Current Pharmaceutical Design - Volume 28, Issue 17, 2022

A peptic ulcer is a lesion located in the esophagus, stomach, and upper intestine, caused by an imbalance between acid secretion and the release of protective mucus. This pathology is prevalent in approximately 14% of the world population and is commonly treated with proton pump inhibitors and type 2 histaminergic receptor antagonists, however, these drugs present concerning side effects that may lead to gastric cancer. In this sense, this research aimed to present the main heterocyclics studied in recent years. The screening method for the choice of articles was based on the selection of publications between 2000 and 2021 present in the Science Direct, Web of Science, Capes, and Scielo databases, by using the descriptors ''new derivatives'', “heterocyclics” “antiulcerogenic”, “gastroprotective” and “antisecretor”. This research showed that the most used rings in the development of anti-ulcer drugs were benzimidazole, quinazoline, thiazole, and thiadiazole. The results also portray several types of modern in silico, in vitro and in vivo assays, as well as the investigation of different mechanisms of action, with emphasis on proton pump inhibition, type 2 histaminergic receptor blockers, potassium competitive acid blockers, type E prostaglandin agonism, anti-secretory activity and anti-oxidant action. Additionally, the review evidenced the presence of the nitrogen atom in the heterocyclic ring as a determinant of the potential of the compound. This research suggests new alternatives for the treatment of gastric lesions, which may be more potent and cause fewer side effects than the currently used, and tend to evolve into more advanced studies in the coming years.

The poor solubility, lack of targetability, quick renal clearance, and degradability of many therapeutic and imaging agents strongly limit their applications inside the human body. Amphiphilic copolymers having self-assembling properties can form core-shell structures called micelles, a promising nanocarrier for hydrophobic drugs, plasmid DNA, oligonucleotides, small interfering RNAs (siRNAs), and imaging agents. Fabrication of micelles loaded with different pharmaceutical agents provides numerous advantages, including therapeutic efficacy, diagnostic sensitivity, and controlled release to the desired tissues. Moreover, their smaller particle size (10-100 nm) and modified surfaces with different functional groups (such as ligands) help them to accumulate easily in the target location, enhancing cellular uptake and reducing unwanted side effects. Furthermore, the release of the encapsulated agents may also be triggered from stimuli-sensitive micelles under different physiological conditions or by an external stimulus. In this review article, we discuss the recent advancements in formulating and targeting of different natural and synthetic micelles, including block copolymer micelles, cationic micelles, and dendrimers-, polysaccharide- and protein-based micelles for the delivery of different therapeutic and diagnostic agents. Finally, their applications, outcomes, and future perspectives have been summarized.

Acid-sensitive ion channels (ASICs) are cationic channels activated by extracellular protons and widely distributed in the nervous system of mammals. It belongs to the ENaC/DEG family and has four coding genes: ASIC1, ASIC2, ASIC3, and ASIC4, which encode eight subunit proteins: ASIC1a, ASIC1b, ASIC1b2, ASIC2a, ASIC2b, ASIC3, ASIC4, and ASIC5. Different subtypes of ASICs have different distributions in the central nervous system, and they play an important role in various physiological and pathological processes of the central nervous system, including synaptic plasticity, anxiety disorders, fear conditioning, depressionrelated behavior, epilepsy, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, malignant Glioma, pain, and others. This paper reviewed the recent studies of ASICs on the central nervous system to improve the understanding of ASICs’ physiological functions and pathological effects. This article also references studying the molecular mechanisms and therapeutic measures of nervous system-related diseases.

Integrins are a class of cell surface adhesion molecules composed of α subunit (ITGA) and β subunit (ITGB). They belong to heterodimer transmembrane glycoproteins. Their main function in organisms is as the receptor of cell adhesion molecules (CAMs) and extracellular matrix (ECM). According to the current research integration analysis, integrin α9 (ITGA9) is one of the integrin subunits, and there are few studies on ITGA9 among integrins. ITGA9 can improve cell migration and regulate various cellular biological functions, such as tumor cell proliferation, adhesion, invasion, and angiogenesis. However, its abnormal expression mechanism in cancer and its specific role in tumor growth and metastasis are still unknown to a great extent. This review reveals the role of ITGA9 in the complex pathogenesis of many tumors and cancers, providing a new direction for the treatment of tumors and cancers. Relevant studies were retrieved and collected through the PubMed system. After determining ITGA9 as the research object, we found a close relationship between ITGA9 and tumorigenesis by analyzing the research articles on ITGA9 in the PubMed system in the last 15 years and further determined the references mainly based on the influencing factors of the articles. Thus, the role of ITGA9 in tumor and cancer genesis, proliferation, and metastasis was reviewed and analyzed. ITGA9 is an integrin subunit, which has been proved to be abnormally expressed in many tumors. After sorting and analyzing the research data, it was found that the abnormal expression of ITGA9 in a variety of tumors, including glioblastoma, rhabdomyosarcoma, melanoma, hepatocellular carcinoma, nasopharyngeal carcinoma, multiple myeloma, non-small cell lung cancer, and prostate cancer, was closely related to the proliferation, metastasis, adhesion, and angiogenesis of tumor cells. These results suggest that ITGA9 plays an important role in the occurrence and development of tumors. The integrin subunit ITGA9 may serve as a biomarker for the diagnosis of tumors and a potential therapeutic target for anti-tumor therapies.

Nowadays, there is an urgent need to discover and develop long-term and effective antimicrobial and biofilm-inhibiting compounds. Employing combination therapies using novel drug delivery systems and also natural antimicrobial substances is a promising strategy in this field. Nanoparticles (NPs)-based materials have become well appreciated in recent times due to their function as antimicrobial agents or carriers for promoting the bioavailability and effectiveness of antibiotics. Flavonoids belong to the promising groups of bioactive compounds abundantly found in fruits, vegetables, spices, and medicinal plants with strong antimicrobial features. Flavonoids and NPs have the potential to work as alternatives to the conventional antimicrobial agents, when used alone as well as in combination. Different classes of flavonoid NPs may be particularly advantageous in treating microbial infections. The most important antimicrobial mechanisms of flavonoid NPs include oxidative stress induction, non-oxidative mechanisms, and metal ion release. However, the efficacy of flavonoid NPs against pathogens and drug-resistant pathogens changes according to their physicochemical characteristics as well as the particular structure of microbial cell wall and enzymatic composition. In this review, we provide an outlook on the antimicrobial mechanism of flavonoid-based NPs and the crucial factors involved in it.

Background: Impaired wound healing is one of the most noteworthy features and troublesome complications of diabetes mellitus, which arouses a rising global health concern without potent remedies. Thrombin is the major hemostatic agent applied at wound healing initiation and recently gained therapeutic credits in later phases. However, a rare investigation achieved prolonged use of thrombin and probed the detailed mechanism. Objective: The objective of this study is to investigate the effects and mechanism of thrombin on diabetic skin wound healing. Methods: The effect of thrombin on fibroblast proliferation, α-SMA, and Collagen I expression was firstly studied in vitro by Cell Counting Kit 8 (CCK8) and western blotting. Then, the specific phosphorylation site of SMAD2/3 and their ERK1/2 dependence during thrombin treatment were assessed by western blotting for mechanism exploration. After that, full-thickness wound defects were established in diabetic male SD rats and treated with thrombin in the presence or absence of PD98059 to observe the in vivo effects of thrombin and to confirm its ERK dependence. Results: We found that thrombin promoted fibroblast proliferation and their α-SMA and Collagen I production. Mechanistically, thrombin induced phosphorylation of Smad2 linker region (Ser245/250/255) through ERK1/2 phosphorylation but promoted phosphorylation of Smad3 linker region (Ser204) independent of ERK1/2. Histological results showed that thrombin facilitated wound healing by promoting α-SMA and Collagen I expression, which was not abolished by inhibiting ERK phosphorylation. Conclusion: Collectively, this study validated the therapeutic efficacy of thrombin on diabetic wound healing and identified both ERK-dependent and -independent Smad2/3 linker region phosphorylation as the essential signaling events in this process.