Mycobacterium is acid fast genus of bacteria that include many pathogenic and non pathogenic spec... more Mycobacterium is acid fast genus of bacteria that include many pathogenic and non pathogenic species. Treatment is made quite difficult by the presence of metabolically silent, persistent or dormant bacteria within host lesions, which are not susceptible to the anti-mycobacteria drugs that usually kill growing bacteria but not persistent mycobacteria. The emergence of antibiotic resistance strains has raised the need towards the development of new antibiotics or drug molecules which can kill or suppress the growth of pathogenic Mycobacterium species. Novel efforts in developing drugs that target the intracellular metabolism of M. tuberculosis often focus on metabolic pathways that are specific to mycobacterium. Potential drug targets were also identified from pathways related to lipid metabolism, carbohydrate metabolism, amino acid metabolism, energy metabolism, vitamin and cofactor biosynthetic pathways and nucleotide metabolism. The objective this paper was to review those mycobacterium metabolic pathways as drug target and the problems of current TB drugs. The crucial problems of current TB therapy are development of multi-drug resistance and inefficiency of current TB drug to kill or inhibit non growing mycobacterium. The identification of drug target from that unique metabolism of mycobacterium is crucial to develop new drug for persistent and latent infection of tuberculosis. Despite an urgent need for new therapies targeting persistent bacteria, our knowledge of bacterial metabolism throughout the course of infection remains rudimentary. Therefore, better understanding on the physiology of mycobacterium during the latent period will help in the identification of new drug targets that can act on the persistent mycobacterium. Identification of these targets will to produce new drugs against tuberculosis that will overcome the limitations of existing drugs such as, prolonged chemotherapy, failure against persistent infection and multidrug resistance. INTRODUCTION The genus Mycobacterium comprises non pathogenic and pathogenic species that infect both humans and animals. The genus Mycobacterium encompasses 71 validly named species and 32 species are known to be pathogenic to humans or animals [1]. Tuberculosis is a mycobacterium infection that affects a wide range of mammals including humans. Mycobacterium tuberculosis is a tenacious and remarkably successful pathogen that has latently infected one third of the world population. Each year there are eight million of new tuberculosis (TB) cases and two million deaths [2]. M. bovis is the causative agent of bovine tuberculosis, a chronic and occasionally fatal infectious disease primarily infecting cattle and other livestock; but is capable of infecting a wide range of mammals and other vertebrates, including humans [3]. M. bovis is very closely related to M. tuberculosis, a virulent tubercle bacillus estimated to infect a third of the world's population and cause the deaths of 1.4 million people each year. In an attempt to prevent tuberculosis infections more than 3 billion individuals have been immunized with M. bovis BCG, a live attenuated derivative of M. bovis [4]. The increasing emergencies of drug resistance tuberculosis and immune compromising disease and allows latent infection to reactivate or render individual more susceptible to TB pose further challenges for effective control of the disease in human [5]. Ethiopia is one of the 27 high MDR-TB countries; it is ranked 15 th with more than 5000 estimated MDR-TB patients each year. According to the WHO report, the prevalence of MDR-TB has been 2.8% in newly diagnosed patients; it is reportedly even higher in patients who have previously received anti-TB treatment 21% [6]. Published studies on MDR-TB are increasingly available worldwide, but accurate data on drug-resistant TB in Ethiopia is limited [7]. Some recent study shows that a quarter of TB patients were having persistent TB clinical signs after receiving there commended drugs and duration of therapy. Most of the respondents were living in the rural community and they might not report early to health institutes in Ethiopia [8] Currently, TB chemotherapy is made up of a cocktail of first-line drugs; isoniazid (INH), rifampin (RIF), pyrazinamide (PZA) and ethambutol (EMB), given for six months [9, 10]. If the treatment fails as a result of bacterial drug resistance, or intolerance to one or more drugs, second-line drugs are used, such as para-aminosalicylate (PAS), kanamycin (KAN), fluoroquinolones (FQ), capreomycin (CAP), ethionamide (ETA) and cycloserine (CYS), that are generally either less effective or more toxic with serious side effects [9]. Agents with unclear roles in drug-resistant TB treatment are called third-line anti-TB drugs such as clofazimine, linezolid, amoxicillin/clavulanate, thioacetazone, and imipenem/cilastatin and high-dose isoniazid.
Journal of immunotherapy (Hagerstown, Md. : 1997), 2016
Bcl-2 family comprises proapoptotic and antiapoptotic proteins. The balance between these protein... more Bcl-2 family comprises proapoptotic and antiapoptotic proteins. The balance between these proteins is critical for the survival of the cells. Overexpression of the antiapoptotic protein, Bcl-2, is the hallmark of follicular lymphoma (FL). High expression of Bcl-2 provides survival advantage and may facilitate chemotherapeutic resistance in FL. In the present study, we examined expression profile of Bcl-2 family proteins such as Bcl-2, Bcl-xL, and Bim in human FL cell lines, HF1A3 and HF28. We assessed the correlation between the expression levels of these proteins and cells' sensitivity to dexamethasone (Dex)-mediated and B-cell receptor (BCR)-mediated apoptosis. Here, we show that Dex and anti-BCR-induced synergistic apoptosis which correlated with significant downregulation of Bcl-xL, inhibition of ERK1/2 phosphorylation and accumulation of nonphosphorylated Bim. However, HF28 cells were less sensitive than HF1A3 cells to Dex-induced and anti-BCR-induced apoptosis due to high ...
Germinal center (GC) B cells undergo apoptosis after B cell receptor (BCR) ligation, unless they ... more Germinal center (GC) B cells undergo apoptosis after B cell receptor (BCR) ligation, unless they receive CD40-mediated survival signal from helper T cells. In the present study, we used a human follicular lymphoma cell line HF1A3, as an in vitro model to study the selection process in germinal centers. We show here that BCR ligation led to immediate ERK1/2 activation and phosphorylations of its downstream targets, Bim EL/L and Bcl-2 (at Ser70) which resulted in short-term survival. On the other hand, during the late phase of BCR signaling, ERK1/2 phosphorylation was inhibited which resulted in apoptosis. In addition, CD40 signaling led to sustained ERK1/2 activation and up-regulation of Bcl-xL in BCR-primed HF1A3 GC B cells. In conclusion, MEK-ERK pathway and Bcl-2 family proteins are crucial players in BCR-mediated survival/apoptosis and CD40-mediated survival.
Despite the high potential of school water supply, sanitation and hygiene education to contribute... more Despite the high potential of school water supply, sanitation and hygiene education to contribute to the achievement of the Millennium Development Goals for water supply, sanitation and hygiene sector, water supply, sanitation and hygiene education is either missing or poorly grounded in most schools in Ethiopia. The objective of this study was to identify and evaluate the existing water supply, sanitation and hygiene situations and practices in all Kindergarten, primary and secondary schools in Shebedino Wereda with the aim of promoting and scaling-up best practices. The study design was community-based cross sectional assessment, which employed quantitative and qualitative methods. Data were collected using pre-tested structured questionnaires, topic guides and inspection formats. Graduating class environmental health students of Hawassa University, translators from local languages to Amharic or English together with the principal investigators participated in the data collection....
The addition of rituximab (RTX) to standard chemotherapy has improved the treatment of B-cell mal... more The addition of rituximab (RTX) to standard chemotherapy has improved the treatment of B-cell malignancies. We show here that RTX and dexamethasone (Dex) induced synergistic apoptosis in follicular lymphoma cell lines. However, apoptosis was delayed by RTX-induced early protective signaling. RTX-induced early signaling also decreased Dex-induced apoptosis and led to phosphorylation of ERK1/2, Bcl-2 (at serine 70) and phosphorylation/degradation of BimL/EL. All these events were prevented by the MEK inhibitor, UO126. Therefore, we suggest that RTX-induced ERK-mediated signaling events lead to protection from apoptosis during early signaling and that blocking of Bim and Bcl-2 phosphorylation might be used as a novel strategy for lymphoma treatment.
Bovine tuberculosis is a chronic infectious zoonotic disease of domestic animals and humans. It i... more Bovine tuberculosis is a chronic infectious zoonotic disease of domestic animals and humans. It is characterized by formation of granulomas in tissue especially the lungs, lymph nodes, liver, intestines and the kidneys. Mycobacterium bovis is the main etiological agent of BTB (Bovine tuberculosis) which is an acid fast staining bacterium due to waxy substance (mycolic acid) present in its bacterial cell wall. The bacteria can be transmitted by both aerogenous and enterogenous routes. In Ethiopia bovine tuberculosis is endemic and mostly transmitted to humans through ingestion of unpasteurized contaminated milk and contact with infected animals. Disease causes development of miliary tubercular lesions, chronic cough, obstructions of air passages and alimentary tract or blood vessels and enlargement of lymph nodes. A spectrum of Cell-Mediated Immune responses (CMI) predominate infection, projecting the role of macrophages and T-cell populations. In advanced stage, there is increased humoral response. Tuberculinization test, single intradermal test and comparative intradermal test, is the valuable delayed type hyper sensitivity test used for diagnosing TB in live animal, and used in TB eradication and for international trade. Vaccination of calves with attenuated bovine-strain of tuberculosis bacterium, known as Bacillus of Calmette and Guerin (BCG) and testing and culling are important measure in BTB control and prevention en-demic area like Ethiopia. It is important to pasteurize milk before human consumption to reduce public health risk.
Mycobacterium is acid fast genus of bacteria that include many pathogenic and non pathogenic spec... more Mycobacterium is acid fast genus of bacteria that include many pathogenic and non pathogenic species. Treatment is made quite difficult by the presence of metabolically silent, persistent or dormant bacteria within host lesions, which are not susceptible to the anti-mycobacteria drugs that usually kill growing bacteria but not persistent mycobacteria. The emergence of antibiotic resistance strains has raised the need towards the development of new antibiotics or drug molecules which can kill or suppress the growth of pathogenic Mycobacterium species. Novel efforts in developing drugs that target the intracellular metabolism of M. tuberculosis often focus on metabolic pathways that are specific to mycobacterium. Potential drug targets were also identified from pathways related to lipid metabolism, carbohydrate metabolism, amino acid metabolism, energy metabolism, vitamin and cofactor biosynthetic pathways and nucleotide metabolism. The objective this paper was to review those mycobacterium metabolic pathways as drug target and the problems of current TB drugs. The crucial problems of current TB therapy are development of multi-drug resistance and inefficiency of current TB drug to kill or inhibit non growing mycobacterium. The identification of drug target from that unique metabolism of mycobacterium is crucial to develop new drug for persistent and latent infection of tuberculosis. Despite an urgent need for new therapies targeting persistent bacteria, our knowledge of bacterial metabolism throughout the course of infection remains rudimentary. Therefore, better understanding on the physiology of mycobacterium during the latent period will help in the identification of new drug targets that can act on the persistent mycobacterium. Identification of these targets will to produce new drugs against tuberculosis that will overcome the limitations of existing drugs such as, prolonged chemotherapy, failure against persistent infection and multidrug resistance. INTRODUCTION The genus Mycobacterium comprises non pathogenic and pathogenic species that infect both humans and animals. The genus Mycobacterium encompasses 71 validly named species and 32 species are known to be pathogenic to humans or animals [1]. Tuberculosis is a mycobacterium infection that affects a wide range of mammals including humans. Mycobacterium tuberculosis is a tenacious and remarkably successful pathogen that has latently infected one third of the world population. Each year there are eight million of new tuberculosis (TB) cases and two million deaths [2]. M. bovis is the causative agent of bovine tuberculosis, a chronic and occasionally fatal infectious disease primarily infecting cattle and other livestock; but is capable of infecting a wide range of mammals and other vertebrates, including humans [3]. M. bovis is very closely related to M. tuberculosis, a virulent tubercle bacillus estimated to infect a third of the world's population and cause the deaths of 1.4 million people each year. In an attempt to prevent tuberculosis infections more than 3 billion individuals have been immunized with M. bovis BCG, a live attenuated derivative of M. bovis [4]. The increasing emergencies of drug resistance tuberculosis and immune compromising disease and allows latent infection to reactivate or render individual more susceptible to TB pose further challenges for effective control of the disease in human [5]. Ethiopia is one of the 27 high MDR-TB countries; it is ranked 15 th with more than 5000 estimated MDR-TB patients each year. According to the WHO report, the prevalence of MDR-TB has been 2.8% in newly diagnosed patients; it is reportedly even higher in patients who have previously received anti-TB treatment 21% [6]. Published studies on MDR-TB are increasingly available worldwide, but accurate data on drug-resistant TB in Ethiopia is limited [7]. Some recent study shows that a quarter of TB patients were having persistent TB clinical signs after receiving there commended drugs and duration of therapy. Most of the respondents were living in the rural community and they might not report early to health institutes in Ethiopia [8] Currently, TB chemotherapy is made up of a cocktail of first-line drugs; isoniazid (INH), rifampin (RIF), pyrazinamide (PZA) and ethambutol (EMB), given for six months [9, 10]. If the treatment fails as a result of bacterial drug resistance, or intolerance to one or more drugs, second-line drugs are used, such as para-aminosalicylate (PAS), kanamycin (KAN), fluoroquinolones (FQ), capreomycin (CAP), ethionamide (ETA) and cycloserine (CYS), that are generally either less effective or more toxic with serious side effects [9]. Agents with unclear roles in drug-resistant TB treatment are called third-line anti-TB drugs such as clofazimine, linezolid, amoxicillin/clavulanate, thioacetazone, and imipenem/cilastatin and high-dose isoniazid.
Journal of immunotherapy (Hagerstown, Md. : 1997), 2016
Bcl-2 family comprises proapoptotic and antiapoptotic proteins. The balance between these protein... more Bcl-2 family comprises proapoptotic and antiapoptotic proteins. The balance between these proteins is critical for the survival of the cells. Overexpression of the antiapoptotic protein, Bcl-2, is the hallmark of follicular lymphoma (FL). High expression of Bcl-2 provides survival advantage and may facilitate chemotherapeutic resistance in FL. In the present study, we examined expression profile of Bcl-2 family proteins such as Bcl-2, Bcl-xL, and Bim in human FL cell lines, HF1A3 and HF28. We assessed the correlation between the expression levels of these proteins and cells' sensitivity to dexamethasone (Dex)-mediated and B-cell receptor (BCR)-mediated apoptosis. Here, we show that Dex and anti-BCR-induced synergistic apoptosis which correlated with significant downregulation of Bcl-xL, inhibition of ERK1/2 phosphorylation and accumulation of nonphosphorylated Bim. However, HF28 cells were less sensitive than HF1A3 cells to Dex-induced and anti-BCR-induced apoptosis due to high ...
Germinal center (GC) B cells undergo apoptosis after B cell receptor (BCR) ligation, unless they ... more Germinal center (GC) B cells undergo apoptosis after B cell receptor (BCR) ligation, unless they receive CD40-mediated survival signal from helper T cells. In the present study, we used a human follicular lymphoma cell line HF1A3, as an in vitro model to study the selection process in germinal centers. We show here that BCR ligation led to immediate ERK1/2 activation and phosphorylations of its downstream targets, Bim EL/L and Bcl-2 (at Ser70) which resulted in short-term survival. On the other hand, during the late phase of BCR signaling, ERK1/2 phosphorylation was inhibited which resulted in apoptosis. In addition, CD40 signaling led to sustained ERK1/2 activation and up-regulation of Bcl-xL in BCR-primed HF1A3 GC B cells. In conclusion, MEK-ERK pathway and Bcl-2 family proteins are crucial players in BCR-mediated survival/apoptosis and CD40-mediated survival.
Despite the high potential of school water supply, sanitation and hygiene education to contribute... more Despite the high potential of school water supply, sanitation and hygiene education to contribute to the achievement of the Millennium Development Goals for water supply, sanitation and hygiene sector, water supply, sanitation and hygiene education is either missing or poorly grounded in most schools in Ethiopia. The objective of this study was to identify and evaluate the existing water supply, sanitation and hygiene situations and practices in all Kindergarten, primary and secondary schools in Shebedino Wereda with the aim of promoting and scaling-up best practices. The study design was community-based cross sectional assessment, which employed quantitative and qualitative methods. Data were collected using pre-tested structured questionnaires, topic guides and inspection formats. Graduating class environmental health students of Hawassa University, translators from local languages to Amharic or English together with the principal investigators participated in the data collection....
The addition of rituximab (RTX) to standard chemotherapy has improved the treatment of B-cell mal... more The addition of rituximab (RTX) to standard chemotherapy has improved the treatment of B-cell malignancies. We show here that RTX and dexamethasone (Dex) induced synergistic apoptosis in follicular lymphoma cell lines. However, apoptosis was delayed by RTX-induced early protective signaling. RTX-induced early signaling also decreased Dex-induced apoptosis and led to phosphorylation of ERK1/2, Bcl-2 (at serine 70) and phosphorylation/degradation of BimL/EL. All these events were prevented by the MEK inhibitor, UO126. Therefore, we suggest that RTX-induced ERK-mediated signaling events lead to protection from apoptosis during early signaling and that blocking of Bim and Bcl-2 phosphorylation might be used as a novel strategy for lymphoma treatment.
Bovine tuberculosis is a chronic infectious zoonotic disease of domestic animals and humans. It i... more Bovine tuberculosis is a chronic infectious zoonotic disease of domestic animals and humans. It is characterized by formation of granulomas in tissue especially the lungs, lymph nodes, liver, intestines and the kidneys. Mycobacterium bovis is the main etiological agent of BTB (Bovine tuberculosis) which is an acid fast staining bacterium due to waxy substance (mycolic acid) present in its bacterial cell wall. The bacteria can be transmitted by both aerogenous and enterogenous routes. In Ethiopia bovine tuberculosis is endemic and mostly transmitted to humans through ingestion of unpasteurized contaminated milk and contact with infected animals. Disease causes development of miliary tubercular lesions, chronic cough, obstructions of air passages and alimentary tract or blood vessels and enlargement of lymph nodes. A spectrum of Cell-Mediated Immune responses (CMI) predominate infection, projecting the role of macrophages and T-cell populations. In advanced stage, there is increased humoral response. Tuberculinization test, single intradermal test and comparative intradermal test, is the valuable delayed type hyper sensitivity test used for diagnosing TB in live animal, and used in TB eradication and for international trade. Vaccination of calves with attenuated bovine-strain of tuberculosis bacterium, known as Bacillus of Calmette and Guerin (BCG) and testing and culling are important measure in BTB control and prevention en-demic area like Ethiopia. It is important to pasteurize milk before human consumption to reduce public health risk.
Uploads
Papers by Jemal Adem