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Modulation of Matrix Metalloproteinases by Plant-derived Products

Anuar NNM, Zulkafali NIN, Ugusman A

Curr Cancer Drug Targets, 2021;21(2):91-106.
PMID: 33222671 DOI: 10.2174/1568009620666201120144838

Matrix metalloproteinases (MMPs) are a group of zinc-dependent metalloendopeptidases that are responsible for the degradation, repair, and remodeling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases, such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic, and food industries. This review summarises the current knowledge of plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signaling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviors, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.
Fulltext Exploring the Relationship of Perivascular Adipose Tissue Inflammation and the Development of Vascular Pathologies

Rami AZA, Hamid AA, Anuar NNM, Aminuddin A, Ugusman A

Mediators Inflamm, 2022;2022:2734321.
PMID: 35177953 DOI: 10.1155/2022/2734321

Initially thought to only provide mechanical support for the underlying blood vessels, perivascular adipose tissue (PVAT) has now emerged as a regulator of vascular function. A healthy PVAT exerts anticontractile and anti-inflammatory actions on the underlying vasculature via the release of adipocytokines such as adiponectin, nitric oxide, and omentin. However, dysfunctional PVAT produces more proinflammatory adipocytokines such as leptin, resistin, interleukin- (IL-) 6, IL-1β, and tumor necrosis factor-alpha, thus inducing an inflammatory response that contributes to the pathogenesis of vascular diseases. In this review, current knowledge on the role of PVAT inflammation in the development of vascular pathologies such as atherosclerosis and hypertension was discussed.
Effective Modalities of Periodontitis Induction in Rat Model

Khuda F, Baharin B, Anuar NNM, Satimin BSF, Nasruddin NS

J Vet Dent, 2024 Jan;41(1):49-57.
PMID: 37259505 DOI: 10.1177/08987564231178459

Induction of periodontal disease using the rat model is the preferred model for human periodontal disease studies that are related to gene expression, mechanisms of inflammatory regulation, microbial and host responses, resolution, and the healing process. There are 3 methods that are frequently used to induce periodontal disease, which are: ligature application, oral bacterial inoculation, and the lipopolysaccharide injection technique. In the ligature model, sterile non-absorbable sutures or orthodontic wires are widely used to induce local irritation and bacterial plaque accumulation. Secondly, mono and mixed cultures of periodontal bacteria are inoculated orally by gavage or topical application. Lastly, lipopolysaccharide extracted from pathogenic bacteria can be directly injected into the gingival sulcus to induce inflammation and stimulate osteoclastogenesis and alveolar bone loss. Among these methods, ligature application induces inflammation and alveolar bone resorption more promptly compared to other methods. This review will provide an overview of the main induction methods in experimental periodontal disease, with their advantages and disadvantages.
The Development of Organotin(IV) N-Ethyl-N-Benzyldithiocarbamate Complexes: A Study on Their Synthesis, Characterization, and Cytocidal Effects on A549 Cell Line

Abd Aziz NA, Awang N, Kamaludin NF, Anuar NNM, Hamid A, Chan KM, et al.

Anticancer Agents Med Chem, 2024;24(12):942-953.
PMID: 38629375 DOI: 10.2174/0118715206309421240402093335

BACKGROUND: Organotin(IV) complexes of dithiocarbamate are vital in medicinal chemistry, exhibiting potential in targeting cancer cells due to their unique properties that enhance targeted delivery. This study aimed to synthesize and characterize organotin(IV) N-ethyl-N-benzyldithiocarbamate complexes (ONBDCs) and evaluate their cytotoxicity against A549 cells, which are commonly used as a model for human lung cancer research.
METHODS: The two ONBDC derivatives - ONBDC 1 (dimethyltin(IV) N-ethyl-N-benzyldithiocarbamate) and ONBDC 2 (triphenyltin(IV) N-ethyl-N-benzyldithiocarbamate) - were synthesized via the reaction of tin(IV) chloride with N-ethylbenzylamine in the presence of carbon disulfide. A range of analytical techniques, including elemental analysis, IR spectroscopy, NMR spectroscopy, UV-Vis spectrometry, TGA/DTA analysis, and X-ray crystallography, was conducted to characterize these compounds comprehensively. The cytotoxic effects of ONBDCs against A549 cells were evaluated using MTT assay.
RESULTS: Both compounds were synthesized and characterized successfully via elemental and spectroscopies analysis. MTT assay revealed that ONBDC 2 demonstrated remarkable cytotoxicity towards A549 cells, with an IC50 value of 0.52 μM. Additionally, ONBDC 2 displayed significantly higher cytotoxic activity against the A549 cell line when compared to the commercially available chemotherapeutic agent cisplatin (IC50: 32 μM).
CONCLUSION: Thus, it was shown that ONBDC 2 could have important anticancer properties and should be further explored as a top contender for creating improved and specialized cancer treatments.
Fulltext The Role of Anthocyanin in Modulating Diabetic Cardiovascular Disease and Its Potential to Be Developed as a Nutraceutical

Sapian S, Taib IS, Katas H, Latip J, Zainalabidin S, Hamid ZA, et al.

Pharmaceuticals (Basel), 2022 Oct 30;15(11).
PMID: 36355516 DOI: 10.3390/ph15111344

Cardiovascular disease (CVD) is directly linked to diabetes mellitus (DM), and its morbidity and mortality are rising at an alarming rate. Individuals with DM experience significantly worse clinical outcomes due to heart failure as a CVD consequence than non-diabetic patients. Hyperglycemia is the main culprit that triggers the activation of oxidative damage, inflammation, fibrosis, and apoptosis pathways that aggravate diabetic CVD progression. In recent years, the development of phytochemical-based nutraceutical products for diabetic treatment has risen due to their therapeutic properties. Anthocyanin, which can be found in various types of plants, has been proposed for preventing and treating various diseases, and has elicited excellent antioxidative, anti-inflammation, anti-fibrosis, and anti-apoptosis effects. In preclinical and clinical studies, plants rich in anthocyanin have been reported to attenuate diabetic CVD. Therefore, the development of anthocyanin as a nutraceutical in managing diabetic CVD is in demand. In this review, we unveil the role of anthocyanin in modulating diabetic CVD, and its potential to be developed as a nutraceutical for a therapeutic strategy in managing CVD associated with DM.
Pharmacological interventions for intraplaque neovascularization in atherosclerosis

Ugusman A, Hisam NSN, Othman NS, Anuar NNM, Hamid AA, Kumar J, et al.

Pharmacol Ther, 2024 Jul 06;261:108685.
PMID: 38977083 DOI: 10.1016/j.pharmthera.2024.108685

Advanced atherosclerosis is linked to plaque instability, which can result in rupture and the onset of a heart attack. Evidence gathered from human atheroma plaques indicates that intraplaque neovascularization poses a risk to plaque stability and may lead to plaque hemorrhage. Hence, targeting the neovascularization within the atheroma plaque has the potential to mitigate the plaque's vulnerability. While neovascularization has been extensively explored in the context of cancer, research on pharmacological inhibition of this phenomenon in atherosclerosis remains limited. This systematic review aimed to comprehensively assess current and emerging pharmacological interventions for inhibiting intraplaque neovascularization in preclinical settings. Electronic databases (Web of Science, PubMed, Scopus, and Ovid) were searched from January 2013 until February 1, 2024. Preclinical studies reporting the effect of any pharmacological interventions targeting intraplaque neovascularization were included. A total of 10 articles involving in vivo animal studies were eligible for inclusion, with five of them incorporating in vitro experiments to complement their in vivo findings. The pharmacological interventions studied were axitinib, ghrelin, K5, rosuvastatin, atorvastatin, 3PO, everolimus, melatonin, Si-Miao-Yong-A, and protocatechuic aldehyde. All the interventions showed a positive impact in inhibiting intraplaque neovascularization in various atherosclerotic animal models through various signaling pathways. This review provides valuable insights into pharmacological approaches to attenuate intraplaque neovascularization that could serve as a promising therapeutic avenue to enhance plaque stability.