Current Enzyme Inhibition - Volume 19, Issue 2, 2023

Background: Cancer is the abnormal growth of cells in the body due to an imbalance in the normal apoptotic pathways. The abnormality in the cancer cells makes them malignant. Various types of treatment, including chemotherapy, radiation therapy, targeted therapy, and immunotherapy (IMT), are used for cancer. Mesenchymal-epithelial transition factor (c-Met) belongs to the tyrosine kinase receptor family and is overexpressed in various types of cancers. c-Met is a proto-oncogene and facilitates a wide range of biological functions, including cell proliferation, growth, migration, invasion, and angiogenesis, through interaction with its sole ligand hepatocyte growth factor (HGF). Currently, various c-mesenchymal-epithelial transition (c-MET) inhibitors and antibodies are in human trials for their anti-cancer activity. Introduction: The c-MET is a kinase receptor for hepatocyte growth factor (HGF). It is wellrecognized for its tumorigenic potential. HGF binding with c-Met leads to c-Met dimerization and c- Met phosphorylation, which in turn activates many intracellular signalling pathways, including ERK1/2, MAPK, STAT3, Rac1, and PI3K/AKT. These pathways regulate the proliferation, invasion, and migration of cancer cells. Upon binding of HGF to c-MET, a series of phosphorylation reactions get started, which leads to transcription and translation of various proteins, followed by abnormal growth of cancerous tissues due to dysregulation of the cell cycle. The HGF/c-MET signalling pathways have shown their potential in the development of many cancers, including gastric cancer (GC). Several clinical trials have evaluated the therapeutic benefits of MET-targeted therapies involving various agents, such as anti-MET antibodies, anti-HGF antibodies, and tyrosine kinase inhibitors (TKIs). Various c-MET inhibitors are in clinical trials. The current review is focussed on the critical role of the HGF/c-MET pathways in the progression of various cancers, including GC. In addition, this review will also focus on the combination potential of c-MET inhibitors with immuno-oncology drugs, such as programmed cell death protein 1 (PD-1) inhibitors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, tumor necrosis factor (TNF) receptor (OX-40) agonists, etc. Materials and Methods: The method adopted for the study was primarily based on the secondary search through a systematic review of the literature. Results: A study of recent literature and various preclinical and human trials suggests the effectiveness of c-MET inhibitors (alone or in combination) in different cancer types, including GC. In this paper, the results have been elaborated as to how many papers/manuscripts/publications on the topic are present, how many drugs are in Phase I/II/ III/RCT, etc., and that how many papers report on the clinical outcomes of which agent/drug (mentioned in percentage). Conclusion: The use of c-MET inhibitors and antibodies has emerged as a latent therapeutic approach for the treatment of various types of cancer. The c-MET inhibitors can also be used in combination with various immunotherapeutic drugs, like PD-1 inhibitors, OX-40 agonists, etc.

Introduction: Overexpression of tyrosinase in humans causes an increase in melanin production in the skin, which can result in hyperpigmentation consequences such as freckles, melasma, age spots, and melanoma. Free radicals also play a significant role in the increase of the biosynthesis of melanin. Tyrosinase inhibitors capable of inhibiting the biosynthesis of melanin are currently used in various hyperpigmentation and cosmetic agents to control the formation of freckles. Several synthetic tyrosinase inhibitors have been associated with several serious side effects. Also, synthetic antioxidants have many toxicological side effects, including carcinogenicity. There is an increasing interest in the search for natural tyrosinase inhibitors and antioxidant agents. Aims: The objective of this study is to evaluate total polyphenol and flavonoid contents as well as examine the antioxidative and tyrosinase inhibitory effects of A. sicula L. aqueous extract. Methods: Antioxidant activities were evaluated using superoxide radical scavenging and reducing power methods. Moreover, a tyrosinase inhibitory assay was used to determine anti-hyperpigmentation. Results: The results showed that this extract was rich in total polyphenols (58.01 ± 1.18 micrograms of gallic acid equivalents per milligrams of extract) and flavonoids (17.91 ± 1.81 micrograms quercetin equivalents per milligram of extract). A. sicula L. aqueous extract was capable of scavenging free radicals (IC50 = 11.87 ± 0.13 μg/mL) and acting as a strong reducing agent (A 0.5= 6.37 ± 0.42 μg/mL). A. sicula L. had a potent tyrosinase inhibitory potential (IC50= 12.63 ± 1.15 μg/mL), which was higher compared to kojic acid used as a standard (IC50= 25,23 ± 0,78 μg/mL, p <0.001). Conclusion: These results support that A. sicula L. could be a new source of antioxidant and cosmetic use. Further studies focusing on the isolation and characterization of active principles of antioxidant and tyrosinase inhibitory activities are needed.

Introduction: Oxidative stress plays a critical role in the pathological process of Alzheimer’s disease (AD). There is a growing interest in natural anti-oxidants and cholinesterase inhibitors from medicinal plants that may aid in the prevention of oxidative injury and treatment of AD. Considering this, Athamanta sicula L. is found to be an important medicinal plant. Aims: The aim of the current study was to investigate the total phenolic content, antioxidant, and anticholinesterase properties of aqueous (AqE) and methanolic extracts (MethE) from Athamanta sicula L. (A. sicula L.). Methods: The phenanthroline, ABTS free radical scavenging, and β-carotene bleaching methods were utilized to assess the antioxidant capacity. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory methods were used to determine the anti-cholinesterase effect. Results: These extracts were found to be rich in phenolic contents. They were capable of scavenging free radicals, inhibiting lipid peroxidation, and reducing agents. A. sicula L. had a remarkable cholinesterase inhibitory effect. Conclusion: These results support that A. sicula L. could be a new source of anti-oxidant and anticholinesterase natural drugs. Further studies on the isolation and characterization of active principles of anti-oxidant and tyrosinase inhibitory activities are needed.

Introduction: Oxidative stress plays a major role in developing diabetes complications; therefore, it is possible to use natural antioxidants as therapeutic agents for diabetes. Aims: This study aimed to find an important source of phenolics from Athamanta sicula L. (A. sicula) and confirm that this plant could be a significant source of medically important natural compounds by confirming its antioxidant, α-amylase and α-glucosidase inhibitory potential. Methods: Antioxidant property was performed using 2,2′-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, metal chelating, and cupric reducing antioxidant capacity methods. The α-amylase and α- glucosidase inhibitory activities were investigated using an in vitro model. Moreover, polyphenols and flavonoid contents of the tested extracts were carried out. Results: The methanolic extract exhibited the highest phenolic and flavonoid content compared to the aqueous extract. However, aqueous extract possessed the strongest antioxidant activity (DPPH scavenging, metal chelating, and Cupric ion reducing antioxidant capacities), α-amylase and α-glucosidase inhibitory effects. No correlation between phenolic content and antioxidant and enzyme inhibitory activities of A. sicula L. extracts was observed. Conclusion: The results showed that this plant could be a significant source of medically important natural compounds.

Background: Diabetes type II is one of the most serious metabolic diseases in the world attracting the attention of many researchers who predict that diabetes will be one of the top major causes of disability or death in the coming few decades. To tackle this disease several classes of synthetic molecules were developed to target certain enzymes that are involved in sugar metabolism. Herbal extracts targeting diabetes have witnessed renascence in the last few decades with the introduction of highly effective herbal remedies that effectively regulate sugar levels in the blood. Methods: In this work, we studied the interaction of molecules from the Zygophyllum sp. with the main enzymes involved in sugar metabolism (alpha-amylase and DPP-4) using Molecular Operating Environment (MOE) as a molecular docking technique. The choice of Zygophyllum sp. was based on an ethnopharmacological local survey. Results: The obtained results showed that myristic acid gave the best score equal to -7.5471 Kcal/mol for alpha-amylase and -9.0457 Kcal/mol for DPP-4. Palmitic acid also gave a good score equal to - 7.4528 Kcal/mol with DPP-4. Conclusion: The calculated scores of molecules from Zygophyllum sp. were better than those calculated with the known inhibitors. The results demonstrated that many molecules showed good affinity to two important enzymes involved in type II diabetes, suggesting that these molecules may possess potential hypoglycemic and antidiabetic effects. These results added further scientific evidence supporting the folk use of Zygophyllum sp. in targeting diabetes and suggested its potential as a valuable source of antidiabetic drug leads.

Background: Emerging data indicate that BCHE, a gene encoding the enzyme butyrylcholinesterase, is a negative prognostic marker in MYCN-amplified neuroblastoma. Levels of butyrylcholinesterase in children newly diagnosed with neuroblastoma are proportional to MYCN amplification and the response to therapy. To better understand the functions of butyrylcholinesterase in neuroblastoma, we examine interactions of this enzyme with several neuroblastoma-associated kinases and provide in depth review of known associations. Methods: BCHE-deleted cells (KO) were produced from MYCN-amplified BE(2)-C cells (WT) by the CRISPR-Cas9 targeted disruption of the BCHE locus. Activation levels of several oncoproteins and the expression of N-Myc in KO were compared to WT cells. N-Myc protein expression, multiplexed detection of relative protein expression and phosphorylation of 71 tyrosine kinases and 17 proteins in the MAPK pathway were assessed using Western immunoblotting and microarrays in exponentially growing untreated cells and in cells exposed to the genotoxic stress. Results: BCHE locus disruption and butyrylcholinesterase deficiency result in the loss of N-Myc protein and a significant deactivation of several kinases associated with the aggressive neuroblastoma phenotype as well as major changes in the phosphorylation of upstream and downstream partners of these kinases. Conclusion: Butyrylcholinesterase appears to contribute to the activation of several pathways in MYCN-amplified cells including FGF-R1, Ltk, TrkB, and Ros1. Deletion of BCHE and ensuing butyrylcholinesterase deficit deactivate these pathways suggesting the role of BChE as a novel druggable target in neuroblastoma therapy.

Background: Around ten novel pyrazoline and pyrazolidine derivatives were designed and synthesized by the condensation of piperine, hydrazine hydrate, phenylhydrazine, aromatic carboxylic acid, and ethanol. Methods: The synthesized compounds (2, 3, 4a-d, and 5a-d) were characterized by FTIR, 1HNMR, mass spectral, and elemental analysis. Pharmacokinetic, physicochemical, drug-likeness, and medicinal chemistry friendliness parameters were also predicted by in silico methods. Results: Furthermore, compounds were screened for in vitro anti-inflammatory activity by the HRBC membrane stabilization method using diclofenac sodium as the standard drug. The tested compounds showed moderate anti-inflammatory activity compared to the standard drug. The molecular docking studies of significantly active (4d) and least active compounds (5d) were also carried out in the active sites of an arachidonate-12-lipoxygenase target in order to study the putative binding pattern of the study compounds. Conclusion: According to the findings of this study, further lead identification as well as lead optimization techniques will be required in the near future in order to get potent analogues.

Background: Calamintha nepeta is a plant from the Lamiaceae family that is known for its traditional use to treat diabetes among Algerian populations. However, till now, there has been no research work to confirm this activity. Objectives: This work aimed to evaluate the amylase inhibitory activity of essential oils and phenolic compounds from both methanolic and aqueous extracts of Algerian Calamintha nepeta (L.). Methods: The essential oil was obtained by hydrodistillation and analyzed using GC and then GC/MS. Aqueous and methanolic extracts were obtained from the remains of the hydrodistillation. Total phenolic compounds were quantified using the Folin-Ciocalteu method. The amylase inhibitory activity of the extracts was determined by testing their ability to inhibit alpha-amylase. Results: The extraction yield was 0.67 % (w/w) for the essential oil, and 11.85 and 4.38 % (w/w) for the aqueous and methanolic extracts, respectively. The essential oil analysis revealed that menthone, menthol, pulegone, and pulegone oxide were the main components of the oil. The total phenolic compounds in the aqueous and methanolic extracts were 41.81 and 32.92 mg GAE/g DW, respectively. The extracts inhibited α-amylase activity with IC50 values of 24.46, 31.54, and 115.47 mg/ml for the methanolic extract, essential oil, and aqueous extract, respectively. Conclusion: The different extracts of Calamintha nepeta showed an interesting composition and significant amylase inhibitory activity, emphasizing their successful use in traditional medicine.

Background: Rhanterium adpressum is an endemic and desert plant found in Algerian Sahara, it is used by the local population in cheese production and folk medicine as an antidiuretic and antimicrobial. Objective: This study aimed to analyse the phytochemical composition of Rhanterium adpressum extracts by GC-MS and assess their inhibitory potential on α-amylase and α-glucosidase enzymes linked to diabetes. Methods: Two solvents were used for extraction: petroleum ether and dichloromethane. The obtained extracts were then analysed by GC-MS and in vitro tested for their antidiabetic activity. Results: GC-MS analysis of extracts from R. adpressum flowers revealed various phytocompounds, such as (-)-Spathulenol, alpha.-Amyrin, Lupeol and Cedran-diol in petroleum ether extract; 1HCycloprop[ e]azulen-7-ol, 5(1H)-Azulenone and alpha-cardinol in dichloromethane extract. Petroleum ether extract exhibited a good in vitro antidiabetic activity in comparison to dichloromethane extract. Conclusion: This research confirms the antidiabetic activity of petroleum ether extract when compared with dichloromethane extract; other studies are needed for purification and in vivo study of biocompounds from Rhanterium adpressum. This investigation offers scientific data that flowers of Rhanterium adpressum exhibit in vitro anti-diabetic effect.

Background: Clinical studies have already revealed the ubiquitous neuroprotective role of curcumin in neuronal deterioration, but it cannot be used alone due to its truncated bioavailability. Currently, many such approaches are functional, which overcome this issue either by increasing the solubility or absorption. These approaches carry a costlier treatment. One more tactic is present but less focused i.e., by limiting the intestine and liver enzymatic metabolism; by this approach, curcumin will be more available for its beneficial outcome. Objective: The goal of this study was to evaluate the impact of Lactobacillus rhamnosus and diclofenac on the neuroprotective effects of curcumin against scopolamine-induced dementia. Methods: Physical parameters involved a novel tank test, T maze test, whereas neurochemical parameters include brain oxidative stress and acetylcholinesterase (Ache) inhibition activity in a zebrafish dementia model. Results: Our results demonstrated that curcumin with Lactobacillus rhamnosus and diclofenac significantly (p<0.05) reduced anxiety, memory deficits, and brain oxidative stress compared to the alone curcumin- treated group. Conclusion: This result approves that curcumin with L.rhamnosus and diclofenac have superior activity compared to curcumin alone. However, further clinical studies are needed to validate these findings.