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Amrita Muralikrishnan,1 Mahendran Sekar,1 Vinoth Kumarasamy,2 Siew Hua Gan,1 Subban Ravi,3 Vetriselvan Subramaniyan,4 Ling Shing Wong,5 Yuan Seng Wu,6 Farrah Syazana Khattulanuar,7 Nur Najihah Izzati Mat Rani7 1School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan, Malaysia; 2Department of Parasitology & Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, 56000, Malaysia; 3Department of Chemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India; 4Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, Selangor 47500, Malaysia; 5Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia; 6Sunway Microbiome Centre & Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, Selangor, 47500, Malaysia; 7Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, Perak, 30450, MalaysiaCorrespondence: Mahendran Sekar, School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan, Malaysia, Email mahendran.sekar@moansh.edu Vinoth Kumarasamy, Department of Parasitology & Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, Kuala Lumpur, 56000, Malaysia, Email vinoth@ukm.edu.myAbstract: Decursin is a pyranocoumarin compounds which are rare secondary metabolic plant products, isolated from the roots of Angelica gigas (A. gigas). The native Korean species Angelica gigas Nakai (AGN) is widely used as a remedy for a variety of medical conditions including hematopoiesis, improving women’s circulation, as sedatives, analgesics and tonic. It is unique because of the presence of substantial amounts of pyranocoumarins including decursin, decursinol, and decursinol angelate. In this review, we provide a comprehensive insight into the distribution, morphology, and chemical composition of A. gigas. A detailed discussion regarding the biological applications of decursin based on the literature retrieved from PubMed, ScienceDirect, Scopus, and Google Scholar from 2000 to the present has been discussed. Both in vitro and in vivo studies have demonstrated that decursin has potential neuroprotective, anti-inflammatory, anti-melanogenic, anti-angiogenic, antioxidant, and anti-visceral properties. Mechanistic findings establish its significance in regulating important signalling pathways, triggering apoptosis, and preventing metastasis in different cancer types. The review additionally addressed the isolation methods, biosynthesis, physiochemical characteristics, toxicity and pharmacokinetic profile of decursin. The present state of clinical studies including A. gigas is investigated, emphasizing its advancements and possibilities in the field of translational medicine. Keywords: decursin, Angelica gigas, pyranocoumarins, biosynthesis, pharmacology

Aathira Sujathan Nair,1 Mahendran Sekar,1 Siew Hua Gan,1 Vinoth Kumarasamy,2 Vetriselvan Subramaniyan,3 Yuan Seng Wu,4 Nur Najihah Izzati Mat Rani,5 Subban Ravi,6 Ling Shing Wong7 1School of Pharmacy, Monash University Malaysia, Bandar Sunway, Subang Jaya, Selangor, 47500, Malaysia; 2Department of Parasitology & Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, 56000, Malaysia; 3Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, Selangor, 47500, Malaysia; 4Sunway Microbiome Centre & Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, Selangor, 47500, Malaysia; 5Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, Perak, 30450, Malaysia; 6Department of Chemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India; 7Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, MalaysiaCorrespondence: Mahendran Sekar, School of Pharmacy, Monash University Malaysia, Bandar Sunway, Subang Jaya, Selangor, 47500, Malaysia, Email mahendran.sekar@monash.edu Vinoth Kumarasamy, Department of Parasitology & Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, Kuala Lumpur, 56000, Malaysia, Email vinoth@ukm.edu.myAbstract: Lawsone, a naturally occurring organic compound also called hennotannic acid, obtained mainly from Lawsonia inermis (Henna). It is a potential drug-like molecule with unique chemical and biological characteristics. Traditionally, henna is used in hair and skin coloring and is also a medicinal herb for various diseases. It is also widely used as a starting material for the synthesis of various drug molecules. In this review, we investigate on the chemistry, biosynthesis, physical and biological properties of lawsone. The results showed that lawsone has potential antioxidant, anti-inflammatory, antimicrobial and antitumor properties. It also induces cell cycle inhibition and programmed cell death in cancer, making it a potential chemotherapeutic agent. Additionally, inhibition of pro-inflammatory cytokine production makes it an essential treatment for inflammatory diseases. Exploration of its biosynthetic pathway can pave the way for its development into targets for new drug development. In future, well-thought-out clinical studies should be made to verify its safety and efficacy. Keywords: lawsone, Lawsonia inermis, henna, antitumor, antioxidant, anti-inflammatory, antimicrobial

Muhamad Azrul Amir Yusri,1 Mahendran Sekar,2,3 Ling Shing Wong,4 Siew Hua Gan,2 Subban Ravi,5 Vetriselvan Subramaniyan,6 Nur Najihah Izzati Mat Rani,7 Kumarappan Chidambaram,8 M Yasmin Begum,9 Mohankumar Ramar,10 Sher Zaman Safi,11 Siddharthan Selvaraj,12 Yuan Seng Wu,13 Palanisamy Revathy,14 Shivkanya Fuloria,15 Neeraj Kumar Fuloria,15 Pei Teng Lum,1 Sinouvassane Djearamane16 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, Perak, Malaysia; 2School of Pharmacy, Monash University Malaysia, Bandar Sunway, Subang Jaya, Selangor, Malaysia; 3Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, India; 4Faculty of Health and Life Sciences, INTI International University, Nilai, Malaysia; 5Department of Chemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India; 6Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Subang Jaya, Selangor, Malaysia; 7Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, Perak, Malaysia; 8Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, Saudi Arabia; 9Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia; 10Department of Surgical Research, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, RI, USA; 11Faculty of Medicine, Bioscience and Nursing, MAHSA University, Bandar Saujana Putra, Jenjarom, Selangor, Malaysia; 12Faculty of Dentistry, AIMST University, Bedong, Kedah, Malaysia; 13Department of Biological Sciences and Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Subang Jaya, Selangor, Malaysia; 14Department of Computer Applications, Gobi Arts & Science College, Gobichettipalayam, Tamil Nadu, India; 15Faculty of Pharmacy, AIMST University, Bedong, Kedah, Malaysia; 16Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar, Perak, MalaysiaCorrespondence: Ling Shing Wong, Faculty of Health and Life Sciences, INTI International University, Nilai, Malaysia, Tel +6014 3034057, Email lingshing.wong@newinti.edu.my Sinouvassane Djearamane, Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar, Perak, Malaysia, Tel +6016 4037685, Email biochsinouvas07@gmail.comAbstract: Celastrol is a naturally occurring chemical isolated from Tripterygium wilfordii Hook. f., root extracts widely known for their neuroprotective properties. In this review, we focus on the efficacy of celastrol in mitigating memory impairment (MI) in both in vivo and in vitro models. Scopus, PubMed and Web of Science databases were utilised to locate pertinent literatures that explore the effects of celastrol in the brain, including its pharmacokinetics, bioavailability, behavioral effects and some of the putative mechanisms of action on memory in many MI models. To date, preclinical studies strongly suggest that celastrol is highly effective in enhancing the cognitive performance of MI animal models, particularly in the memory domain, including spatial, recognition, retention and reference memories, via reduction in oxidative stress and attenuation of neuro-inflammation, among others. This review also emphasised the challenges and potential associated enhancement of medication delivery for MI treatment. Additionally, the potential structural alterations and derivatives of celastrol in enhancing its physicochemical and drug-likeness qualities are examined. The current review demonstrated that celastrol can improve cognitive performance and mitigate MI in several preclinical investigations, highlighting its potential as a natural lead molecule for the design and development of a novel neuroprotective medication.Graphical Abstract: Keywords: celastrol, memory impairment, neuroprotection, drug discovery, natural products

Naurah Nabihah Nasir,1 Mahendran Sekar,2,3 Subban Ravi,4 Ling Shing Wong,5 Sreenivas Patro Sisinthy,6 Siew Hua Gan,2 Vetriselvan Subramaniyan,7 Kumarappan Chidambaram,8 Nur Najihah Izzati Mat Rani,6 M Yasmin Begum,9 Mohankumar Ramar,10 Sher Zaman Safi,11 Siddharthan Selvaraj,12 Senthil Kumar Chinna Maruthu,13 Shivkanya Fuloria,14 Neeraj Kumar Fuloria,14 Pei Teng Lum,1 Sinouvassane Djearamane15 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, Perak, 30450, Malaysia; 2School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, 47500, Malaysia; 3Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Institute of Medical and Technical Sciences, Saveetha Dental College and Hospital, Saveetha University, Chennai, Tamil Nadu, 600077, India; 4Department of Chemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 641021, India; 5Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia; 6Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, Perak, 30450, Malaysia; 7Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Subang Jaya, Selangor, Malaysia; 8Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia; 9Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, 61421, Saudi Arabia; 10Department of Surgical Research, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, RI, 02903, USA; 11Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom, Selangor, 42610, Malaysia; 12Faculty of Dentistry, AIMST University, Bedong, Kedah, 08100, Malaysia; 13Department of Pharmacology, Karpagam College of Pharmacy, Coimbatore, Tamilnadu, 641032, India; 14Faculty of Pharmacy, AIMST University, Bedong, Kedah, 08100, Malaysia; 15Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar, Perak, 31900, MalaysiaCorrespondence: Ling Shing Wong, Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia, Tel +6014 – 3034057, Email lingshing.wong@newinti.edu.my Sinouvassane Djearamane, Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar, 31900, Perak, Malaysia, Tel +6016 – 4037685, Email biochsinouvas07@gmail.comAbstract: Streptonigrin is an aminoquinone alkaloid isolated from Streptomyces flocculus and is gaining attention as a drug molecule owing to its potential antitumor and antibiotic effects. It was previously used as an anticancer drug but has been discontinued because of its toxic effects. However, according to the most recent studies, the toxicity of streptonigrin and its structurally modified derivatives has been reduced while maintaining their potential pharmacological action at lower concentrations. To date, many investigations have been conducted on this molecule and its derivatives to determine the most effective molecule with low toxicity to enable new drug discovery. Therefore, the main objective of this study is to provide a comprehensive review and to discuss the prospects for streptonigrin and its derived compounds, which may boost the molecule as a highly interesting target molecule for new drug design, development and therapy. To complete this review, relevant literature was collected from several scientific databases, including Google Scholar, PubMed, Scopus and ScienceDirect. Following a complete screening, the obtained information is summarized in the present review to provide a good reference and accelerate the development and utilization of streptonigrin and its derivatives as pharmaceuticals.Graphical Abstract: Keywords: streptonigrin, chemistry, biosynthesis, pharmacology, anticancer, antibacterial

Nurul Amirah Mohd Zaid,1,* Mahendran Sekar,1,* Srinivasa Reddy Bonam,2,* Siew Hua Gan,3 Pei Teng Lum,1 M Yasmin Begum,4 Nur Najihah Izzati Mat Rani,5 Jaishree Vaijanathappa,6 Yuan Seng Wu,7,8 Vetriselvan Subramaniyan,9 Neeraj Kumar Fuloria,10 Shivkanya Fuloria10 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, 30450, Malaysia; 2Institut National de la Santé et de la Recherche Médicale; Centre de Recherche des Cordeliers, Equipe-Immunopathologie et Immunointervention Thérapeutique, Sorbonne Université, Université de Paris, Paris, France; 3School of Pharmacy, Monash University Malaysia, Selangor Darul Ehsan, 47500, Malaysia; 4Department of Pharmaceutics, College of Pharmacy, King Khalid University (KKU), Asir-Abha, 61421, Saudi Arabia; 5Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, 30450, Malaysia; 6Faculty of Life Sciences, JSS Academy of Higher Education and Research Mauritius, Vacoas-Phoenix, Mauritius; 7Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 8Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 9Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor, 42610, Malaysia; 10Faculty of Pharmacy, AIMST University, Kedah, 08100, Malaysia*These authors contributed equally to this workCorrespondence: Mahendran SekarDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh, 30450, Perak, MalaysiaTel +6016 – 3346653Fax +605 – 2536634Email mahendransekar@unikl.edu.myAbstract: The skin is the largest organ in the human body, composed of the epidermis and the dermis. It provides protection and acts as a barrier against external menaces like allergens, chemicals, systemic toxicity, and infectious organisms. Skin disorders like cancer, dermatitis, psoriasis, wounds, skin aging, acne, and skin infection occur frequently and can impact human life. According to a growing body of evidence, several studies have reported that natural products have the potential for treating skin disorders. Building on this information, this review provides brief information about the action of the most important in vitro and in vivo research on the use of ten selected natural products in inflammatory, neoplastic, and infectious skin disorders and their mechanisms that have been reported to date. The related studies and articles were searched from several databases, including PubMed, Google, Google Scholar, and ScienceDirect. Ten natural products that have been reported widely on skin disorders were reviewed in this study, with most showing anti-inflammatory, antioxidant, anti-microbial, and anti-cancer effects as the main therapeutic actions. Overall, most of the natural products reported in this review can reduce and suppress inflammatory markers, like tumor necrosis factor-alpha (TNF-α), scavenge reactive oxygen species (ROS), induce cancer cell death through apoptosis, and prevent bacteria, fungal, and virus infections indicating their potentials. This review also highlighted the challenges and opportunities of natural products in transdermal/topical delivery systems and their safety considerations for skin disorders. Our findings indicated that natural products might be a low-cost, well-tolerated, and safe treatment for skin diseases. However, a larger number of clinical trials are required to validate these findings. Natural products in combination with modern drugs, as well as the development of novel delivery mechanisms, represent a very promising area for future drug discovery of these natural leads against skin disorders.Keywords: natural products, skin disorder, dermatitis, psoriasis, skin cancer, anti-inflammatory, drug delivery

Kah Min Yap,1 Mahendran Sekar,1 Shivkanya Fuloria,2 Yuan Seng Wu,3,4 Siew Hua Gan,5 Nur Najihah Izzati Mat Rani,6 Vetriselvan Subramaniyan,7 Chandrakant Kokare,8 Pei Teng Lum,1 M Yasmin Begum,9 Shankar Mani,10 Dhanalekshmi Unnikrishnan Meenakshi,11 Kathiresan V Sathasivam,12 Neeraj Kumar Fuloria2 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia; 2Faculty of Pharmacy, AIMST University, Kedah, 08100, Malaysia; 3Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 4Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 5School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan, 47500, Malaysia; 6Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia; 7Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor, 42610, Malaysia; 8Department of Pharmaceutics, Sinhgad Technical Education Society’s, Sinhgad Institute of Pharmacy, Narhe, Pune, 411041, India; 9Department of Pharmaceutics, College of Pharmacy, King Khalid University (KKU), Asir-Abha, 61421, Saudi Arabia; 10Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, Mandya, Karnataka, 571418, India; 11College of Pharmacy, National University of Science and Technology, Muscat, 130, Oman; 12Faculty of Applied Sciences, AIMST University, Kedah, 08100, MalaysiaCorrespondence: Neeraj Kumar Fuloria; Shivkanya FuloriaFaculty of Pharmacy, AIMST University, Kedah, 08100, MalaysiaTel +60 16 4037685; +60 14 3034057Email neerajkumar@aimst.edu.my; shivkanya_fuloria@aimst.edu.myAbstract: Despite recent advances in the diagnosis and treatment of breast cancer (BC), it remains a global health issue affecting millions of women annually. Poor prognosis in BC patients is often linked to drug resistance as well as the lack of effective therapeutic options for metastatic and triple-negative BC. In response to these unmet needs, extensive research efforts have been devoted to exploring the anti-BC potentials of natural products owing to their multi-target mechanisms of action and good safety profiles. Various medicinal plant extracts/essential oils and natural bioactive compounds have demonstrated anti-cancer activities in preclinical BC models. Despite the promising preclinical results, however, the clinical translation of natural products has often been hindered by their poor stability, aqueous solubility and bioavailability. There have been attempts to overcome these limitations, particularly via the use of nano-based drug delivery systems (NDDSs). This review highlights the tumour targeting mechanisms of NDDSs, the advantages and disadvantages of the major classes of NDDSs and their current clinical status in BC treatment. Besides, it also discusses the proposed anti-BC mechanisms and nanoformulations of nine medicinal plants’ extracts/essential oils and nine natural bioactive compounds; selected via the screening of various scientific databases, including PubMed, Scopus and Google Scholar, based on the following keywords: “Natural Product AND Nanoparticle AND Breast Cancer”. Overall, these nanoformulations exhibit improved anti-cancer efficacy against preclinical BC models, with some demonstrating biocompatibility with normal cell lines and mouse models. Further clinical studies are, however, warranted to ascertain their efficacy and biocompatibility in humans.Keywords: breast cancer, drug delivery, molecular mechanisms, nanoparticles, natural products, phytomedicine

Mohd Nasarudin Watroly,1 Mahendran Sekar,1 Shivkanya Fuloria,2 Siew Hua Gan,3 Srikanth Jeyabalan,4 Yuan Seng Wu,5,6 Vetriselvan Subramaniyan,7 Kathiresan V Sathasivam,8 Subban Ravi,9 Nur Najihah Izzati Mat Rani,10 Pei Teng Lum,1 Jaishree Vaijanathappa,11 Dhanalekshmi Unnikrishnan Meenakshi,12 Shankar Mani,13 Neeraj Kumar Fuloria2 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia; 2Faculty of Pharmacy & Centre of Excellence for Biomaterials Engineering, AIMST University, Kedah, 08100, Malaysia; 3School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan, 47500, Malaysia; 4Department of Pharmacology, Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research (DU), Chennai, Tamil Nadu, 600116, India; 5Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 6Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 7Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor, 42610, Malaysia; 8Faculty of Applied Science & Centre of Excellence for Biomaterials Engineering, AIMST University, Kedah, 08100, Malaysia; 9Department of Chemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, 640 021, India; 10Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia; 11Department of Pharmaceutical Chemistry, School of Life Sciences, JSS Academy of Higher Education and Research Mauritius, Vacoas, Mauritius; 12College of Pharmacy, National University of Science and Technology, Muscat, 130, Oman; 13Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, Mandya, Karnataka, 571418, IndiaCorrespondence: Neeraj Kumar Fuloria; Shivkanya FuloriaFaculty of Pharmacy & Centre of Excellence for Biomaterials Engineering, AIMST University, Kedah, 08100, MalaysiaTel +60 16 4037685; +60 14 3034057Email neerajkumar@aimst.edu.my; shivkanya_fuloria@aimst.edu.myAbstract: Anthraquinones (AQs) are found in a variety of consumer products, including foods, nutritional supplements, drugs, and traditional medicines, and have a wide range of pharmacological actions. Rubiadin, a 1,3-dihydroxy-2-methyl anthraquinone, primarily originates from Rubia cordifolia Linn (Rubiaceae). It was first discovered in 1981 and has been reported for many biological activities. However, no review has been reported so far to create awareness about this molecule and its role in future drug discovery. Therefore, the present review aimed to provide comprehensive evidence of Rubiadin’s phytochemistry, biosynthesis, physicochemical properties, biological properties and therapeutic potential. Relevant literature was gathered from numerous scientific databases including PubMed, ScienceDirect, Scopus and Google Scholar between 1981 and up-to-date. The distribution of Rubiadin in numerous medicinal plants, as well as its method of isolation, synthesis, characterisation, physiochemical properties and possible biosynthesis pathways, was extensively covered in this review. Following a rigorous screening and tabulating, a thorough description of Rubiadin’s biological properties was gathered, which were based on scientific evidences. Rubiadin fits all five of Lipinski’s rule for drug-likeness properties. Then, the in depth physiochemical characteristics of Rubiadin were investigated. The simple technique for Rubiadin’s isolation from R. cordifolia and the procedure of synthesis was described. Rubiadin is also biosynthesized via the polyketide and chorismate/o-succinylbenzoic acid pathways. Rubiadin is a powerful molecule with anticancer, antiosteoporotic, hepatoprotective, neuroprotective, anti-inflammatory, antidiabetic, antioxidant, antibacterial, antimalarial, antifungal, and antiviral properties. The mechanism of action for the majority of the pharmacological actions reported, however, is unknown. In addition to this review, an in silico molecular docking study was performed against proteins with PDB IDs: 3AOX, 6OLX, 6OSP, and 6SDC to support the anticancer properties of Rubiadin. The toxicity profile, pharmacokinetics and possible structural modifications were also described. Rubiadin was also proven to have the highest binding affinity to the targeted proteins in an in silico study; thus, we believe it may be a potential anticancer molecule. In order to present Rubiadin as a novel candidate for future therapeutic development, advanced studies on preclinical, clinical trials, bioavailability, permeability and administration of safe doses are necessary.Keywords: Rubiadin, Rubia cordifolia, biosynthesis, physicochemical properties, anticancer, pharmacology

Nur Zulaikha Azwa Zuraini,1 Mahendran Sekar,1 Yuan Seng Wu,2,3 Siew Hua Gan,4 Srinivasa Reddy Bonam,5 Nur Najihah Izzati Mat Rani,6 M Yasmin Begum,7 Pei Teng Lum,1 Vetriselvan Subramaniyan,8 Neeraj Kumar Fuloria,9 Shivkanya Fuloria9 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia; 2Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 3Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor, 47500, Malaysia; 4School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan, 47500, Malaysia; 5Institut National de la Santé et de la Recherche Médicale, Centre de Recherché des Cordeliers, Sorbonne Université, Université de Paris, Paris, France; 6Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, Malaysia; 7Department of Pharmaceutics, College of Pharmacy, King Khalid University (KKU), Asir-Abha, 61421, Saudi Arabia; 8Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor, 42610, Malaysia; 9Faculty of Pharmacy & Centre of Excellence for Biomaterials Engineering, AIMST University, Kedah, 08100, MalaysiaCorrespondence: Mahendran SekarDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, 30450, MalaysiaTel +6016 – 3346653Fax +605 – 2536634Email mahendransekar@unikl.edu.myAbstract: Cardiovascular diseases (CVDs) are one of the leading causes of morbidity and mortality in both developed and developing countries, affecting millions of individuals each year. Despite the fact that successful therapeutic drugs for the management and treatment of CVDs are available on the market, nutritional fruits appear to offer the greatest benefits to the heart and have been proved to alleviate CVDs. Experimental studies have also demonstrated that nutritional fruits have potential protective effects against CVDs. The aim of the review was to provide a comprehensive summary of scientific evidence on the effect of 10 of the most commonly available nutritional fruits reported against CVDs and describe the associated mechanisms of action. Relevant literatures were searched and collected from several scientific databases including PubMed, ScienceDirect, Google Scholar and Scopus. In the context of CVDs, 10 commonly consumed nutritious fruits including apple, avocado, grapes, mango, orange, kiwi, pomegranate, papaya, pineapple, and watermelon were analysed and addressed. The cardioprotective mechanisms of the 10 nutritional fruits were also compiled and highlighted. Overall, the present review found that the nutritious fruits and their constituents have significant benefits for the management and treatment of CVDs such as myocardial infarction, hypertension, peripheral artery disease, coronary artery disease, cardiomyopathies, dyslipidemias, ischemic stroke, aortic aneurysm, atherosclerosis, cardiac hypertrophy and heart failure, diabetic cardiovascular complications, drug-induced cardiotoxicity and cardiomyopathy. Among the 10 nutritional fruits, pomegranate and grapes have been well explored, and the mechanisms of action are well documented against CVDs. All of the nutritional fruits mentioned are edible and readily accessible on the market. Consuming these fruits, which may contain varying amounts of active constituents depending on the food source and season, the development of nutritious fruits-based health supplements would be more realistic for consistent CVD protection.Keywords: nutritional fruits, cardiovascular diseases, heart disease, antioxidant, hypertension, nutraceuticals

Kah Min Yap,1 Mahendran Sekar,1 Lay Jing Seow,1 Siew Hua Gan,2 Srinivasa Reddy Bonam,3 Nur Najihah Izzati Mat Rani,4 Pei Teng Lum,1 Vetriselvan Subramaniyan,5 Yuan Seng Wu,5 Neeraj Kumar Fuloria,6 Shivkanya Fuloria6 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, 30450, Perak, Malaysia; 2School of Pharmacy, Monash University Malaysia, Bandar Sunway, 47500, Selangor Darul Ehsan, Malaysia; 3Institut National de la Santé et de la Recherche Médicale; Centre de Recherche des Cordeliers, Equipe-Immunopathologie et Immunointervention Thérapeutique, Sorbonne Université, Université de Paris, Paris, France; 4Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, 30450, Perak, Malaysia; 5Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor, 42610, Malaysia; 6Faculty of Pharmacy, AIMST University, Kedah, 08100, MalaysiaCorrespondence: Mahendran Sekar Tel +6016 – 3346653Fax +605 – 2536634Email mahendransekar@unikl.edu.myAbstract: Globally, breast cancer is the most common cancer type and is one of the most significant causes of deaths in women. To date, multiple clinical interventions have been applied, including surgical resection, radiotherapy, endocrine therapy, targeted therapy and chemotherapy. However, 1) the lack of therapeutic options for metastatic breast cancer, 2) resistance to drug therapy and 3) the lack of more selective therapy for triple-negative breast cancer are some of the major challenges in tackling breast cancer. Given the safe nature of natural products, numerous studies have focused on their anti-cancer potentials. Mangifera indica, commonly known as mango, represents one of the most extensively investigated natural sources. In this review, we provide a comprehensive overview of M. indica extracts (bark, kernel, leaves, peel and pulp) and phytochemicals (mangiferin, norathyriol, gallotannins, gallic acid, pyrogallol, methyl gallate and quercetin) reported for in vitro and in vivo anti-breast cancer activities and their underlying mechanisms based on relevant literature from several scientific databases, including PubMed, Scopus and Google Scholar till date. Overall, the in vitro findings suggest that M. indica extracts and/or phytochemicals inhibit breast cancer cell growth, proliferation, migration and invasion as well as trigger apoptosis and cell cycle arrest. In vivo results demonstrated that there was a reduction in breast tumor xenograft growth. Several potential mechanisms underlying the anti-breast cancer activities have been reported, which include modulation of oxidative status, receptors, signalling pathways, miRNA expression, enzymes and cell cycle regulators. To further explore this medicinal plant against breast cancer, future research directions are addressed. The outcomes of the review revealed that M. indica extracts and their phytochemicals may have potential benefits in the management of breast cancer in women. However, to validate its utility in the creation of innovative and potent therapeutic agents to treat breast cancer, more dedicated research, especially clinical studies are needed to explore the anti-breast cancer potentials of M. indica extracts and their phytochemicals.Keywords: mango, Mangifera indica, mangiferin, breast cancer, molecular mechanism, natural products, women’s health

Mercury is a type of hazardous and toxic pollutant that can result in detrimental effects on the environment and human health. This review is aimed at discussing the state-of-the-art progress on the recent developments on the toxicity of mercury and its chemical compounds. More than 210 recent works of literature are covered in this review. It first delineates the types (covering elemental mercury, inorganic mercury compounds, organic mercury compounds), structures, and sources of mercury. It then discusses the pharmacokinetic profile of mercury, molecular mechanisms of mercury toxicity, and clinical manifestation of acute and chronic mercury toxicity to public health. It also elucidates the mercury toxicity to the environment and human health in detail, covering ecotoxicity, neurotoxicity diseases, neurological diseases, genotoxicity and gene regulation, immunogenicity, pregnancy and reproductive system damage, cancer promotion, cardiotoxicity, pulmonary diseases, and renal disease. In order to mitigate the adverse effects of mercury, strategies to overcome mercury toxicity are recommended. Finally, some future perspectives are provided in order to advance this field of research in the future., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The global COVID-19 pandemic arising from SARS-CoV-2 has impacted many lives, gaining interest worldwide ever since it was first identified in December 2019. Till 2023, 752 million cumulative cases and 6.8 million deaths were documented globally. COVID-19 has been rapidly evolving, affecting virus transmissibility and properties and contributing to increased disease severity. The Omicron is the most circulating variant of concern. Although success in its treatment has indicated progress in tackling the virus, limitations in delivering the current antiviral agents in battling emerging variants remain remarkable. With the latest advancements in nanotechnology for controlling infectious diseases, liposomes have the potential to counteract SARS-CoV-2 because of their ability to employ different targeting strategies, incorporating monoclonal antibodies for the active and passive targeting of infected patients. This review will present a concise summary of the possible strategies for utilizing immunoliposomes to improve current treatment against the occurrence of SARS-CoV-2 and its variants., Competing Interests: The authors declare that they have no conflicts of interest or financial competing interests., (© 2023 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

Background: Excitotoxicity is a condition in which neurons are damaged/injured by the over-activation of glutamate receptors. Excitotoxins play a crucial part in the progression of several neurological diseases. Marsilea quadrifolia Linn ( M. quadrifolia ) is a very popular aquatic medicinal plant that has been utilised for a variety of therapeutic benefits since ancient times. Its chemical composition is diverse and includes phenolic compounds, tannins, saponins, flavonoids, steroids, terpenoids, alkaloids, carbohydrates and several others that possess antioxidant properties. Objective: The objective of the present study was to investigate the neuroprotective potential of M. quadrifolia against monosodium glutamate (MSG)-induced excitotoxicity in rats. Methods: A high-performance thin-layer chromatography (HPTLC) analysis of chloroform extract of M. quadrifolia (CEMQ) was conducted to identify the major constituents. Further, the in silico docking analysis was carried out on selected ligands. To confirm CEMQ's neuroprotective effects, the locomotor activity, non-spatial memory, and learning were assessed. Results and discussion: The present study confirmed that CMEQ contains quercetin and its derivatives in large. The in-silico findings indicated that quercetin has a better binding affinity (-7.9 kcal/mol) towards the protein target 5EWJ. Animals treated with MSG had 1) a greater reduction in the locomotor score and impairment in memory and learning 2) a greater increase in the blood levels of calcium and sodium and 3) neuronal disorganization, along with cerebral edema and neuronal degeneration in the brain tissues as compared to normal control animals. The changes were however, significantly improved in animals which received standard drug memantine (20 mg/kg) and CEMQ (200 and 400 mg/kg) as compared to the negative control. It is plausible that the changes seen with CEMQ may be attributed to the N-methyl-D-aspartate (NMDA) antagonistic properties. Conclusion: Overall, this study indicated that M. quadrifolia ameliorated MSG-induced neurotoxicity. Future investigations are required to explore the neuroprotective mechanism of M. quadrifolia and its active constituents, which will provide exciting insights in the therapeutic management of neurological disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Subramanian, Tamilanban, Sekar, Begum, Atiya, Ramachawolran, Wong, Subramaniyan, Gan, Mat Rani, Wu, Chinni, Fuloria and Fuloria.)

Vascular endothelial growth factor (VEGF) signals cell survival, cell migration, osteogenesis, cell proliferation, angiogenesis, and vascular permeability by binding to VEGF receptor 2 (VEGFR-2). Osteosarcoma is the most common primary bone cancer, majorly affects young adults. Activation of VEGFR-2 signaling is a therapeutic target for osteosarcoma. The present study aimed to evaluate the potency of stylopine in regulation of the VEGFR-2 signaling pathway and its anti-tumour effect human MG-63 osteosarcoma cells. The in silico study on benzylisoquinoline alkaloids was carried out for analyzing and shortlisting of compounds using a virtual screening, Lipinski's rule, bioavailability graphical RADAR plot, pharmacokinetics, toxicity, and molecular docking studies. Among the benzylisoquinoline alkaloids, stylopine was selected and subjected to in-vitro studies against human MG-63 osteosarcoma cells. Various experiments such as MTT assay, EtBr/AO staining, mitochondrial membrane potential assessment, transwell migration assay, gene expression analysis by a quantitative real time polymerase chain reaction (qRT-PCR) method, SDS-PAGE followed by immunoblotting were performed to evaluate its anti-tumour effect as compared to standard axitinib. The MTT assay indicates that stylopine inhibits cell proliferation in MG-63 cells. Similarly, as confirmed by the EtBr/Ao staining method, the MMP assay indicates that stylopine induces mitochondrial membrane damage and apoptosis as compared to axitinib. Moreover, stylopine inhibits the VEGF-165 induced MG-63 cell migration by a trans-well migration assay. The immunoblotting and qRT-PCR analysis showed that stylopine inhibits the VEGF-165 induced VEGFR2 expression in MG-63 cells. It is concluded that stylopine has potential to regulate VEGFR2 and can inhibit osteosarcoma cells to offer a new drug candidate for the treatment of bone cancer in future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Velayutham, Thamaraikani, Wahab, Khalid, Ramachawolran, Abullais, Wong, Sekar, Gan, Ebenezer, Ravikumar, Subramaniyan, Mat Rani, Wu and Jeyabalan.)

Background: Dodonaea viscosa Jacq. ( D. viscosa ) belongs to the family of Sapindaceae, commonly known as " Sinatha, " and is used as a traditional medicine for treating wounds due to its high flavonoids content. However, to date there is no experimental evidence on its flavonoid-rich fraction of D. viscosa formulation as an agent for healing wounds. Objective: The present study aimed to evaluate the wound healing effect of ethyl acetate fraction of D. viscosa leaves on dermal wounds. Methods: The ethyl acetate fraction was produced from a water-ethanol extract of D. viscosa leaves and was quantitatively evaluated using the HPLC technique. The in-vivo wound healing ability of the ethyl acetate fraction of D. viscosa ointment (DVFO, 2.5%w/w and 5%w/w) was investigated in Sprague-Dawley rats utilizing an incision and excision paradigm with povidone-iodine ointment (5% w/w) as a control. The percentage of wound closure, hydroxyproline and hexosamine concentrations, tensile strength and epithelialization duration were measured. Subsequently, histopathology analysis of skin samples as well as western blots were performed for collagen type 3 (COL3A1), basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Results: The ethyl acetate fraction of D. viscosa revealed flavonoids with high concentrations of quercetin (6.46% w/w) and kaempferol (0.132% w/w). Compared to the control group, the DVFO (2.5% and 5.0% w/w) significantly accelerated wound healing in both models, as demonstrated by quicker wound contraction, epithelialization, elevated hydroxyproline levels and increased tensile strength. Histopathological investigations also revealed that DVFO treatment improved wound healing by re-epithelialization, collagen formation and vascularization of damaged skin samples. Western blot analysis further demonstrated an up-regulation of COL3A, vascular endothelial growth factor and bFGF protein in wound granulation tissue of the DVFO-treated group ( p < 0.01). Conclusion: It is concluded that flavonoid-rich D. viscosa ethyl acetate fraction promotes wound healing by up-regulating the expressions of COL3A, VEGF and bFGF protein in wound granulation tissue. However, extensive clinical and pre-clinical research on the flavonoid-rich fraction of D. viscosa is needed to determine its significant impact in the healing of human wounds., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Subramanian, Duraipandian, Alsayari, Ramachawolran, Wong, Sekar, Gan, Subramaniyan, Seethalakshmi, Jeyabalan, Dhanasekaran, Chinni, Mat Rani and Wahab.)

Obsessive-compulsive disorder (OCD) is a chronic and complex psychiatric disorder that usually includes both obsessions and compulsions. Morinda citrifolia L. (Noni) is a functional food and it is a well-known plant due to its potential therapeutic effects on human health in many disorders including neurological and neurodegenerative diseases. The purpose of this study was to evaluate the potential effect of M. citrifolia fruits extract (MCFE) against obsessive-compulsive disorder using the marble burying and nestlet shredding behavior mice models. In addition, brain neurotransmitters such as dopamine (DA), serotonin and noradrenaline (NA) were also assessed. Five mice were placed in each of the different groups, and the treatment was given to the animals for a period of 15 days. The marble burying test was evaluated for 30 min on days 1, 7, and 14 while the nestlet shredding test was evaluated for 60 min on days 2, 8, and 15. Treatments with MCFE (100 and 200 mg/kg, p.o.) significantly improved in both behavior tasks when compared to the control group. In addition, diazepam (2 mg/kg, i.p.) and fluoxetine (15 mg/kg, p.o.) were also significantly improved in both tasks when compared with the control mice. Further locomotor activity study revealed that MCFE and fluoxetine did not affect the locomotor functions when compared to vehicle treated mice. In contrast, diazepam significantly decreased locomotion when compared to the control group. The significant amelioration of biogenic amines were observed in the MCFE-treated animals with increased serotonin levels. The histopathology of the brain, liver, and kidney tissues after MCFE administration revealed normal morphological structure with no signs of toxicity or abnormalities. All these results together suggest that MCFE can be a potential drug candidate for the treatment of OCD. Future research should focus on theidentification and the anti-compulsive activity of the constituents from M . citrifolia ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jeyabalan, Bala, Subramanian, Jabaris, Sekar, Wong, Subramaniyan, Chidambaram, Gan, Mat Rani, Begum, Safi, Selvaraj, Al Fatease, Alamri, Vijeepallam, Fuloria, Fuloria and Djearamane.)

In the last decade, nanoparticle-based therapeutic modalities have emerged as promising treatment options for cancer and infectious diseases. To improve prognosis, chemotherapeutic and antimicrobial drugs must be delivered selectively to the target sites. Researchers have increasingly focused their efforts on improving drug delivery, with a particular emphasis on cancer and infectious diseases. When drugs are administered systemically, they become diluted and can diffuse to all tissues but only until the immune system intervenes and quickly removes them from circulation. To enhance and prolong the systemic circulation of drugs, nanocarriers have been explored and used; however, nanocarriers have a major drawback in that they can trigger immune responses. Numerous nanocarriers for optimal drug delivery have been developed using innovative and effective biointerface technologies. Autologous cell-derived drug carriers, such as outer membrane vesicles (OMVs), have demonstrated improved bioavailability and reduced toxicity. Thus, this study investigates the use of biomimetic OMVs as biomimetic vaccine carriers against infections and cancers to improve our understanding in the field of nanotechnology. In addition, discussion on the advantages, disadvantages, and future prospects of OMVs will also be explored. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Biology-Inspired Nanomaterials > Protein and Virus-Based Structures., (© 2022 Wiley Periodicals LLC.)

Multi antibiotic-resistant bacterial infections are on the rise due to the overuse of antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the pathogens listed under the category of serious threats where vancomycin remains the mainstay treatment despite the availability of various antibacterial agents. Recently, decreased susceptibility to vancomycin from clinical isolates of MRSA has been reported and has drawn worldwide attention as it is often difficult to overcome and leads to increased medical costs, mortality, and longer hospital stays. Development of antibiotic delivery systems is often necessary to improve bioavailability and biodistribution, in order to reduce antibiotic resistance and increase the lifespan of antibiotics. Liposome entrapment has been used as a method to allow higher drug dosing apart from reducing toxicity associated with drugs. The surface of the liposomes can also be designed and enhanced with drug-release properties, active targeting, and stealth effects to prevent recognition by the mononuclear phagocyte system, thus enhancing its circulation time. The present review aimed to highlight the possible targeting strategies of liposomes against MRSA bacteremia systemically while investigating the magnitude of this effect on the minimum inhibitory concentration level., (Copyright © 2021 Elsevier B.V. All rights reserved.)