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Traumatic brain injury (TBI) is the leading cause of death and disability worldwide and has complicated underlying pathophysiology. Numerous TBI animal models have been developed over the past decade to effectively mimic the human TBI pathophysiology. These models are of mostly mammalian origin including rodents and non‐human primates. However, the mammalian models demanded higher costs and have lower throughput often limiting the progress in TBI research. Thus, this systematic review aims to discuss the potential benefits of non‐mammalian TBI models in terms of their face validity in resembling human TBI. Three databases were searched as follows: PubMed, Scopus, and Embase, for original articles relating to non‐mammalian TBI models, published between January 2010 and December 2019. A total of 29 articles were selected based on PRISMA model for critical appraisal. Zebrafish, both larvae and adult, was found to be the most utilized non‐mammalian TBI model in the current literature, followed by the fruit fly and roundworm. In conclusion, non‐mammalian TBI models have advantages over mammalian models especially for rapid, cost‐effective, and reproducible screening of effective treatment strategies and provide an opportunity to expedite the advancement of TBI research., Traumatic brain injury (TBI) perpetuates lifelong and dynamic effects on health and well‐being. Most of the animal models previously developed to study the TBI pathophysiology were focused mainly on mammalian animal model. Despite of all the contributions that they offered, these mammalian animal models have some drawback such as huge sample size needed and very costly which resulted in lengthy process of preclinical development phase with hindered reproducibility option. Hence, this systematic review gathered all the previous non‐mammalian animal model used in TBI research from January 2010 to December 2019 via 3 search engines which were Embase, Scopus, and PubMed. PRISMA method was chosen to select the research article for the discussion. The result shown on 3 popular species comprised of Danio rerio (zebrafish), Drosophila melanogaster (fruit fly), and Caenorhabditis elegans (roundworm). Criteria that were discussed were mainly on type of animal model, the functional findings, pathophysiological outcomes, and the limitation of the respective models. In conclusion, this non‐mammalian animal model provides more simplistic approach to bridge the knowledge gaps within TBI research and may shorten the preclinical process for the final findings on the outcome prevention and cure.

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.

Sphaeranthus indicus L. is a medicinal herb having widespread traditional uses for treating common ailments. The present research work aims to explore the in-depth phytochemical composition and in vitro reactivity of six different polarity solvents (methanol, n-hexane, benzene, chloroform, ethyl acetate, and n-butanol) extracts/fractions of S. indicus flowers. The phytochemical composition was accomplished by determining total bioactive contents, HPLC-PDA polyphenolic quantification, and UHPLC-MS secondary metabolomics. The reactivity of the phenolic compounds was tested through the following biochemical assays: antioxidant (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum, and metal chelation) and enzyme inhibition (AChE, BChE, α-glucosidase, α-amylase, urease, and tyrosinase) assays were performed. The methanol extract showed the highest values for phenolic (94.07 mg GAE/g extract) and flavonoid (78.7 mg QE/g extract) contents and was also the most active for α-glucosidase inhibition as well as radical scavenging and reducing power potential. HPLC-PDA analysis quantified rutin, naringenin, chlorogenic acid, 3-hydroxybenzoic acid, gallic acid, and epicatechin in a significant amount. UHPLC-MS analysis of methanol and ethyl acetate extracts revealed the presence of well-known phytocompounds; most of these were phenolic, flavonoid, and glycoside derivatives. The ethyl acetate fraction exhibited the highest inhibition against tyrosinase and urease, while the n-hexane fraction was most active for α-amylase. Moreover, principal component analysis highlighted the positive correlation between bioactive compounds and the tested extracts. Overall, S. indicus flower extracts were found to contain important phytochemicals, hence could be further explored to discover novel bioactive compounds that could be a valid starting point for future pharmaceutical and nutraceuticals applications.

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Metabolic reprogramming represents an important cancer hallmark in CRC. Reprogramming core metabolic pathways in cancer cells, such as glycolysis, glutaminolysis, oxidative phosphorylation, and lipid metabolism, is essential to increase energy production and biosynthesis of precursors required to support tumor initiation and progression. Accumulating evidence demonstrates that activation of oncogenes and loss of tumor suppressor genes regulate metabolic reprogramming through the downstream signaling pathways. Protein kinases, such as AKT and c-MYC, are the integral components that facilitate the crosstalk between signaling pathways and metabolic pathways in CRC. This review provides an insight into the crosstalk between signaling pathways and metabolic reprogramming in CRC. Targeting CRC metabolism could open a new avenue for developing CRC therapy by discovering metabolic inhibitors and repurposing protein kinase inhibitors/monoclonal antibodies.

Sphaeranthus indicus L. is a medicinal herb having widespread traditional uses for treating common ailments. The present research work aims to explore the in-depth phytochemical composition and in vitro reactivity of six different polarity solvents (methanol, n-hexane, benzene, chloroform, ethyl acetate, and n-butanol) extracts/fractions of S. indicus flowers. The phytochemical composition was accomplished by determining total bioactive contents, HPLC-PDA polyphenolic quantification, and UHPLC-MS secondary metabolomics. The reactivity of the phenolic compounds was tested through the following biochemical assays: antioxidant (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum, and metal chelation) and enzyme inhibition (AChE, BChE, α-glucosidase, α-amylase, urease, and tyrosinase) assays were performed. The methanol extract showed the highest values for phenolic (94.07 mg GAE/g extract) and flavonoid (78.7 mg QE/g extract) contents and was also the most active for α-glucosidase inhibition as well as radical scavenging and reducing power potential. HPLC-PDA analysis quantified rutin, naringenin, chlorogenic acid, 3-hydroxybenzoic acid, gallic acid, and epicatechin in a significant amount. UHPLC-MS analysis of methanol and ethyl acetate extracts revealed the presence of well-known phytocompounds; most of these were phenolic, flavonoid, and glycoside derivatives. The ethyl acetate fraction exhibited the highest inhibition against tyrosinase and urease, while the n-hexane fraction was most active for α-amylase. Moreover, principal component analysis highlighted the positive correlation between bioactive compounds and the tested extracts. Overall, S. indicus flower extracts were found to contain important phytochemicals, hence could be further explored to discover novel bioactive compounds that could be a valid starting point for future pharmaceutical and nutraceuticals applications.

Epilepsy is a devastating neurological condition exhibited by repeated spontaneous and unpredictable seizures afflicting around 70 million people globally. The basic pathophysiology of epileptic seizures is still elusive, reflecting an extensive need for further research. Developing a novel animal model is crucial in understanding disease mechanisms as well as in assessing the therapeutic target. Most of the pre-clinical epilepsy research has been focused on rodents. Nevertheless, zebrafish disease models are relevant to human disease pathophysiology hence are gaining increased attention nowadays. The current study for the very first time developed a pilocarpine-induced chronic seizure-like condition in adult zebrafish and investigated the modulation in several neuroinflammatory genes and neurotransmitters after pilocarpine exposures. Seizure score analysis suggests that compared to a single dose, repeated dose pilocarpine produces chronic seizure-like effects maintaining an average seizure score of above 2 each day for a minimum of 10 days. Compared to the single dose pilocarpine treated group, there was increased mRNA expression of HMGB1, TLR4, TNF-&alpha, IL-1, BDNF, CREB-1, and NPY, whereas decreased expression of NF-&kappa, B was upon the repeated dose of pilocarpine administration. In addition, the epileptic group demonstrates modulation in neurotransmitters levels such as GABA, Glutamate, and Acetylcholine. Moreover, proteomic profiling of the zebrafish brain from the normal and epileptic groups from LCMS/MS quantification detected 77 and 13 proteins in the normal and epileptic group respectively. Summing up, the current investigation depicted that chemically induced seizures in zebrafish demonstrated behavioral and molecular alterations similar to classical rodent seizure models suggesting the usability of adult zebrafish as a robust model to investigate epileptic seizures.

The morphology, size, and surface area of nanoparticles (NPs), with the existence of functional groups on their surface, contribute to the drug binding affinity, distribution of the payload in different organs, and targeting of a particular tumor for exerting effective antitumor activity in vivo. However, the inherent chemical structure of NPs causing unpredictable biodistribution with a toxic outcome still poses a serious challenge in clinical chemotherapy. In this study, carbonate apatite (CA), citrate-modified CA (CMCA) NPs, and &alpha, ketoglutaric acid-modified CA (&alpha, KAMCA) NPs were employed as carriers of anticancer drugs for antitumor, pharmacokinetic, and toxicological analysis in a murine breast cancer model. The results demonstrated almost five-fold enhanced tumor regression in the cyclophosphamide (CYP)-loaded &alpha, KAMCA NP-treated group compared to the group treated with CYP only. Also, NPs promoted much higher drug accumulation in blood and tumor in comparison with the drug injected without a carrier. In addition, doxorubicin (DOX)-loaded NPs exhibited less accumulation in the heart, indicating less potential myocardial toxicity in mice compared to free DOX. Our findings, thus, conclude that CA, CMCA, and &alpha, KAMCA NPs extended the circulation half-life and enhanced the anticancer effect with reduced toxicity of conventional chemotherapeutics in healthy organs, signifying that they are promising drug delivery devices in breast cancer treatment.

The aim of this study was to investigate the cytotoxic, antiproliferative activity and the induction of apoptosis by L-amino acid oxidase isolated from Calloselasma rhodostoma crude venom (CR-LAAO) on human colon cancer cells. CR-LAAO was purified using three chromatographic steps: molecular exclusion using G-50 gel filtration resin, ion-exchange by MonoQ column and desalted on a G25 column. The purity and identity of the isolated CR-LAAO was confirmed by SDS-PAGE and LC-MS/MS. CR-LAAO demonstrated time- and dose-dependent cytotoxic activity on SW480 (primary human colon cancer cells) and SW620 (metastatic human colon cancer cells) with an EC50 values of 6 μg/ml and 7 μg/ml at 48 hr, respectively. Quantification of apoptotic cells based on morphological features demonstrated significant increase in apoptotic cell population in both SW480 and SW620 cells which peaked at 48 hr. Significant increase in caspase-3 activity and reduction in Bcl-2 levels were demonstrated following CR-LAAO treatment. These data provide evidence on the potential anticancer activity of CR-LAAO from the venom of C. rhodostoma for therapeutic intervention of human colon cancer.

Acute kidney injury (AKI) following Eastern Russell’s viper (Daboia siamensis) envenoming is a significant symptom in systemically envenomed victims. A number of venom components have been identified as causing the nephrotoxicity which leads to AKI. However, the precise mechanism of nephrotoxicity caused by these toxins is still unclear. In the present study, we purified two proteins from D. siamensis venom, namely RvPLA2 and RvMP. Protein identification using LCMS/MS confirmed the identity of RvPLA2 to be snake venom phospholipase A2 (SVPLA2) from Thai D. siamensis venom, whereas RvMP exhibited the presence of a factor X activator with two subunits. In vitro and in vivo pharmacological studies demonstrated myotoxicity and histopathological changes of kidney, heart, and spleen. RvPLA2 (3–10 µg/mL) caused inhibition of direct twitches of the chick biventer cervicis muscle preparation. After administration of RvPLA2 or RvMP (300 µg/kg, i.p.) for 24 h, diffuse glomerular congestion and tubular injury with minor loss of brush border were detected in envenomed mice. RvPLA2 and RvMP (300 µg/kg, i.p.) also induced congestion and tissue inflammation of heart muscle as well as diffuse congestion of mouse spleen. This study showed the significant roles of PLA2 and SVMP in snake bite envenoming caused by Thai D. siamensis and their similarities with observed clinical manifestations in envenomed victims. This study also indicated that there is a need to reevaluate the current treatment strategies for Thai D. siamensis envenoming, given the potential for irreversible nephrotoxicity.

Alzheimer&rsquo, s disease (AD) is a chronic neurodegenerative brain disease that is characterized by impairment in cognitive functioning as well as the presence of intraneuronal neurofibrillary tangles (NFTs) and extracellular senile plaques. There is a growing interest in the potential of phytochemicals to improve memory, learning, and general cognitive abilities. The Malaysian herb Orthosiphon stamineus is a traditional remedy that possesses anti-inflammatory, anti-oxidant, and free-radical scavenging abilities, all of which are known to protect against AD. Previous studies have reported that intracerebroventricular (ICV) administration of streptozotocin (STZ) mimics a condition similar to that observed in AD. This experiment thus aimed to explore if an ethanolic leaf extract of O. stamineus has the potential to be a novel treatment for AD in a rat model and can reverse the STZ- induced learning and memory dysfunction. The results of this study indicate that O. stamineus has the potential to be potentially effective against AD-like condition, as both behavioral models employed in this study was observed to be able to reverse memory impairment. Treatment with the extract was able to decrease the up-regulated expression levels of amyloid precursor protein (APP), microtubule associated protein tau (MAPT), Nuclear factor kappa-light-chain-enhancer of activated B cells (NFᴋB), glycogen synthase kinase 3 alpha (GSK3&alpha, ), and glycogen synthase kinase 3 beta (GSK3&beta, ) genes indicating the extract&rsquo, s neuroprotective ability. These research findings suggest that the O. stamineus ethanolic extract demonstrated an improved effect on memory, and hence, could serve as a potential therapeutic target for the treatment of neurodegenerative diseases such as AD.

Malayan krait (Bungarus candidus) is a medically important snake species found in Southeast Asia. The neurotoxic effects of envenoming present as flaccid paralysis of skeletal muscles. It is unclear whether geographical variation in venom composition plays a significant role in the degree of clinical neurotoxicity. In this study, the effects of geographical variation on neurotoxicity and venom composition of B. candidus venoms from Indonesia, Malaysia and Thailand were examined. In the chick biventer cervicis nerve-muscle preparation, all venoms abolished indirect twitches and attenuated contractile responses to nicotinic receptor agonists, with venom from Indonesia displaying the most rapid neurotoxicity. A proteomic analysis indicated that three finger toxins (3FTx), phospholipase A2 (PLA2) and Kunitz-type serine protease inhibitors were common toxin groups in the venoms. In addition, venom from Thailand contained L-amino acid oxidase (LAAO), cysteine rich secretory protein (CRISP), thrombin-like enzyme (TLE) and snake venom metalloproteinase (SVMP). Short-chain post-synaptic neurotoxins were not detected in any of the venoms. The largest quantity of long-chain post-synaptic neurotoxins and non-conventional toxins was found in the venom from Thailand. Analysis of PLA2 activity did not show any correlation between the amount of PLA2 and the degree of neurotoxicity of the venoms. Our study shows that variation in venom composition is not limited to the degree of neurotoxicity. This investigation provides additional insights into the geographical differences in venom composition and provides information that could be used to improve the management of Malayan krait envenoming in Southeast Asia.