With an understanding of immunity in the tumor microenvironment, immunotherapy turns out to be a ... more With an understanding of immunity in the tumor microenvironment, immunotherapy turns out to be a powerful tool in the clinic to treat many cancers. The strategies applied in cancer immunotherapy mainly include blockade of immune checkpoints, adoptive transfer of engineered cells, such as T cells, natural killer cells, and macrophages, cytokine therapy, cancer vaccines, and oncolytic virotherapy. Many factors, such as product price, off-target side effects, immunosuppressive tumor microenvironment, and cancer cell heterogeneity, affect the treatment efficacy of immunotherapies against cancers. In addition, some treatments, such as chimeric antigen receptor (CAR) T cell therapy, are more effective in treating patients with lymphoma, leukemia, and multiple myeloma rather than solid tumors. To improve the efficacy of targeted immunotherapy and reduce off-target effects, delivery systems for immunotherapies have been developed in past decades using tools such as nanoparticles, hydrogel m...
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2021
The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells,... more The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells, the enhancement of Tregs-mediated trogocytosis that contribute delayed maturation of antigen presenting cell (APC), and the high Tregs/CD+8 ratio that maintained low threshold of CD+8 cells in the tumor microenvironment (TME); all represent the nuances in the immune evasive strategies of pancreatic ductal adenocarcinoma (PDAC). PDAC is the most aggressive type of pancreatic cancers characterized by poor prognosis and extremely low survivability. Over the years, fraternity of scientists have developed therapeutic agents that can bolster the capacity of the antitumor immunity, usually via the inhibition of immune checkpoints. While this immune checkpoint inhibition therapy represents one major jab from immunity to PDAC, this cancer remains highly resistant due to the acme of desmoplasia in its TME. In this review, we discuss the mechanisms of various checkpoint receptors/ligands axes that are relevant to the fitness of PDAC in its oncogenic ring. These checkpoints include PD-1, CTLA-4, ICOS, TIM-3, TIGIT, BTLA, BTN3A, and VISTA. In addition, we provided evidences that are relevant to the understanding of immune checkpoint inhibition, with extensive outline of immune checkpoint inhibitors that are critical to the treatment of PDAC. Finally, we discuss recently known intricacies of PDAC-mediated immunosuppression, and current advances in treatment options. Having realized that the overall scenario between PDAC and antitumor immunity is like the throwing of jabs in a ring, we therefore discuss future directions and prospect that can knock out PDAC in favor of immunity and humanity.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2021
The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells,... more The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells, the enhancement of Tregs-mediated trogocytosis that contribute delayed maturation of antigen presenting cell (APC), and the high Tregs/CD+8 ratio that maintained low threshold of CD+8 cells in the tumor microenvironment (TME); all represent the nuances in the immune evasive strategies of pancreatic ductal adenocarcinoma (PDAC). PDAC is the most aggressive type of pancreatic cancers characterized by poor prognosis and extremely low survivability. Over the years, fraternity of scientists have developed therapeutic agents that can bolster the capacity of the antitumor immunity, usually via the inhibition of immune checkpoints. While this immune checkpoint inhibition therapy represents one major jab from immunity to PDAC, this cancer remains highly resistant due to the acme of desmoplasia in its TME. In this review, we discuss the mechanisms of various checkpoint receptors/ligands axes that are relevant to the fitness of PDAC in its oncogenic ring. These checkpoints include PD-1, CTLA-4, ICOS, TIM-3, TIGIT, BTLA, BTN3A, and VISTA. In addition, we provided evidences that are relevant to the understanding of immune checkpoint inhibition, with extensive outline of immune checkpoint inhibitors that are critical to the treatment of PDAC. Finally, we discuss recently known intricacies of PDAC-mediated immunosuppression, and current advances in treatment options. Having realized that the overall scenario between PDAC and antitumor immunity is like the throwing of jabs in a ring, we therefore discuss future directions and prospect that can knock out PDAC in favor of immunity and humanity.
The evolutional development of the RNA translation process that leads to protein synthesis based ... more The evolutional development of the RNA translation process that leads to protein synthesis based on naturally occurring amino acids has its continuation via synthetic biology, the so-called rational bioengineering. Genetic code expansion (GCE) explores beyond the natural translational processes to further enhance the structural properties and augment the functionality of a wide range of proteins. Prokaryotic and eukaryotic ribosomal machinery have been proven to accept engineered tRNAs from orthogonal organisms to efficiently incorporate noncanonical amino acids (ncAAs) with rationally designed side chains. These side chains can be reactive or functional groups, which can be extensively utilized in biochemical, biophysical, and cellular studies. Genetic code extension offers the contingency of introducing more than one ncAA into protein through frameshift suppression, multi-site-specific incorporation of ncAAs, thereby increasing the vast number of possible applications. However, di...
The evolutional development of the RNA translation process that leads to protein synthesis based ... more The evolutional development of the RNA translation process that leads to protein synthesis based on naturally occurring amino acids has its continuation via synthetic biology, the so-called rational bioengineering. Genetic code expansion (GCE) explores beyond the natural translational processes to further enhance the structural properties and augment the functionality of a wide range of proteins. Prokaryotic and eukaryotic ribosomal machinery have been proven to accept engineered tRNAs from orthogonal organisms to efficiently incorporate noncanonical amino acids (ncAAs) with rationally designed side chains. These side chains can be reactive or functional groups, which can be extensively utilized in biochemical, biophysical, and cellular studies. Genetic code extension offers the contingency of introducing more than one ncAA into protein through frameshift suppression, multi-site-specific incorporation of ncAAs, thereby increasing the vast number of possible applications. However, di...
The release of cytochrome c into the cytoplasm via the mitochondrial membrane represents a signif... more The release of cytochrome c into the cytoplasm via the mitochondrial membrane represents a significant step in programmed cell death. Bcl-2 family proteins play a crucial role as they regulate mitochondrial membrane permeability to cytochrome c. Bfl-1 belongs to the antiapoptotic subfamily of Bcl-2 protein which forms inhibitory heterodimeric complex with Bid thereby preventing the role of Bid in the disruption of Bax/Bcl-XL and Bak/Bcl-XL heterodimeric assembly critical for Bax and Bak dimerization in membrane permeability to cytochrome c. This Bfl1 intracellular attitude connotes one major mechanism of cellular immortality in cancer cells. Other role played by Bfl-1 includes regulation of immunity, neutrophil development, maturation of B-cells and in post allergic mast cell. Cancer cells overexpress Bfl-1. Here, we hypothesize that cancer cells also overexpress Bid due to accumulated mutation but not to a threshold commensurate with the overexpressed Bfl-1. Therefore, using inhibi...
The release of cytochrome c into the cytoplasm via the mitochondrial membrane represents a signif... more The release of cytochrome c into the cytoplasm via the mitochondrial membrane represents a significant step in programmed cell death. Bcl-2 family proteins play a crucial role as they regulate mitochondrial membrane permeability to cytochrome c. Bfl-1 belongs to the antiapoptotic subfamily of Bcl-2 protein which forms inhibitory heterodimeric complex with Bid thereby preventing the role of Bid in the disruption of Bax/Bcl-XL and Bak/Bcl-XL heterodimeric assembly critical for Bax and Bak dimerization in membrane permeability to cytochrome c. This Bfl1 intracellular attitude connotes one major mechanism of cellular immortality in cancer cells. Other role played by Bfl-1 includes regulation of immunity, neutrophil development, maturation of B-cells and in post allergic mast cell. Cancer cells overexpress Bfl-1. Here, we hypothesize that cancer cells also overexpress Bid due to accumulated mutation but not to a threshold commensurate with the overexpressed Bfl-1. Therefore, using inhibi...
The invasiveness and low survivability on the part of patients associated with cancer continues t... more The invasiveness and low survivability on the part of patients associated with cancer continues to raise global concern. Different approaches have been used in the treatment and restoration of normalcy in cancer patients. However, most of the therapeutic strategies employed are challenged with high cost, low efficacy, high toxicity, and multiple side effects. In recent times, emergent studies have provided evidence that functional foods and their bioactive components serve roles as potential agents in the prevention and treatment of cancers. Moreover, global interest has focused on how this chemoprevention potential of functional foods can be explored as plant-based medicines for drug development. Although, the literature is replete with the mechanism of chemoprevention elicited by individual components of functional foods, there are limited reports on their overall anti-cancer mechanisms. Therefore, this systematic review aims to unify the anti-cancer mechanisms of functional foods...
The passage of time that evoke aging; the tilted redox balance that contribute oxidative entropy;... more The passage of time that evoke aging; the tilted redox balance that contribute oxidative entropy; the polarization of microglia cells that produce inflammatory phenotype; all represent the intricacies of CNS-dependent disease progression. Neurological diseases that result from CNS injury raise social concerns and the available therapeutic strategies are frustrated by low efficacy, high toxicity, and multiple side effects. However, emergent studies have shown the neuroprotective role of natural compounds - including chalcones - with high efficacy in the protection of CNS structures. These compounds reportedly demonstrate neurotrophic mechanism through the upregulation of neurotrophic factors, anti-apoptotic Bcl-2, and downregulation of Bax protein; anti-neuroinflammatory mechanism via the inhibition of neuroinflammatory pathways, attenuated secretion of pro-inflammatory cytokines, prevention of blood brain barrier (BBB) disruption, and protection against nerve senescence; antioxidant mechanism through the upregulation of Nrf2 activities, inhibition of Keap1, synthesis of antioxidant enzymes, and maintenance of high antioxidant/oxidant ratio. All these mechanisms represent chalcones' neuroprotective mechanisms. In this review, we highlight different pathways involved in CNS-related diseases and elucidate various mechanisms by which chalcones can perturb these shunts as a potential therapeutic modality.
The recent outcry in the search for direct keap1 inhibitors requires a quicker and more effective... more The recent outcry in the search for direct keap1 inhibitors requires a quicker and more effective drug discovery process which is an inherent property of the Computer Aided Drug Discovery (CADD) to bring drug candidates into the clinic for patient's use. This Keap1 (negative regulator of ARE master activator) is emerging as a therapeutic strategy to combat oxidative stress-orchestrated diseases. The advances in computer algorithm and compound databases require that we highlight the functionalities that this technology possesses that can be exploited to target Keap1-Nrf2 PPI. Therefore, in this review, we uncover the in silico approaches that had been exploited towards the identification of keap1 inhibition in the light of appropriate fitting with relevant amino acid residues, we found 3 and 16 other compounds that perfectly fit keap1 kelch pocket/domain. Our goal is to harness the parameters that could orchestrate keap1 surface druggability by utilizing hotspot regions for virtual fragment screening and identification of hotspot residues.
Diabetic nephropathy (DN) is a chronic complication of diabetes mellitus (DM) with approximately ... more Diabetic nephropathy (DN) is a chronic complication of diabetes mellitus (DM) with approximately 30-40% of patients with DM developing nephropathy, and it is the leading cause of end-stage renal diseases and diabetic morbidity. The pathogenesis of DN is primarily associated with irregularities in the metabolism of glucose and lipid leading to hyperglycemia-induced oxidative stress, which has been a major target together with blood pressure regulation in the control of DN progression. However, the regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a highly conserved protein kinase for maintaining energy balance and cellular growth and repair has been implicated in the development of DM and its complications. Therefore, targeting AMPK pathway has been explored as a therapeutic strategy for the treatment of diabetes and its complication, although most of the mechanisms have not been fully elucidated. In this review, we discuss the structure of AMPK relevant to understanding its allosteric regulation and its role in the pathogenesis and progression of DN. We also identify therapeutic agents that modulate AMPK and its downstream targets with their specific mechanisms of action in the treatment of DN.
Despite recent progresses in its treatment, malignant cutaneous melanoma remains a cancer with ve... more Despite recent progresses in its treatment, malignant cutaneous melanoma remains a cancer with very poor prognosis. Emerging evidences suggest that the receptor for advance glycation end products (RAGE) plays a key role in melanoma progression through its activation in both cancer and stromal cells. In tumors, RAGE activation is fueled by numerous ligands, S100B and HMGB1 being the most notable, but the role of many other ligands is not well understood and should not be underappreciated. Here, we provide a review of the current role of RAGE in melanoma and conclude that targeting RAGE in melanoma could be an approach to improve the outcomes of melanoma patients.
Snake venom metalloproteinases (SVMPs) represent a diverse group of multi-domain proteins with se... more Snake venom metalloproteinases (SVMPs) represent a diverse group of multi-domain proteins with several biological activities such as the ability to induce hemorrhage, proteolytic degradation of fibrinogen and fibrin, induction of apoptosis and inhibition of platelet aggregation. Due to these activities, SVMPs are responsible for many of the well-known pathological phenotypes in snake envenomations caused particularly by species from the Viperidae family and the Crotalinae subfamily. These proteins have been classified based on their size and domain structure into P-I, P-II and P-III classes. Comparatively, members of the P-I SVMPs possess the simplest structures, formed by the catalytic metalloproteinase domain only; the P-II SVMPs are moderately more complex, having the canonical disintegrin domain in addition to the metalloproteinase domain; members of the P-III class are more structurally varied, comprising the metalloproteinase, disintegrin-like, and cysteine-rich domains. Proteolytic cleavage, repeated domain loss and presence of other ancillary domains are responsible for structural diversities in the P-III class. However, studies continue to unveil the relationship between the structure and function of these proteins. In this review, we recovered evidences from literature on the structural peculiarities and functional classification of Snake Venom Metalloproteinases. In addition, we reflect on diversities that exist among each class while taking into account specific and up-to-date class-based activities.
With an understanding of immunity in the tumor microenvironment, immunotherapy turns out to be a ... more With an understanding of immunity in the tumor microenvironment, immunotherapy turns out to be a powerful tool in the clinic to treat many cancers. The strategies applied in cancer immunotherapy mainly include blockade of immune checkpoints, adoptive transfer of engineered cells, such as T cells, natural killer cells, and macrophages, cytokine therapy, cancer vaccines, and oncolytic virotherapy. Many factors, such as product price, off-target side effects, immunosuppressive tumor microenvironment, and cancer cell heterogeneity, affect the treatment efficacy of immunotherapies against cancers. In addition, some treatments, such as chimeric antigen receptor (CAR) T cell therapy, are more effective in treating patients with lymphoma, leukemia, and multiple myeloma rather than solid tumors. To improve the efficacy of targeted immunotherapy and reduce off-target effects, delivery systems for immunotherapies have been developed in past decades using tools such as nanoparticles, hydrogel m...
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2021
The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells,... more The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells, the enhancement of Tregs-mediated trogocytosis that contribute delayed maturation of antigen presenting cell (APC), and the high Tregs/CD+8 ratio that maintained low threshold of CD+8 cells in the tumor microenvironment (TME); all represent the nuances in the immune evasive strategies of pancreatic ductal adenocarcinoma (PDAC). PDAC is the most aggressive type of pancreatic cancers characterized by poor prognosis and extremely low survivability. Over the years, fraternity of scientists have developed therapeutic agents that can bolster the capacity of the antitumor immunity, usually via the inhibition of immune checkpoints. While this immune checkpoint inhibition therapy represents one major jab from immunity to PDAC, this cancer remains highly resistant due to the acme of desmoplasia in its TME. In this review, we discuss the mechanisms of various checkpoint receptors/ligands axes that are relevant to the fitness of PDAC in its oncogenic ring. These checkpoints include PD-1, CTLA-4, ICOS, TIM-3, TIGIT, BTLA, BTN3A, and VISTA. In addition, we provided evidences that are relevant to the understanding of immune checkpoint inhibition, with extensive outline of immune checkpoint inhibitors that are critical to the treatment of PDAC. Finally, we discuss recently known intricacies of PDAC-mediated immunosuppression, and current advances in treatment options. Having realized that the overall scenario between PDAC and antitumor immunity is like the throwing of jabs in a ring, we therefore discuss future directions and prospect that can knock out PDAC in favor of immunity and humanity.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2021
The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells,... more The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells, the enhancement of Tregs-mediated trogocytosis that contribute delayed maturation of antigen presenting cell (APC), and the high Tregs/CD+8 ratio that maintained low threshold of CD+8 cells in the tumor microenvironment (TME); all represent the nuances in the immune evasive strategies of pancreatic ductal adenocarcinoma (PDAC). PDAC is the most aggressive type of pancreatic cancers characterized by poor prognosis and extremely low survivability. Over the years, fraternity of scientists have developed therapeutic agents that can bolster the capacity of the antitumor immunity, usually via the inhibition of immune checkpoints. While this immune checkpoint inhibition therapy represents one major jab from immunity to PDAC, this cancer remains highly resistant due to the acme of desmoplasia in its TME. In this review, we discuss the mechanisms of various checkpoint receptors/ligands axes that are relevant to the fitness of PDAC in its oncogenic ring. These checkpoints include PD-1, CTLA-4, ICOS, TIM-3, TIGIT, BTLA, BTN3A, and VISTA. In addition, we provided evidences that are relevant to the understanding of immune checkpoint inhibition, with extensive outline of immune checkpoint inhibitors that are critical to the treatment of PDAC. Finally, we discuss recently known intricacies of PDAC-mediated immunosuppression, and current advances in treatment options. Having realized that the overall scenario between PDAC and antitumor immunity is like the throwing of jabs in a ring, we therefore discuss future directions and prospect that can knock out PDAC in favor of immunity and humanity.
The evolutional development of the RNA translation process that leads to protein synthesis based ... more The evolutional development of the RNA translation process that leads to protein synthesis based on naturally occurring amino acids has its continuation via synthetic biology, the so-called rational bioengineering. Genetic code expansion (GCE) explores beyond the natural translational processes to further enhance the structural properties and augment the functionality of a wide range of proteins. Prokaryotic and eukaryotic ribosomal machinery have been proven to accept engineered tRNAs from orthogonal organisms to efficiently incorporate noncanonical amino acids (ncAAs) with rationally designed side chains. These side chains can be reactive or functional groups, which can be extensively utilized in biochemical, biophysical, and cellular studies. Genetic code extension offers the contingency of introducing more than one ncAA into protein through frameshift suppression, multi-site-specific incorporation of ncAAs, thereby increasing the vast number of possible applications. However, di...
The evolutional development of the RNA translation process that leads to protein synthesis based ... more The evolutional development of the RNA translation process that leads to protein synthesis based on naturally occurring amino acids has its continuation via synthetic biology, the so-called rational bioengineering. Genetic code expansion (GCE) explores beyond the natural translational processes to further enhance the structural properties and augment the functionality of a wide range of proteins. Prokaryotic and eukaryotic ribosomal machinery have been proven to accept engineered tRNAs from orthogonal organisms to efficiently incorporate noncanonical amino acids (ncAAs) with rationally designed side chains. These side chains can be reactive or functional groups, which can be extensively utilized in biochemical, biophysical, and cellular studies. Genetic code extension offers the contingency of introducing more than one ncAA into protein through frameshift suppression, multi-site-specific incorporation of ncAAs, thereby increasing the vast number of possible applications. However, di...
The release of cytochrome c into the cytoplasm via the mitochondrial membrane represents a signif... more The release of cytochrome c into the cytoplasm via the mitochondrial membrane represents a significant step in programmed cell death. Bcl-2 family proteins play a crucial role as they regulate mitochondrial membrane permeability to cytochrome c. Bfl-1 belongs to the antiapoptotic subfamily of Bcl-2 protein which forms inhibitory heterodimeric complex with Bid thereby preventing the role of Bid in the disruption of Bax/Bcl-XL and Bak/Bcl-XL heterodimeric assembly critical for Bax and Bak dimerization in membrane permeability to cytochrome c. This Bfl1 intracellular attitude connotes one major mechanism of cellular immortality in cancer cells. Other role played by Bfl-1 includes regulation of immunity, neutrophil development, maturation of B-cells and in post allergic mast cell. Cancer cells overexpress Bfl-1. Here, we hypothesize that cancer cells also overexpress Bid due to accumulated mutation but not to a threshold commensurate with the overexpressed Bfl-1. Therefore, using inhibi...
The release of cytochrome c into the cytoplasm via the mitochondrial membrane represents a signif... more The release of cytochrome c into the cytoplasm via the mitochondrial membrane represents a significant step in programmed cell death. Bcl-2 family proteins play a crucial role as they regulate mitochondrial membrane permeability to cytochrome c. Bfl-1 belongs to the antiapoptotic subfamily of Bcl-2 protein which forms inhibitory heterodimeric complex with Bid thereby preventing the role of Bid in the disruption of Bax/Bcl-XL and Bak/Bcl-XL heterodimeric assembly critical for Bax and Bak dimerization in membrane permeability to cytochrome c. This Bfl1 intracellular attitude connotes one major mechanism of cellular immortality in cancer cells. Other role played by Bfl-1 includes regulation of immunity, neutrophil development, maturation of B-cells and in post allergic mast cell. Cancer cells overexpress Bfl-1. Here, we hypothesize that cancer cells also overexpress Bid due to accumulated mutation but not to a threshold commensurate with the overexpressed Bfl-1. Therefore, using inhibi...
The invasiveness and low survivability on the part of patients associated with cancer continues t... more The invasiveness and low survivability on the part of patients associated with cancer continues to raise global concern. Different approaches have been used in the treatment and restoration of normalcy in cancer patients. However, most of the therapeutic strategies employed are challenged with high cost, low efficacy, high toxicity, and multiple side effects. In recent times, emergent studies have provided evidence that functional foods and their bioactive components serve roles as potential agents in the prevention and treatment of cancers. Moreover, global interest has focused on how this chemoprevention potential of functional foods can be explored as plant-based medicines for drug development. Although, the literature is replete with the mechanism of chemoprevention elicited by individual components of functional foods, there are limited reports on their overall anti-cancer mechanisms. Therefore, this systematic review aims to unify the anti-cancer mechanisms of functional foods...
The passage of time that evoke aging; the tilted redox balance that contribute oxidative entropy;... more The passage of time that evoke aging; the tilted redox balance that contribute oxidative entropy; the polarization of microglia cells that produce inflammatory phenotype; all represent the intricacies of CNS-dependent disease progression. Neurological diseases that result from CNS injury raise social concerns and the available therapeutic strategies are frustrated by low efficacy, high toxicity, and multiple side effects. However, emergent studies have shown the neuroprotective role of natural compounds - including chalcones - with high efficacy in the protection of CNS structures. These compounds reportedly demonstrate neurotrophic mechanism through the upregulation of neurotrophic factors, anti-apoptotic Bcl-2, and downregulation of Bax protein; anti-neuroinflammatory mechanism via the inhibition of neuroinflammatory pathways, attenuated secretion of pro-inflammatory cytokines, prevention of blood brain barrier (BBB) disruption, and protection against nerve senescence; antioxidant mechanism through the upregulation of Nrf2 activities, inhibition of Keap1, synthesis of antioxidant enzymes, and maintenance of high antioxidant/oxidant ratio. All these mechanisms represent chalcones' neuroprotective mechanisms. In this review, we highlight different pathways involved in CNS-related diseases and elucidate various mechanisms by which chalcones can perturb these shunts as a potential therapeutic modality.
The recent outcry in the search for direct keap1 inhibitors requires a quicker and more effective... more The recent outcry in the search for direct keap1 inhibitors requires a quicker and more effective drug discovery process which is an inherent property of the Computer Aided Drug Discovery (CADD) to bring drug candidates into the clinic for patient's use. This Keap1 (negative regulator of ARE master activator) is emerging as a therapeutic strategy to combat oxidative stress-orchestrated diseases. The advances in computer algorithm and compound databases require that we highlight the functionalities that this technology possesses that can be exploited to target Keap1-Nrf2 PPI. Therefore, in this review, we uncover the in silico approaches that had been exploited towards the identification of keap1 inhibition in the light of appropriate fitting with relevant amino acid residues, we found 3 and 16 other compounds that perfectly fit keap1 kelch pocket/domain. Our goal is to harness the parameters that could orchestrate keap1 surface druggability by utilizing hotspot regions for virtual fragment screening and identification of hotspot residues.
Diabetic nephropathy (DN) is a chronic complication of diabetes mellitus (DM) with approximately ... more Diabetic nephropathy (DN) is a chronic complication of diabetes mellitus (DM) with approximately 30-40% of patients with DM developing nephropathy, and it is the leading cause of end-stage renal diseases and diabetic morbidity. The pathogenesis of DN is primarily associated with irregularities in the metabolism of glucose and lipid leading to hyperglycemia-induced oxidative stress, which has been a major target together with blood pressure regulation in the control of DN progression. However, the regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a highly conserved protein kinase for maintaining energy balance and cellular growth and repair has been implicated in the development of DM and its complications. Therefore, targeting AMPK pathway has been explored as a therapeutic strategy for the treatment of diabetes and its complication, although most of the mechanisms have not been fully elucidated. In this review, we discuss the structure of AMPK relevant to understanding its allosteric regulation and its role in the pathogenesis and progression of DN. We also identify therapeutic agents that modulate AMPK and its downstream targets with their specific mechanisms of action in the treatment of DN.
Despite recent progresses in its treatment, malignant cutaneous melanoma remains a cancer with ve... more Despite recent progresses in its treatment, malignant cutaneous melanoma remains a cancer with very poor prognosis. Emerging evidences suggest that the receptor for advance glycation end products (RAGE) plays a key role in melanoma progression through its activation in both cancer and stromal cells. In tumors, RAGE activation is fueled by numerous ligands, S100B and HMGB1 being the most notable, but the role of many other ligands is not well understood and should not be underappreciated. Here, we provide a review of the current role of RAGE in melanoma and conclude that targeting RAGE in melanoma could be an approach to improve the outcomes of melanoma patients.
Snake venom metalloproteinases (SVMPs) represent a diverse group of multi-domain proteins with se... more Snake venom metalloproteinases (SVMPs) represent a diverse group of multi-domain proteins with several biological activities such as the ability to induce hemorrhage, proteolytic degradation of fibrinogen and fibrin, induction of apoptosis and inhibition of platelet aggregation. Due to these activities, SVMPs are responsible for many of the well-known pathological phenotypes in snake envenomations caused particularly by species from the Viperidae family and the Crotalinae subfamily. These proteins have been classified based on their size and domain structure into P-I, P-II and P-III classes. Comparatively, members of the P-I SVMPs possess the simplest structures, formed by the catalytic metalloproteinase domain only; the P-II SVMPs are moderately more complex, having the canonical disintegrin domain in addition to the metalloproteinase domain; members of the P-III class are more structurally varied, comprising the metalloproteinase, disintegrin-like, and cysteine-rich domains. Proteolytic cleavage, repeated domain loss and presence of other ancillary domains are responsible for structural diversities in the P-III class. However, studies continue to unveil the relationship between the structure and function of these proteins. In this review, we recovered evidences from literature on the structural peculiarities and functional classification of Snake Venom Metalloproteinases. In addition, we reflect on diversities that exist among each class while taking into account specific and up-to-date class-based activities.
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Papers by Olamide Olaoba