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Studies on Copper and Aβ1-16-Induced Conformational Changes in CAG/CTG Trinucleotide Repeats Sequence
Full text linkDNA conformation and stability are critical for the normal cell functions, which control many cellular processes in life, such as replication, transcription, DNA repair, etc. The accumulation of amyloid-β peptide (Aβ) and Copper (Cu) are the etiological factors for neurodegenerative diseases and hypothesized that they can cause DNA instability. In the current investigation, we studied copper and Aβ1-16 induced conformation and stability changes in CAG/CTG sequences and found alterations from B-DNA to altered B-conformation. Further, the interaction of the copper and Aβ1-16 with CAG/CTG sequences was studied by molecular docking modeling and results indicated that the interaction of copper and Aβ1-16 was through the hydrogen bond formation between adenine, guanine, and cytocine. This study illustrates the role of the copper and Aβ1-16 in modulating the DNA conformation and stability.DNA conformation and stability are critical for the normal cell functions, which control many cellular processes in life, such as replication, transcription, DNA repair, etc. The accumulation of amyloid-β peptide (Aβ) and Copper (Cu) are the etiological factors for neurodegenerative diseases and hypothesized that they can cause DNA instability. In the current investigation, we studied copper and Aβ1-16 induced conformation and stability changes in CAG/CTG sequences and found alterations from B-DNA to altered B-conformation. Further, the interaction of the copper and Aβ1-16 with CAG/CTG sequences was studied by molecular docking modeling and results indicated that the interaction of copper and Aβ1-16 was through the hydrogen bond formation between adenine, guanine, and cytocine. This study illustrates the role of the copper and Aβ1-16 in modulating the DNA conformation and stability
L-Asparaginase a Biotherapeutic for Acute Lymphoblastic Leukemia-A Molecular Perspective
Full text linkL-asparaginase (L-asparagine amino hydrolase) is an enzyme which was clinically proved as an antitumor agent to treat acute lymphoblastic leukemia. It catalyzes L-asparagine hydrolysis to L-aspartate and ammonia, and the depletion of asparagine causes cytotoxicity to leukemic cells. Microbial L-asparaginase (ASNase) production has attracted good attention regarding its cost effectiveness and ecofriendliness. The focus of this review is to provide a discussion regarding the microbial ASNase production, purification, its mechanism of action, sources, therapeutic side effects and focusing on the future prospects like protein engineering, recombinant microorganisms to develop a efficient therapeutics with significantly less side effects. This study is also focusing on the production of ASNases from new sources with improvement in the availability as a drug, and issues related to reducing the cost of the drug by improving the pharmacokinetics, pharmaco-dynamics and toxicological profiles in producing the ASNase enzyme.L-asparaginase (L-asparagine amino hydrolase) is an enzyme which was clinically proved as an antitumor agent to treat acute lymphoblastic leukemia. It catalyzes L-asparagine hydrolysis to L-aspartate and ammonia, and the depletion of asparagine causes cytotoxicity to leukemic cells. Microbial L-asparaginase (ASNase) production has attracted good attention regarding its cost effectiveness and ecofriendliness. The focus of this review is to provide a discussion regarding the microbial ASNase production, purification, its mechanism of action, sources, therapeutic side effects and focusing on the future prospects like protein engineering, recombinant microorganisms to develop a efficient therapeutics with significantly less side effects. This study is also focusing on the production of ASNases from new sources with improvement in the availability as a drug, and issues related to reducing the cost of the drug by improving the pharmacokinetics, pharmaco-dynamics and toxicological profiles in producing the ASNase enzyme
Compositions and methods for detecting mycobacterium
Full text linkThe present disclosure provides methods of detecting mycobacterium in an individual, generally involving detecting antibody to a mycobacterial lipid in a biological sample obtained from the individual. The present disclosure further provides compositions and kits for carrying out the methodsThe present disclosure provides methods of detecting mycobacterium in an individual, generally involving detecting antibody to a mycobacterial lipid in a biological sample obtained from the individual. The present disclosure further provides compositions and kits for carrying out the method
Ascertaining fetal Zika virus infection based on IgM antibody test in endemic settings
Full text linkFirst, the authors' rationale to include a Zika virus (ZIKV)‐specific IgM antibody test as part of the positive case definition, despite the test's cross‐reactivity with other Flavivirus infections and immunizations, is not clear. As described previously2, the levels of anti‐ZIKV IgM may appear elevated as a result of antibody cross‐reaction among viruses of the same family. A false‐positive result could therefore lead to misdiagnosis of an otherwise normal fetus. The International Society of Ultrasound in Obstetrics and Gynecology recommends the use of reverse transcription polymerase chain reaction (RT‐PCR) or consultation with an expert when interpreting ZIKV IgM positive results3. For example, studies in endemic populations in Colombia and Brazil did not include detection of ZIKV IgM antibodies for defining a positive case and instead used only RT‐PCR assays4, 5. Consequently, suggesting that a test for ZIKV IgM antibody alone is sufficient for diagnosing ZIKV would affect outcomes of clinical practice in endemic settings.First, the authors' rationale to include a Zika virus (ZIKV)‐specific IgM antibody test as part of the positive case definition, despite the test's cross‐reactivity with other Flavivirus infections and immunizations, is not clear. As described previously2, the levels of anti‐ZIKV IgM may appear elevated as a result of antibody cross‐reaction among viruses of the same family. A false‐positive result could therefore lead to misdiagnosis of an otherwise normal fetus. The International Society of Ultrasound in Obstetrics and Gynecology recommends the use of reverse transcription polymerase chain reaction (RT‐PCR) or consultation with an expert when interpreting ZIKV IgM positive results3. For example, studies in endemic populations in Colombia and Brazil did not include detection of ZIKV IgM antibodies for defining a positive case and instead used only RT‐PCR assays4, 5. Consequently, suggesting that a test for ZIKV IgM antibody alone is sufficient for diagnosing ZIKV would affect outcomes of clinical practice in endemic settings
Discovery, Semisynthesis, Antiparasitic and Cytotoxic Evaluation of 14-Membered Resorcylic Acid Lactones and Their Derivatives
Full text linkTen antifouling 14-membered resorcylic acid lactones 1–10 were isolated previously with low or trace natural abundance from the zoanthid-derived Cochliobolus lunatus fungus. Further optimization of fermentation conditions led to the isolation of two major natural compounds 7 and 8 with multi-gram quantities. By one or two steps, we semisynthesized the six trace natural compounds 1–6 and a series of derivatives 11–27 of compounds 7 and 8 with high yields (65–95%). Compounds 11–13 showed strong antiplasmodial activity against Plasmodium falciparum with IC50 values of 1.84, 8.36, and 6.95 μM, respectively. Very importantly, 11 and 12 were non-toxic with very safety and high therapeutic indices (CC50/IC50 > 180), and thus representing potential promising leads for antiplasmodial drug discovery. Furthermore, 11 was the only compound showed obvious antileishmanial activity against Leishmania donovani with an IC50 value of 9.22 μM. Compounds 11 and 12 showed the values of IC50 at 11.9 and 17.2 μM against neglected Chagas’ disease causing Trypanosoma cruzi, respectively.Ten antifouling 14-membered resorcylic acid lactones 1–10 were isolated previously with low or trace natural abundance from the zoanthid-derived Cochliobolus lunatus fungus. Further optimization of fermentation conditions led to the isolation of two major natural compounds 7 and 8 with multi-gram quantities. By one or two steps, we semisynthesized the six trace natural compounds 1–6 and a series of derivatives 11–27 of compounds 7 and 8 with high yields (65–95%). Compounds 11–13 showed strong antiplasmodial activity against Plasmodium falciparum with IC50 values of 1.84, 8.36, and 6.95 μM, respectively. Very importantly, 11 and 12 were non-toxic with very safety and high therapeutic indices (CC50/IC50 > 180), and thus representing potential promising leads for antiplasmodial drug discovery. Furthermore, 11 was the only compound showed obvious antileishmanial activity against Leishmania donovani with an IC50 value of 9.22 μM. Compounds 11 and 12 showed the values of IC50 at 11.9 and 17.2 μM against neglected Chagas’ disease causing Trypanosoma cruzi, respectively
Assessment of Novel Curcumin Derivatives as Potent Inhibitors of Inflammation and Amyloid-β Aggregation in Alzheimer's Disease
Full text linkAlzheimer's disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Brain inflammation plays a key role in the progression of AD. Deposition of senile plaques in the brain stimulates an inflammatory response with the overexpression of pro-inflammatory mediators, such as the neuroinflammatory cytokine. interleukin-6. Curcumin has been revealed to be a potential agent for treating AD following different neuroprotective mechanisms, such as inhibition of aggregation and decrease in brain inflammation. We synthesized new curcumin derivatives with the aim of providing good anti-aggregation capacity but also improved anti-inflammatory activity. Nine curcumin derivatives were synthesized by etherification and esterification of the aromatic region. From these derivatives, compound 8 exhibited an anti-inflammatory effect similar to curcumin, while compounds 3, 4, and 10 were more potent. Moreover, when the anti-aggregation activity is considered, compounds 3, 4, 5, 6, and 10 showed biological activity in vitro. Compound 4 exhibited a strong anti-aggregation effect higher than curcumin. Monofunctionalized curcumin derivatives showed better bioactivity than difunctionalized compounds. Moreover, the presence of bulky groups in the chemical structure of curcumin derivatives decreased bioactivity.Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Brain inflammation plays a key role in the progression of AD. Deposition of senile plaques in the brain stimulates an inflammatory response with the overexpression of pro-inflammatory mediators, such as the neuroinflammatory cytokine. interleukin-6. Curcumin has been revealed to be a potential agent for treating AD following different neuroprotective mechanisms, such as inhibition of aggregation and decrease in brain inflammation. We synthesized new curcumin derivatives with the aim of providing good anti-aggregation capacity but also improved anti-inflammatory activity. Nine curcumin derivatives were synthesized by etherification and esterification of the aromatic region. From these derivatives, compound 8 exhibited an anti-inflammatory effect similar to curcumin, while compounds 3, 4, and 10 were more potent. Moreover, when the anti-aggregation activity is considered, compounds 3, 4, 5, 6, and 10 showed biological activity in vitro. Compound 4 exhibited a strong anti-aggregation effect higher than curcumin. Monofunctionalized curcumin derivatives showed better bioactivity than difunctionalized compounds. Moreover, the presence of bulky groups in the chemical structure of curcumin derivatives decreased bioactivity
American trypanosomiasis, or Chagas disease, in Panama: a chronological synopsis of ecological and epidemiological research
Full text linkAmerican trypanosomiasis, or Chagas disease, is a growing public health problem in Panama, and further forest degradation due to human population growth is expected to worsen the situation. Most people infected with the parasite Trypanosoma cruzi are silently ill, and their life expectancy is severely compromised, which contributes to further deterioration of living conditions in endemic regions. Here, we review the outcomes of nearly 100 years of ecological and epidemiological investigation about Chagas disease in Panama, in an attempt to highlight progress, identify needs, and re-orient future efforts. Rhodnius pallescens and Triatoma dimidiata are both primary vectors of T. cruzi in Panama, but R. pallescens seems more efficient in human-altered forest ecosystems due to a greater degree of association with Attalea butyracea. In contrast, T. dimidiata transmits T. cruzi efficiently under more sylvatic conditions (e.g. settlements inside old-growth or secondary forest patches), where its populations reach considerable numbers irrespective of the absence of A. butyracea. A trend of increasing forest degradation, suburbanization, and development of tourism in Panama favoring the establishment of A. butyracea and other palm tree species (Acrocomia sp.) suggests that a colonist species like R. pallescens will continue to play a more prominent role in the transmission of T. cruzi than a forest specialist like T. dimidiata. However, studies about the taxonomic status and ecology of these vectors are still needed in Panama to address their transmission potential fully. The implementation of an active surveillance system and education programs could greatly minimize the risk of Chagas disease transmission in Panama, preventing fatal infections in children from endemic areasAmerican trypanosomiasis, or Chagas disease, is a growing public health problem in Panama, and further forest degradation due to human population growth is expected to worsen the situation. Most people infected with the parasite Trypanosoma cruzi are silently ill, and their life expectancy is severely compromised, which contributes to further deterioration of living conditions in endemic regions. Here, we review the outcomes of nearly 100 years of ecological and epidemiological investigation about Chagas disease in Panama, in an attempt to highlight progress, identify needs, and re-orient future efforts. Rhodnius pallescens and Triatoma dimidiata are both primary vectors of T. cruzi in Panama, but R. pallescens seems more efficient in human-altered forest ecosystems due to a greater degree of association with Attalea butyracea. In contrast, T. dimidiata transmits T. cruzi efficiently under more sylvatic conditions (e.g. settlements inside old-growth or secondary forest patches), where its populations reach considerable numbers irrespective of the absence of A. butyracea. A trend of increasing forest degradation, suburbanization, and development of tourism in Panama favoring the establishment of A. butyracea and other palm tree species (Acrocomia sp.) suggests that a colonist species like R. pallescens will continue to play a more prominent role in the transmission of T. cruzi than a forest specialist like T. dimidiata. However, studies about the taxonomic status and ecology of these vectors are still needed in Panama to address their transmission potential fully. The implementation of an active surveillance system and education programs could greatly minimize the risk of Chagas disease transmission in Panama, preventing fatal infections in children from endemic area
Discovery, Semisynthesis, Antiparasitic and Cytotoxic Evaluation of 14-Membered Resorcylic Acid Lactones and Their Derivatives
Full text linkTen antifouling 14-membered resorcylic acid lactones 1–10 were isolated previously with low or trace natural abundance from the zoanthid-derived Cochliobolus lunatus fungus. Further optimization of fermentation conditions led to the isolation of two major natural compounds 7 and 8 with multi-gram quantities. By one or two steps, we semisynthesized the six trace natural compounds 1–6 and a series of derivatives 11–27 of compounds 7 and 8 with high yields (65–95%). Compounds 11–13 showed strong antiplasmodial activity against Plasmodium falciparum with IC50 values of 1.84, 8.36, and 6.95μM, respectively. Very importantly, 11 and 12 were non-toxic with very safety and high therapeutic indices (CC50/IC50>180), and thus representing potential promising leads for antiplasmodial drug discovery. Furthermore, 11 was the only compound showed obvious antileishmanial activity against Leishmania donovani with an IC50 value of 9.22μM. Compounds 11 and 12 showed the values of IC50 at 11.9 and 17.2μM against neglected Chagas’ disease causing Trypanosoma cruzi, respectivelyTen antifouling 14-membered resorcylic acid lactones 1–10 were isolated previously with low or trace natural abundance from the zoanthid-derived Cochliobolus lunatus fungus. Further optimization of fermentation conditions led to the isolation of two major natural compounds 7 and 8 with multi-gram quantities. By one or two steps, we semisynthesized the six trace natural compounds 1–6 and a series of derivatives 11–27 of compounds 7 and 8 with high yields (65–95%). Compounds 11–13 showed strong antiplasmodial activity against Plasmodium falciparum with IC50 values of 1.84, 8.36, and 6.95μM, respectively. Very importantly, 11 and 12 were non-toxic with very safety and high therapeutic indices (CC50/IC50>180), and thus representing potential promising leads for antiplasmodial drug discovery. Furthermore, 11 was the only compound showed obvious antileishmanial activity against Leishmania donovani with an IC50 value of 9.22μM. Compounds 11 and 12 showed the values of IC50 at 11.9 and 17.2μM against neglected Chagas’ disease causing Trypanosoma cruzi, respectivel
Comparative study between open and laparoscopic ventral hernia repair: A prospective non-randomized single institutional study
Full text linkIntroduction: In this modern era of surgery, laparoscopic surgery has gained paramount importance. There is continued debate on the role of laparoscopy in ventral hernia repair. Although laparoscopic repair has become increasingly popular, its outcomes need further evaluation. This is a prospective study designed to compare open ventral hernia repair with laparoscopic repair.
Materials and Methods: This study included patients who consented for midline ventral hernia operation at our institution from October 2013 to April 2015; data on relevant history, clinical examination, and appropriate investigations were collected. A total of 81 patients were operated after obtaining written consent. A total of 51 patients underwent open mesh repair whereas 31 underwent laparoscopic intra peritoneal mesh repair. The statistical software namely SPSS 15.0, MedCalc 9.0.1 were used.
Results: In the open group, majority were incisional hernias; in the laparoscopy group, majority were umbilical hernia. Age distribution and mean duration of surgery was comparable in both the groups. Significant decrease in postoperative pain, overall complication rate, length of hospital stay, and return to normal activity was noted in the laparoscopy group (P < 0.001). There were no cases of mesh infection or recurrence with a mean follow-up of 12 months.
Conclusion: Laparoscopic ventral hernia repair holds a promising alternative to novel repair and the short-term results are encouraging. The technique is a little sophisticated and needs experience when compared to open repair.Introduction: In this modern era of surgery, laparoscopic surgery has gained paramount importance. There is continued debate on the role of laparoscopy in ventral hernia repair. Although laparoscopic repair has become increasingly popular, its outcomes need further evaluation. This is a prospective study designed to compare open ventral hernia repair with laparoscopic repair.
Materials and Methods: This study included patients who consented for midline ventral hernia operation at our institution from October 2013 to April 2015; data on relevant history, clinical examination, and appropriate investigations were collected. A total of 81 patients were operated after obtaining written consent. A total of 51 patients underwent open mesh repair whereas 31 underwent laparoscopic intra peritoneal mesh repair. The statistical software namely SPSS 15.0, MedCalc 9.0.1 were used.
Results: In the open group, majority were incisional hernias; in the laparoscopy group, majority were umbilical hernia. Age distribution and mean duration of surgery was comparable in both the groups. Significant decrease in postoperative pain, overall complication rate, length of hospital stay, and return to normal activity was noted in the laparoscopy group (P < 0.001). There were no cases of mesh infection or recurrence with a mean follow-up of 12 months.
Conclusion: Laparoscopic ventral hernia repair holds a promising alternative to novel repair and the short-term results are encouraging. The technique is a little sophisticated and needs experience when compared to open repair
Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015
Full text linkBackground Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development.
Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specifi c mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specifi c death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE diff ered from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate.Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development.
Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specifi c mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specifi c death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE diff ered from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate