosis and autophagy with a cytoprotective effect, while autophagy inhibitors (e.g., 3-methyladenine, chloroquine) can turn off the protective autophagic effect for therapeutic benefits. Several studies showed that autophagy inhibition resulted in a synergistic effect with chemotherapy (e.g., a combination of metformin with gemcitabine/ 5FU). Such drugs possess a unique clinical value in treating pancreatic cancer as well as other autophagy-dependent carcinomas.

Humans have used algae for hundreds of years to make various products viz. agar, fertilizer, food, and pigments. Algae are also used in bioremediation to clean up polluted water and as essential laboratory tools in genomics, proteomics, and other research applications such as environmental warnings. Several special features of algae, including the oxygenic photosynthesis, higher yield in biomass, growth on the non-arable lands, their survival in a wide range of water supplies (contaminated or filtered waters), the production of necessary byproducts and biofuels, the enhancement of soil productivity, and the greenhouse gas emissions, etc. altogether rendered them as vital bio-resources in the sustainable development. Algae and bacteria have been assumed to coexist from the early stages of the development of the earth, and a wide variety of interactions were observed between them which have influenced the ecosystems ranging from the oceans to the lichens. Research has shown that bacteria and algae interact synergistically, especially roseobacter- algae interactions being the most common. These interactions are common to all ecosystems and characterize their primary efficiency. The commercialization of algae for industrial purposes, an important field, is also influenced by this interaction which frequently results in bacterial infections among the consumers. However, the recent findings have revealed that the bacteria improve algal growth and support flocculation which are very crucial in algal biotechnology. Some of the most exciting advancements in the area of algal biotic interactions and potential difficulties were reviewed in this article. Information gleaned in this study would provide a firm foundation for launching more contemporaneous research efforts in understanding and utilizing the algal species in biotechnology industries and medical sectors.

Hypothetical proteins (HPs) are non-predicted sequences that are identified only by open reading frames in sequenced genomes, but their protein products remain uncharacterized by any experimental means. The genome of every species consists of HPs that are involved in various cellular processes and signaling pathways. Annotation of HPs is important as they play a key role in disease mechanisms, drug designing, vaccine production, antibiotic production, and host adaptation. In the case of bacteria, 25-50% of the genome comprises HPs, which are involved in metabolic pathways and pathogenesis. The characterization of bacterial HPs helps to identify virulent proteins that are involved in pathogenesis. This can be done using in-silico studies, which provide sequence analogs, physiochemical properties, cellular or subcellular localization, structure and function validation, and protein-protein interactions. The most diverse types of virulent proteins are exotoxins, endotoxins, and adherent virulent factors that are encoded by virulent genes present on the chromosomal DNA of the bacteria. This review evaluates virulent HPs of pathogenic bacteria, such as Staphylococcus aureus, Chlamydia trachomatis, Fusobacterium nucleatum, and Yersinia pestis. The potential of these HPs as a drug target in bacteria-caused infectious diseases, along with the mode of action and treatment approaches, has been discussed.

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors, highly important in regulating substantial physiologic processes in the brain and the nervous system, and disturbance in their function could contribute to different pathologies. Overstimulation and hyperactivity of NMDARs, termed glutamate toxicity, could promote cell death and apoptosis. Meanwhile, their blockade could lead to dysfunction of the brain and nervous system. A growing body of evidence has demonstrated the prominent role of NMDARs in demyelinating disorders and anti- NMDAR encephalitis. Herein, we provide an overview of NMDARs’ dysfunction in the physiopathology of demyelinating disorders such as multiple sclerosis and neuromyelitis optica spectrum disorders.

About 10-100 billion cells are generated in the human body in a day, and accordingly, 10- 100 billion cells predominantly die for maintaining homeostasis. Dead cells generated by apoptosis are also rapidly engulfed by macrophages (Mθs) to be degraded. In case of the inefficient engulfment of apoptotic cells (ACs) via Mθs, they experience secondary necrosis and thus release intracellular materials, which display damage-associated molecular patterns (DAMPs) and result in diseases. Over the last decades, researchers have also reflected on the significant contribution of microRNAs (miRNAs) to autoimmune diseases through the regulation of Mθs functions. Moreover, miRNAs have shown intricate involvement with completely adjusting basic Mθs functions, such as phagocytosis, inflammation, efferocytosis, tumor promotion, and tissue repair. In this review, the mechanism of efferocytosis containing "Find-Me", "Eat-Me", and "Digest-Me" signals is summarized and the biogenesis of miRNAs is briefly described. Finally, the role of miRNAs in efferocytosis is discussed. It is concluded that miRNAs represent promising treatments and diagnostic targets in impaired phagocytic clearance, which leads to different diseases.

Background: Leishmaniasis and trypanosomiasis are diseases that affect public health worldwide due to their high incidence, morbidity, and mortality. Available treatments are costly, prolonged, and toxic, not to mention the problem of parasite resistance. The development of alternative treatments is justified and polyphenols show promising activity. Objective: The main aim of this mini-review was to analyze the most promising phenolic compounds with reported antileishmanial and antitrypanosomal activity as well as their mechanisms of action. Results: We found that the mode of action of these natural compounds, mainly lignans, neolignans, and flavonoids depends on the organism they act on and includes macrophage activation, induction of morphological changes such as chromatin condensation, DNA fragmentation, accumulation of acidocalcisomes, and glycosomes, Golgi damage and mitochondrial dysfunction as well as negative regulation of mitochondrial enzymes and other essential enzymes for parasite survival such as arginase. This gives a wide scope for future research toward the rational development of anti-kinetoplastid drugs. Conclusion: Although the specific molecular targets, bioavailability, route of administration, and dosages of some of these natural compounds need to be determined, polyphenols and their combinations represent a very promising and safe strategy to be considered for use against Leishmania spp and Trypanosoma spp. In addition, these compounds may provide a scaffold for developing new, more potent, and more selective antiprotozoal agents.