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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

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

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