In Southeast Asia, traditional medicine has a longestablished history and plays an important role in the health care system. Various traditional medicinal plants have been used to treat diseases since ancient times and much of this traditional knowledge remains preserved today. Oroxylum indicum (beko plant) is one of the medicinal herb plants that is widely distributed throughout Asia. It is a versatile plant and almost every part of the plant is reported to possess a wide range of pharmacological activities. Many of the important bioactivities of this medicinal plant is related to the most abundant bioactive constituent found in this plant—the baicalein. Nonetheless, there is still no systematic review to report and vindicate the biological activities and therapeutic potential of baicalein extracted from O. indicum to treat human diseases. In this review, we aimed to systematically present in vivo and in vitro studies searched from PubMed, ScienceDirect, Scopus and Google Scholar database up to 31 March 2020 based on keywords “Oroxylum indicum” and “baicalein”. After an initial screening of titles and abstracts, followed by a full-text analysis and validation, 20 articles that fulfilled all the inclusion and exclusion criteria were included in this systematic review. The searched data comprehensively reported the biological activities and therapeutic potential of baicalein originating from the O. indicum plant for anti-cancer, antibacterial, anti-hyperglycemia, neurogenesis, cardioprotective, anti-adipogenesis, anti-inflammatory and wound healing effects. Nonetheless, we noticed that there was a scarcity of evidence on the efficacy of this natural active compound in human clinical studies. In conclusion, this systematic review article provides new insight into O. indicum and its active constituent baicalein as a prospective complementary therapy from the perspective of modern and scientific aspect. We indicate the potential of this natural product to be developed into more conscientious and judicious evidencebased medicine in the future. However, we also recommend more clinical research to confirm the efficacy and safety of baicalein as therapeutic medicine for patients.

Transplantation of neural stem cells (NSCs) has been proposed as an alternative novel therapy to replace damaged neural circuitry after ischemic stroke onset. Nonetheless, albeit the potential of these cells for stroke therapy, many critical challenges are yet to be overcome to reach clinical applications. The major limitation of the NSC-based therapy is its inability to retain most of the donor stem cells after grafting into an ischemic brain area which is lacking of essential oxygen and nutrients for the survival of transplanted cells. Low cell survival rate limits the capacity of NSCs to repair the injured area and this poses a much more difficult challenge to the NSC-based therapy for ischemic stroke. In order to enhance the survival of transplanted cells, several stem cell culture preconditioning strategies have been employed. For ischemic diseases, hypoxic preconditioning is the most commonly applied strategy since the last few decades. Now, the preconditioning strategies have been developed and expanded enormously throughout years of efforts. This review systematically presented studies searched from PubMed, ScienceDirect, Web of Science, Scopus and the Google Scholar database up to 31 March 2020 based on search words containing the following terms: “precondition” or “pretreatment” and “neural stem cell” and “ischemic stroke”. The searched data comprehensively reported seven major NSC preconditioning strategies including hypoxic condition, small drug molecules such as minocycline, doxycycline, interleukin-6, adjudin, sodium butyrate and nicorandil, as well as electrical stimulation using conductive polymer for ischemic stroke treatment. We discussed therapeutic benefits gained from these preconditioned NSC for in vitro and in vivo stroke studies and the detailed insights of the mechanisms underlying these preconditioning approaches. Nonetheless, we noticed that there was a scarcity of evidence on the efficacy of these preconditioned NSCs in human clinical studies, therefore, it is still too early to draw a definitive conclusion on the efficacy and safety of this active compound for patient usage. Thus, we suggest for more in-depth clinical investigations of this cell-based therapy to develop into more conscientious and judicious evidence-based therapy for clinical application in the future.

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BACKGROUND Ischemic stroke is a condition in which an occluded blood vessel interrupts blood flow to the brain and causes irreversible neuronal cell death. Transplantation of regenerative stem cells has been proposed as a novel therapy to restore damaged neural circuitry after ischemic stroke attack. However, limitations such as low cell survival rates after transplantation remain significant challenges to stem cell-based therapy for ischemic stroke in the clinical setting. In order to enhance the therapeutic efficacy of transplanted stem cells, several biomaterials have been developed to provide a supportable cellular microenvironment or functional modification on the stem cells to optimize their reparative roles in injured tissues or organs. AIM To discuss state-of-the-art functional biomaterials that could enhance the therapeutic potential of stem cell-based treatment for ischemic stroke and provide detailed insights into the mechanisms underlying these biomaterial approaches. METHODS The PubMed, Science Direct and Scopus literature databases were searched using the keywords of “biomaterial” and “ischemic stroke”. All topically-relevant articles were then screened to identify those with focused relevance to in vivo , in vitro and clinical studies related to “stem cells” OR “progenitor cells” OR “undifferentiated cells” published in English during the years of 2011 to 2022. The systematic search was conducted up to September 30, 2022. RESULTS A total of 19 articles matched all the inclusion criteria. The data contained within this collection of papers comprehensively represented 19 types of biomaterials applied on seven different types of stem/progenitor cells, namely mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, neural progenitor cells, endothelial progenitor cells, neuroepithelial progenitor cells, and neuroblasts. The potential major benefits gained from the application of biomaterials in stem cell-based therapy were noted as induction of structural and functional modifications, increased stem cell retention rate in the hostile ischemic microenvironment, and promoting the secretion of important cytokines for reparative mechanisms. CONCLUSION Biomaterials have a relatively high potential for enhancing stem cell therapy. Nonetheless, there is a scarcity of evidence from human clinical studies for the efficacy of this bioengineered cell therapy, highlighting that it is still too early to draw a definitive conclusion on efficacy and safety for patient usage. Future in-depth clinical investigations are necessary to realize translation of this therapy into a more conscientious and judicious evidence-based therapy for clinical application.

Stroke is a cerebrovascular disease, contributing to major morbidity and mortality worldwide, with significant clinical and socioeconomic burdens [1]. In Malaysia, stroke is ranked as the third leading cause of death after ischemic heart disease and pneumonia with an alarming rising trend [2]. There are two major types of strokes, namely ischemic stroke (IS) and haemorrhagic stroke. IS caused by thromboembolic occlusion of cerebral artery is the main type of stroke in Malaysia, in which it is comprised up to two-third of total reported stroke cases, as compared to the haemorrhagic stroke [3]. Main pathological events of brain ischemia include a series of biological reactions such as oxidative stress, inflammatory cytokine release, and ischemic-reperfusion injury, leading to cell apoptosis and irreversible neurological damage [4]. Up to date, recombinant tissue plasminogen activator (rt-PA) is still the gold standard drug approved by Food and Drug Administration (FDA) for the clinical treatment of IS [5]. However, due to its narrow therapeutic window (<4.5h), high re-incidence rate and short half-life (<5 min) [5], the application of rt-PA is limited [6]. Therefore, many researchers are exploring other therapeutic approaches to tackle this disease.    In recent years, increasing evidences have discovered the potential of natural compounds extracted from plants as a promising alternative strategy against IS. Among the potential plant that possess blood-brain barrier properties, an important characteristics as neuroprotective agent for neurological disorder is Oroxylum indicum [6]. It has been reported that O. indicum has a dominant active compound, namely as baicalein that are responsible in this plant’s biological activities [7]. Therefore, in this study, we aimed to evaluate the potential of baicalein extracted from the leaves of Oroxylum indicum to treat the diseases. Briefly, 10 male Sprague Dawley rats were used in this study (n=5). 50 mg/kg b.wt of baicalein was orally administered via oral gavage before and after induction of ischemic stroke by endothelin-1 (ET-1), while control group was given normal saline. Assessments of behavioral scoring using modified neurological severity score (mNSS) and infarct volume by 2,3,5-triphenyltetrazolium chloride (TTC) staining were evaluated as the endpoint of this study.   Results demonstrated that the oral administration of baicalein improved the behavioral scoring of rats in motor test (forelimb flexion and forelimb twisting), contralateral sensory test (paw-whiskers), motor coordination and balance function and reflex test (pinna, corneal, startle and tail reflex) within 24 h -72 h, indicating that the baicalein-treated rats exhibited faster recovery rate as compared to non-treated rats (Figure 1A-D). Such improvements were observed up to two weeks. In addition, histological assessment using TTC staining also revealed reduction of infarct volume in baicalein-treated rats as compared to control rats. However, the percentage of infarct volume to whole brain was not significantly different in both groups (Figure 2). The promising results displayed by baicalein might be contributed by its anti-inflammatory property. Several studies reported that baicalein, a type of flavonoid compound, are responsible in attenuation of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage and inhibit NF-kB activation [7,8]. LPS is the potent macrophage activator, while NF-kB is a transcription factor that can cause inflammatory cytokines release in various cell types [9, 10]. In summary, the present study demonstrates that oral administration of baicalein in ischemic stroke rats could be effectively addressed and improved behavioral scoring in treated rats as early as 24 h after baicalein treatment.