Current Pharmaceutical Design - Volume 28, Issue 3, 2022

Background: Post-surgical adhesion is a common complication after abdominal or pelvic surgeries. Despite improvements in surgical techniques or the application of physical barriers, few improvements have been achieved. It causes bowel obstruction, pelvic pain, and infertility in women and has an adverse effect on the quality of life. Renin-Angiotensin System (RAS) is traditionally considered a blood pressure regulator. However, recent studies have indicated that the RAS plays a vital role in other processes, including oxidative stress, fibrosis, proliferation, inflammation, and wound healing. Angiotensin II (Ang II) is the main upstream effector of the RAS that can bind to the AT1 receptor (ATIR). A growing body of evidence has revealed that targeting Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II type 1 Receptor Blockers (ARBs), and Direct Renin Inhibitors (DRIs) can prevent post-surgical adhesions. Here we provide an overview of the therapeutic effect of RAS antagonists for adhesion. Methods: PubMed, EMBASE, and the Cochrane library were reviewed to identify potential agents targeting the RAS system as a potential approach for post-surgical adhesion. Results: Available evidence suggests the involvement of the RAS signaling pathway in inflammation, proliferation, and fibrosis pathways as well as in post-surgical adhesions. Several FDA-approved drugs are used for targeting the RAS system, and some of them are being tested in different models to reduce fibrosis and improve adhesion after surgery, including telmisartan, valsartan, and enalapril. Conclusion: Identification of the pathological causes of post-surgical adhesion and the potential role of targeting the Renin-Angiotensin System may help to prevent this problem. Based on the pathological function of RAS signaling after surgeries, the administration of ARBs may be considered a novel and efficient approach to prevent postsurgical adhesions. Pre-clinical and clinical studies should be carried out to have better information on the clinical significance of this therapy against post-surgical adhesion formation.

Background: Curcumin possesses multiple bioactivities that have beneficial effects on diabetic foot ulcers. Herein, we aimed to conduct a preclinical systematic review of 9 studies, including a total of 262 animals, to assess the possible mechanisms of curcumin for wound healing in diabetic animals. Methods: Five databases were searched from inception to May 12, 2020; Rev-Man 5.3 software was applied for data analyses. Cochrane Collaboration’s tool 10-item checklist was used to evaluate the methodological quality, and data revealed scores of risk of bias ranging from 2 to 5. Results: Meta-analysis indicated that curcumin had significant effects on wound healing rate and blood vessel density when compared with control (P < 0.05). The wound regeneration properties of curcumin for diabetic wounds are thought to mainly work through the possible mechanisms of antioxidation, enhanced cell proliferation, increased collagen formation, and angiogenesis. However, the anti-inflammatory effect on wounds in diabetic animals remain controversial. Conclusion: The findings indicate that more randomized controlled trials should be pursued to obtain more reliable results regarding inflammatory response. Overall, curcumin might be a probable candidate for diabetic foot ulcers and may contribute to future clinical trials.

Background: Spirooxindoles are privileged scaffolds in medicinal chemistry, which were identified through Wang’s pioneering work as inhibitors of MDM2-p53 interactions. Objective: To design and synthesize 2,6-diarylidenecyclohexanones and dispiro[oxindole-cyclohexanone]- pyrrolidines having potential antitumor effect. Methods: Dispiro[oxindole-cyclohexanone]-pyrrolidines 6a-h were synthesized in a regioselective manner via 1,3-dipolar cycloaddition reaction of 2,6-diarylidenecyclohexanones 3a-h, isatin, and sarcocine. Compounds 6a-h were alkylated to give (7-10)a,b. All compounds were evaluated in vitro for their antitumor activity and cytotoxic selectivity against breast cancer cell lines (MCF-7 and MDA-MB-231), breast fibrosis cell line (MCF10a), and placental cancer cell line (JEG-3). Molecular modeling inside the MDM2 binding site was performed using AutoDock4.2. Results: Synthesized compounds showed antitumor activity comparable to tamoxifen and compounds 3a,b,f,g and 9a,b showed selective cytotoxicity against tumor cells but reduced toxicity toward MCF-10a cells. Molecular modelling shows that both classes of synthesized compounds are predicted to fit the deep hydrophobic cleft on the surface of MDM2 and mimic the interactions between p53 and MDM2. Conclusion: The synthesized compounds have antitumor activity against MCF-7, MDA-MB-231, and JEG-3. Few compounds showed a selective cytotoxic effect and may have the potential to inhibit MDM2 and stimulate p53. In the future, studies regarding the optimization of medicinal chemistry as well as mechanistic studies will be conducted to enhance the inhibition effect of identified compounds and elucidate their mechanism of action.

Since the inception of nanotechnology, several efforts have been dedicated to fabricating diverse nanodevices with exceptional performance. These innovative constructs have been applied in medicine due to their tailorable physicochemical properties (chemical composition, optical activity, spectra, and charge) and morphological attributes (size, shape, and surface area). Moreover, these versatile nanomedicines could promisingly offer better performance over the conventional therapeutic strategies. Broadly speaking, in terms of chemical composition, nanobiomaterials are classified into two predominant categories of organic and inorganic- based components. Despite their success and enormous versatile advancements in the past two decades, the significant progress towards clinical translation has been hampered by their corresponding intrinsic limitations. In this perspective, we give a brief overview of these organic- and inorganic-based materials, highlighting opportunities and challenges towards their utilization in medicine. Finally, we provide an interesting outlook on the lessons learned and look forward to further developing these materials, emphasizing their potential in clinical translation.

Background: Anlotinib is a new tyrosine kinase inhibitor developed in China that targets the receptors for vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, and stem cell factor. Therefore, anlotinib inhibits tumor angiogenesis, representing a new therapeutic alternative for lung cancer. Hypertension is one of its most common adverse effects, leading to discontinuation of the drug and limited clinical usefulness. Objective: The present review aims to summarize the evidence on the prevalence, physiopathology, and management of anlotinib-induced hypertension, as well as its effect on the cancer prognosis. Methods: Searches in Medline, Cochrane Central Library, and Embase were performed using the following terms: anlotinib, adverse effect, hypertension, clinical trial, vascular endothelial growth factor, and anti-angiogenic drugs. Citations were also identified by checking the reference sections of selected papers. Results: Except for a phase I clinical trial with a small sample size (n = 6), almost all the clinical trials on anlotinib have reported the development of anlotinib-induced hypertension. In these trials, the incidence of hypertension ranged from 13% to 67.7%, and that of grade 3/4 hypertension ranged from 4.8% to 16%. Alterations in nitric oxide, endothelin-1, microvascular rarefaction, selective vasoconstrictions, and renal injury have been cited as potential mechanisms leading to anlotinib-induced hypertension. When needed, treatment may include general hygienic measures and pharmacotherapy in some cases. Conclusion: To effectively manage anlotinib-induced hypertension, early prevention, a reasonable dosage regimen, and appropriate treatment are critical to effectively manage anlotinib-induced hypertension. Additionally, anlotinib-induced hypertension may be considered a marker for predicting efficacy.

Melasma is a hypermelanotic skin disorder characterized by dark brown macules of symmetrical sizes and shapes that develop over time. Apart from the multiple etiological factors for melasma, such as hormonal imbalances, thyroid dysfunction, drugs, and contraceptive pills, a new and significant cause has been discovered: the effect of oxidative stress. Oxidative stress is the result of disequilibrium between reactive oxygen species and antioxidants in the cells. It is a key element that can cause skin hypopigmentation or hyperpigmentation. The physiological significance of reactive oxygen species and its function in skin health are addressed in this study. The development process and pathophysiology of reactive oxygen species with melasma disorder are also highlighted and the advantages of integrating antioxidants in clinical and experimental environments are discussed.

Background: Traditionally, various plant extracts having interesting biological properties were the main source of new drugs. In the last 30 years, the role of chemistry in combination with new technologies, like various computational techniques in chemistry, has witnessed a major upsurge in drug discovery and targeted drug delivery. Objective: This article provides a succinct overview of recent techniques of chemistry that have a great impact on the drug development process in general and also against HIV/AIDS. It focuses on new methods employed for drug development with an emphasis on in silico studies, including identifying drug targets, especially the proteins associated with specific diseases. Methods: The rational drug development process starts with the identification of a drug target as the first phase, which helps in the computer-assisted design of new drug molecules. Synthetic chemistry has a major impact on the drug development process because it provides new molecules for future study. Natural products based semisynthesis or microwave assisted synthesis is also involved in developing newly designed drug molecules. Further, the role of analytical chemistry involves extraction, fractionation, isolation and characterization of newly synthesized molecules. Results: Chemistry plays a key role in drug discovery and delivery by natural process or with the help of synthetic nanoparticles or nanomedicines. So, nanochemistry is also deeply involved in the development of new drugs and their applications. Conclusion: The previous era of drug discovery was dominated only by chemistry, but the modern approaches involve a comprehensive knowledge of synthetic chemistry, medicinal chemistry, computational chemistry and the concerned biological phenomenon.

Antimicrobial peptides (AMPs), also known as host defense peptides, are ubiquitous naturally occurring molecules secreted by various cell types of the body. In the skin, AMPs serve as a first-line innate immune defense against exogenous microorganisms, and they orchestrate adaptive immune responses to exert several immunomodulatory functions. Emerging evidence indicates that AMPs not only contribute to certain inflammatory skin diseases but also play a role in skin tumor carcinogenesis. Available data support the hypothesis that AMPs possess both pro-tumor and anti-neoplastic properties. Although inconsistent observations reported by multiple studies make it challenging to summarize the precise roles of AMPs in cancer, the differential expression of AMPs in skin cancers, such as the increased expression of human beta-defensins in squamous cell carcinoma and the ability of cathelicidin LL-37 to induce malignant melanoma cell invasion, implies they have procancer activities. On the other hand, the observation that certain AMPs show cytotoxic activity against cancer cells of the colon and kidney suggests their inherent antitumor properties. In this review, we describe the roles and mechanisms of AMPs in skin cancer development. We believe that further research is needed to elucidate the impact of these AMPs in skin cancer biology and to explore their potential roles as diagnostic/prognostic biomarkers and as novel therapeutic targets.