Clinically, gliomas are classified into four grades, with grade IV glioblastoma multiforme being the most malignant and deadly, which accounts for 50% of all gliomas. Characteristically, glioblastoma involves the aggressive proliferation of cells and invasion of normal brain tissue, outcomes as poor patient prognosis. With the current standard therapy of glioblastoma; surgical resection and radiotherapy followed by adjuvant chemotherapy with temozolomide, it remains fatal, because of the development of drug resistance, tumor recurrence, and metastasis. Therefore, the need for the effective therapeutic option for glioblastoma remains elusive. Previous studies have demonstrated the chemopreventive role of naturally occurring pharmacological agents through preventing or reversing the initiation phase of carcinogenesis or arresting the cancer progression phase. In this review, we discuss the role of natural phytochemicals in the amelioration of glioblastoma, with the aim to improve therapeutic outcomes, and minimize the adverse side effects to improve patient's prognosis and enhancing their quality of life.
Depression is an incapacitating neuropsychiatric disorder. The serotonergic system in the brain plays an important role in the pathophysiology of depression. However, due to delayed and/or poor performance of selective serotonin reuptake inhibitors in treating depressive symptoms, the role of the serotonergic system in depression has been recently questioned further. Evidence from recent studies suggests that increased inflammation and oxidative stress may play significant roles in the pathophysiology of depression. The consequences of these factors can lead to the neuroprogression of depression, involving neurodegeneration, astrocytic apoptosis, reduced neurogenesis, reduced plasticity (neuronal and synaptic), and enhanced immunoreactivity. Specifically, increased proinflammatory cytokine levels have been shown to activate the kynurenine pathway, which causes increased production of quinolinic acid (QA, an N-Methyl-D-aspartate agonist) and decreases the synthesis of serotonin. QA exerts many deleterious effects on the brain via mechanisms including N-methyl-D-aspartate excitotoxicity, increased oxidative stress, astrocyte degeneration, and neuronal apoptosis. QA may also act directly as a pro-oxidant. Additionally, the nuclear translocation of antioxidant defense factors, such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2), is downregulated in depression. Hence, in the present review, we discuss the role of QA in increasing oxidative stress in depression by modulating the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 and thus affecting the synthesis of antioxidant enzymes.
Despite their low incidence rate globally, high-grade gliomas (HGG) remain a fatal primary brain tumor. The recommended therapy often is incapable of resecting the tumor entirely and exclusively targeting the tumor leads to tumor recurrence and dismal prognosis. Additionally, many HGG patients are not well suited for standard therapy and instead, subjected to a palliative approach. HGG tumors are highly infiltrative and the complex tumor microenvironment as well as high tumor heterogeneity often poses the main challenges towards the standard treatment. Therefore, a one-fit-approach may not be suitable for HGG management. Thus, a multimodal approach of standard therapy with immunotherapy, nanomedicine, repurposing of older drugs, use of phytochemicals, and precision medicine may be more advantageous than a single treatment model. This multimodal approach considers the environmental and genetic factors which could affect the patient's response to therapy, thus improving their outcome. This review discusses the current views and advances in potential HGG therapeutic approaches and, aims to bridge the existing knowledge gap that will assist in overcoming challenges in HGG.
Spinal cord injuries (SCIs) are a common form of trauma that leaves a huge trail of morbidity and human suffering in its wake. They occur mostly among the young, causing severe physical, psychological, social and economic burdens. The treatment of this condition has rather been disappointing; most of the management strategies being mainly supportive and prophylactic. In recent years there has been an emerging interest in the use of stem cells to regenerate the nervous tissue that has been damaged or lost. Although there has been much hype and unfounded hope, modest successes have been witnessed, and it is possible that these therapeutic strategies may have much more to offer in the future. This paper will review the current strategies of exploring cell-based therapies, mainly different types of stem cells to treat SCI along with the evidence that has been accumulated over the past decade in a rational bench-to-bedside approach. Furthermore, critical aspects such as the mode of delivery and ethical considerations are also discussed along with feasible suggestions for future translational research to provide a contextual picture of the current state of advancements in this field. The impediments to regeneration in the site of injury are briefly explained along with the benefits and drawbacks of different cell types used in the treatment of this condition. We hope that this review will offer a significant insight into this challenging clinical condition.
Despite numerous advancements in the last decade, human gliomas such as astrocytoma and glioblastoma multiforme have the worst prognoses among all cancers. Anti-psychotic drugs are commonly prescribed to treat mental disorders among cancer patients, and growing empirical evidence has revealed their antitumor, anti-metastatic, anti-angiogenic, anti-proliferative, chemo-preventive, and neo-adjuvant efficacies in various in vitro, in vivo, and clinical glioma models. Anti-psychotic drugs have drawn the attention of physicians and researchers owing to their beneficial effects in the prevention and treatment of gliomas. This review highlights data on the therapeutic potential of various anti-psychotic drugs as anti-proliferative, chemopreventive, and anti-angiogenic agents in various glioma models via the modulation of upstream and downstream molecular targets involved in apoptosis, autophagy, oxidative stress, inflammation, and the cell cycle in in vitro and in vivo preclinical and clinical stages among glioma patients. The ability of anti-psychotic drugs to modulate various signaling pathways and multidrug resistance-conferring proteins that enhance the efficacy of chemotherapeutic drugs with low side-effects exemplifies their great potential as neo-adjuvants and potential chemotherapeutics in single or multimodal treatment approach. Moreover, anti-psychotic drugs confer the ability to induce glioma into oligodendrocyte-like cells and neuronal-like phenotype cells with reversal of epigenetic alterations through inhibition of histone deacetylase further rationalize their use in glioma treatment. The improved understanding of anti-psychotic drugs as potential chemotherapeutic drugs or as neo-adjuvants will provide better information for their use globally as affordable, well-tolerated, and effective anticancer agents for human glioma.
Growing evidence showed the increased prevalence of cancer incidents, particularly colorectal cancer, among type 2 diabetic mellitus patients. Antidiabetic medications such as, insulin, sulfonylureas, dipeptyl peptidase (DPP) 4 inhibitors and glucose-dependent insulinotropic peptide (GLP-1) analogues increased the additional risk of different cancers to diabetic patients. Conversely, metformin has drawn attention among physicians and researchers since its use as antidiabetic drug exhibited beneficial effect in the prevention and treatment of cancer in diabetic patients as well as an independent anticancer drug. This review aims to provide the comprehensive information on the use of metformin at preclinical and clinical stages among colorectal cancer patients. We highlight the efficacy of metformin as an anti-proliferative, chemopreventive, apoptosis inducing agent, adjuvant, and radio-chemosensitizer in various colorectal cancer models. This multifarious effects of metformin is largely attributed to its capability in modulating upstream and downstream molecular targets involved in apoptosis, autophagy, cell cycle, oxidative stress, inflammation, metabolic homeostasis, and epigenetic regulation. Moreover, the review highlights metformin intake and colorectal cancer risk based on different clinical and epidemiologic results from different gender and specific population background among diabetic and non-diabetic patients. The improved understanding of metformin as a potential chemotherapeutic drug or as neo-adjuvant will provide better information for it to be used globally as an affordable, well-tolerated, and effective anticancer agent for colorectal cancer.
The role of steroid/thyroid hormones in the regulation of endocrine cells at the level of the pituitary has remained unclear. Therefore, using single-cell quantitative real-time PCR, we examined absolute amounts of transcripts for nuclear receptors [estrogen receptors (ERs) alpha, beta, and gamma; androgen receptors (ARs) a and b; glucocorticoid receptors (GRs) 1, 2a, and 2b; and thyroid hormone receptors (TRs) alpha1, alpha2, and beta] in pituitary cells of immature (IM) and mature (M) male tilapia, Oreochromis niloticus. In the two reproductive stages, ACTH cells expressed only ERbeta, whereas all other pituitary cell types expressed ERalpha + beta, and a subpopulation coexpressed ARa, ARb, GR1, GR2b, and TRbeta but lacked ERgamma, GR2a, TRalpha1, and TRalpha2. IM males had high percentages of LH cells (IM 46.0% vs. M 10.0%), GH cells (IM 23.3% vs. M 7.9%), and prolactin cells (IM 68.8% vs. M 6.0%) with ERbeta, and TSH cells (IM 19.2% vs. M 0.0%) and MSH cells (IM 25.6% vs. M 0.0%) with ERalpha + TRbeta. A high percentage of FSH cells in IM males expressed ERbeta (IM 46.9% vs. M 18.8%), and FSH cells in M males showed significantly high GR1 transcripts (IM 76.0 +/- 5.0 vs. M 195.0 +/- 10.7 copies per cell; P < 0.05), suggesting that FSH cells are regulated differently in the two reproductive stages. Coexpression of ERalpha + beta in high percentages of cells of the GH family (GH, IM 43.8% vs. M 14.3%; prolactin, IM 8.3% vs. M 59.7%; somatolactin, IM 22.2% vs. M 42.2%) suggests that the expression of both ERs is important for functionality. Thus, differential coexpression of genes for nuclear receptors in subpopulations of pituitary cell types suggests multiple steroid/thyroid hormone regulatory pathways at the level of the pituitary during the two reproductive stages.
Stress is an important aspect of our everyday life and exposure to it is an unavoidable occurrence. In humans, this can come in the form of social stress or physical stress from an injury. Studies in animal models have helped researchers to understand the body's adaptive response to stress in human. Notably, the use of behavioural tests in animal models plays a pivotal role in understanding the neural, endocrine and behavioural changes induced by social stress. Under socially stressed conditions, behavioural parameters are often measured physiological and molecular parameters as changes in behaviour are direct responses to stress and are easily assessed by behavioural tests. Throughout the past few decades, the rodent model has been used as a well-established animal model for stress and behavioural changes. Recently, more attention has been drawn towards using fish as an animal model. Common fish models such as zebrafish, medaka, and African cichlids have the advantage of a higher rate of reproduction, easier handling techniques, sociability and most importantly, share evolutionary conserved genetic make-up, neural circuitry, neuropeptide molecular structure and function with mammalian species. In fact, some fish species exhibit a clear diurnal or seasonal rhythmicity in their stress response, similar to humans, as opposed to rodents. Various social stress models have been established in fish including but not limited to chronic social defeat stress, social stress avoidance, and social stress-related decision-making. The huge variety of behavioural patterns in teleost also aids in the study of more behavioural phenotypes than the mammalian species. In this review, we focus on the use of fish models as alternative models to study the effects of stress on different types of behaviours. Finally, fish behavioural tests against the typical mammalian model-based behavioural test are compared and discussed for their viability.
Spexin (SPX) is a novel neuropeptide, which was first identified in the human genome using bioinformatics. Since then, orthologs of human SPX have been identified in mammalian and non-mammalian vertebrates. The mature sequence of SPX, NWTPQAMLYLKGAQ, is evolutionally conserved across vertebrate species, with some variations in teleost species where Ala at position 13 is substituted by Thr. In mammals, the gene structure of SPX comprises six exons and five introns, however, variation exists within non-mammalian species, goldfish and zebrafish having five exons while grouper has six exons. Phylogenetic and synteny analysis, reveal that SPX is grouped together with two neuropeptides, kisspeptin (KISS) and galanin (GAL) as a family of peptides with a common evolutionary ancestor. A paralog of SPX, termed SPX2 has been identified in non-mammalians but not in the mammalian genome. Ligand-receptor interaction study also shows that SPX acts as a ligand for GAL receptor 2 (2a and 2b in non-mammalian vertebrates) and 3. SPX acts as a neuromodulator with multiple central and peripheral physiological roles in the regulation of insulin release, fat metabolism, feeding behavior, and reproduction. Collectively, this review provides a comprehensive overview of the evolutionary diversity as well as molecular and physiological roles of SPX in mammalian and non-mammalian vertebrate species.
Serotonin (5-HT) is a key regulator of mood and sexual behaviors. 5-HT reuptake inhibitors have been used as antidepressants. Really interesting new gene (RING) finger proteins have been associated with 5-HT regulation but their role remains largely unknown. Some RING finger proteins are involved in the serotonergic system, therefore, we speculate that the gene expression of RING finger protein38 (rnf38) is regulated by the serotonergic system. In the present study, we aimed to identify the full length sequence of medaka (Oryzias latipes) rnf38 mRNA and investigate its association with the serotonergic system using an antidepressant, citalopram (CIT). We identified the full length rnf38 cDNA, which consisted of 2726 nucleotides spanning 12 exons and the deduced protein sequence consisting of 518 amino acid residues including a RING finger domain, a KIT motif and a coiled-coil domain. Medaka exposed to 10(-7)M of CIT showed anxiety-like behavior. The expressions of 5-HT-related genes, pet1, solute carrier family 6, member 4A (slc6a4) and tryptophan hydroxylase (tph2) were significantly low (P<0.05) in the hindbrain. On the other hand, rnf38 gene was significantly high (P<0.05) in the telencephalon and the hypothalamus. This shows that 5-HT synthesis and transport in the hindbrain is suppressed by CIT, which induces rnf38 gene expression in the forebrain where 5-HT neurons project. Thus, the expression of rnf38 is negatively regulated by the serotonergic system.
Gonadotropin-releasing hormone (GnRH) is a reproductive neuropeptide, which controls vertebrate reproduction. In most vertebrates, there are more than two GnRH orthologs in the brain. In cichlid fish, the Nile tilapia (Oreochromis niloticus), GnRH1 is the primary hypophysiotropic hormone, while GnRH2 and GnRH3 are non-hypophysiotropic but neuromodulatory in function. Hypophysiotropic GnRH neurons are thought to inter-communicate, while it remains unknown if hypophysiotropic and non-hypophysiotropic GnRH systems communicate with each other. In the present study, we examined interrelationship between three GnRH types using specific antibodies raised against their respective GnRH associated peptide (GAP) sequence. Double-immunofluorescence labeling coupled with confocal microscopy revealed that in sexually mature males, GnRH-GAP1-immunoreactive (-ir) processes are in proximities of GnRH-GAP3-ir cell somata in the terminal nerve, while GnRH-GAP1-ir cell somata were also accompanied by GnRH-GAP3-ir processes in the preoptic area. However, such interaction was not seen in immature males. Further, there was no interaction between GnRH-GAP2 and GnRH-GAP1 or GnRH-GAP3 neurons. Single cell gene expression analysis revealed co-expression of multiple GnRH receptor genes (gnrhr1 and gnrhr2) in three GnRH-GAP cell types. In mature males, high levels of gnrhr2 mRNA were expressed in GnRH-GAP1-ir cells. In immature males, gnrhr1 and gnrhr2 mRNAs are highly expressed in GnRH-GAP3-ir cells. These results suggest heterologous interactions between the three GnRH-GAP cell types and their potential functional interaction during different reproductive stages.
Hypothalamic gonadotropin-releasing hormone (GnRH) is a key hormone for reproductive functions in vertebrates and non-vertebrates. Although GnRH neuronal system is regulated by several factors such as steroids, neurotransmitters and neuropeptides, it is not fully understood how environmental signals control the GnRH neuronal system. RFamide peptides, members of peptides possessing an Arg-Phe-NH(2) motif at their C-terminus, have recently been characterized as major regulators of GnRH neurons. In particular, two key RFamide peptides, kisspeptin and gonadotropin-inhibitory hormone (GnIH), are emerging as important regulators of the reproductive axis. Kisspeptin acts as the accelerator, directly driving GnRH neurons, whereas GnIH acts as the restraint. In addition, other RFamide peptides such as prolactin-releasing peptide (PrRP), PQRFa peptide, 26RFa/QRFP are also known to control reproduction. These RFamide peptides are regulated by environmental factors such as photoperiods, steroid hormones, metabolic signals, and stress. How environmental signals are integrated by RFamide peptides to regulate reproduction through the GnRH neurons?
In addition to reproduction, gonadotropin-releasing hormone (GnRH) has been postulated to control cholesterol metabolism via cholesterol transport, which is carried out partly by the members of ATP-binding cassette (ABC) transporters G1 (ABCG1) and G4 (ABCG4). However, there is yet to be evidence demonstrating the relationship between these transporters with reference to GnRH neurons. In the present study, we cloned two ABCG1 messenger RNA (mRNA) variants and one ABCG4 mRNA and examined their expression in the brain including GnRH neurons (GnRH1, GnRH2, and GnRH3) in the cichlid tilapia (Oreochromis niloticus). Comparison of nucleotide sequences of the tilapia ABCG1 and ABCG4 with that of other fish species showed that both of these genes are evolutionarily conserved among fishes. ABCG1 and ABCG4 were shown to have high mRNA expressions in the CNS, pituitary, and gonads. In the brain, real-time polymerase chain reaction (PCR) showed that ABCG4 mRNA was higher than ABCG1a in all brain regions including the olfactory bulb (ABCG1=13.34, ABCG4=6796.35; P<0.001), dorsal telencephalon (ABCG1=8.64, ABCG4=10149.13; P=0.001), optic tectum (ABCG1=22.12, ABCG4=13931.04; P<0.01), cerebellum (ABCG1=8.68, ABCG4=12382.90; P<0.01), and preoptic area-midbrain-hypothalamus (ABCG1=21.36, ABCG4=13255.41; P=0.001). Similarly, although ABCG1 mRNA level is much higher in the pituitary compared with the brain, it was still significantly lower compared with ABCG4 (ABCG1=337.73, ABCG4=1157.87; P=0.01). The differential pattern of expression of ABCG1 and ABCG4 in the brain versus pituitary suggests that the two transporters are regulated by different mechanisms. Furthermore, ABCG1 and ABCG4 mRNA expressions were found in all three types of laser-captured GnRH neurons with highly similar percentage of expressions, suggesting that cholesterol efflux from GnRH neurons may require heterodimerization of both ABCG1 and ABCG4.
The phasic emotion, fear, and the tonic emotion, anxiety, have been conventionally inspected in clinical frameworks to epitomize memory acquisition, storage, and retrieval. However, inappropriate expression of learned fear in a safe environment and its resistance to suppression is a cardinal feature of various fear-related disorders. A significant body of literature suggests the involvement of extra-amygdala circuitry in fear disorders. Consistent with this view, the present review underlies incentives for the association between the habenula and fear memory. G protein-coupled receptors (GPCRs) are important to understand the molecular mechanisms central to fear learning due to their neuromodulatory role. The efficacy of a pharmacological strategy aimed at exploiting habenular-GPCR desensitization machinery can serve as a therapeutic target combating the pathophysiology of fear disorders. Originating from this milieu, the conserved nature of orphan GPCRs in the brain, with some having the highest expression in the habenula can lead to recent endeavors in understanding its functionality in fear circuitry.
G-protein coupled receptor 139 (GPR139) is an evolutionarily conserved orphan receptor, predominantly expressing in the habenula of vertebrate species. The habenula has recently been implicated in aversive response and its associated learning. Here, we tested the hypothesis that GPR139 signalling in the habenula may play a role in fear learning in the zebrafish. We examined the effect of intraperitoneal injections of a human GPR139-selective agonist (JNJ-63533054) on alarm substance-induced fear learning using conditioned place avoidance paradigm, where an aversive stimulus is paired with one compartment, while its absence is associated with the other compartment of the apparatus. The results indicate that fish treated with 1 µg/g body weight of GPR139 agonist displayed no difference in locomotor activity and alarm substance-induced fear response. However, avoidance to fear-conditioned compartment was diminished, which suggests that the agonist blocks the consolidation of contextual fear memory. On the other hand, fish treated with 0.1 µg/g body weight of GPR139 agonist spent a significantly longer time in the unconditioned neutral compartment as compared to the conditioned (punished and unpunished) compartments. These results suggest that activation of GPR139 signalling in the habenula may be involved in fear learning and the decision-making process in the zebrafish.
Glioblastoma (GBM), a grade IV brain tumor, is known for its heterogenicity and its resistance to the current treatment regimen. Over the last few decades, a significant amount of new molecular and genetic findings has been reported regarding factors contributing to GBM's development into a lethal phenotype and its overall poor prognosis. MicroRNA (miRNAs) are small non-coding sequences of RNA that regulate and influence the expression of multiple genes. Many research findings have highlighted the importance of miRNAs in facilitating and controlling normal biological functions, including cell differentiation, proliferation, and apoptosis. Furthermore, miRNAs' ability to initiate and promote cancer development, directly or indirectly, has been shown in many types of cancer. There is a clear association between alteration in miRNAs expression in GBM's ability to escape apoptosis, proliferation, and resistance to treatment. Further, miRNAs regulate the already altered pathways in GBM, including P53, RB, and PI3K-AKT pathways. Furthermore, miRNAs also contribute to autophagy at multiple stages. In this review, we summarize the functions of miRNAs in GBM pathways linked to dysregulation of cell cycle control, apoptosis and resistance to treatment, and the possible use of miRNAs in clinical settings as treatment and prediction biomarkers.
The hypothalamic neurohormone kisspeptin-10 (KP-10) was inherently implicated in cholinergic pathologies when aberrant fluctuations of expression patterns and receptor densities were discerned in neurodegenerative micromilieus. That said, despite variable degrees of functional redundancy, KP-10, which is biologically governed by its cognate G-protein-coupled receptor, GPR54, attenuated the progressive demise of α-synuclein (α-syn)-rich cholinergic-like neurons. Under explicitly modeled environments, in silico algorithms further rationalized the surface complementarities between KP-10 and α-syn when KP-10 was unambiguously accommodated in the C-terminal binding pockets of α-syn. Indeed, the neuroprotective relevance of KP-10's binding mechanisms can be insinuated in the amelioration of α-syn-mediated neurotoxicity; yet it is obscure whether these extenuative circumstances are contingent upon prior GPR54 activation. Herein, choline acetyltransferase (ChAT)-positive SH-SY5Y neurons were engineered ad hoc to transiently overexpress human wild-type or E46K mutant α-syn while the mitigation of α-syn-induced neuronal death was ascertained via flow cytometric and immunocytochemical quantification. Recapitulating the specificity observed on cell viability, exogenously administered KP-10 (0.1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated apoptosis and mitochondrial depolarization in cholinergic differentiated neurons. In particular, co-administrations with a GPR54 antagonist, kisspeptin-234 (KP-234), failed to abrogate the robust neuroprotection elicited by KP-10, thereby signifying a GPR54 dispensable mechanism of action. Consistent with these observations, KP-10 treatment further diminished α-syn and ChAT immunoreactivity in neurons overexpressing wild-type and E46K mutant α-syn. Overall, these findings lend additional credence to the previous notion that KP-10's binding zone may harness efficacious moieties of neuroprotective intent.
Dementia with Lewy bodies (DLB) is epitomized by the pathognomonic manifestation of α-synuclein-laden Lewy bodies within selectively vulnerable neurons in the brain. By virtue of prion-like inheritance, the α-synuclein protein inexorably undergoes extensive conformational metamorphoses and culminate in the form of fibrillar polymorphs, instigating calamitous damage to the brain's neuropsychological networks. This epiphenomenon is nebulous, however, by lingering uncertainty over the quasi "pathogenic" behavior of α-synuclein conformers in DLB pathobiology. Despite numerous attempts, a monolithic "α-synuclein" paradigm that is able to untangle the enigma enshrouding the clinicopathological spectrum of DLB has failed to emanate. In this article, we review conceptual frameworks of α-synuclein dependent cell-autonomous and non-autonomous mechanisms that are likely to facilitate the transneuronal spread of degeneration through the neuraxis. In particular, we describe how the progressive demise of susceptible neurons may evolve from cellular derangements perpetrated by α-synuclein misfolding and aggregation. Where pertinent, we show how these bona fide mechanisms may mutually accentuate α-synuclein-mediated neurodegeneration in the DLB brain.
Neuropsychiatric disorders (NPDs) exert a devastating impact on an individual's personal and social well-being, encompassing various conditions and brain anomalies that influence affect, cognition, and behavior. Because the pathophysiology of NPDs is multifactorial, the precise mechanisms underlying the development of such disorders remain unclear, representing a unique challenge in current neuropsychopharmacotherapy. Transient receptor potential vanilloid (TRPV) type channels are a family of ligand-gated ion channels that mainly include sensory receptors that respond to thermal, mechanical and chemical stimuli. TRPV channels are abundantly present in dopaminergic neurons, thus playing a pivotal role in the modulation of the reward system and in pathophysiology of diseases such as stress, anxiety, depression, schizophrenia, neurodegenerative disorders and substance abuse/addiction. Recent evidence has highlighted TRPV channels as potential targets for understanding modulation of the reward system and various forms of addiction (opioids, cocaine, amphetamines, alcohol, nicotine, cannabis). In this review, we discuss the distribution, physiological roles, ligands and therapeutic importance of TRPV channels with regard to NPDs and addiction biology.