Showing papers by "Al-Quds University published in 2021"

Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease 2020(COVID-19) in Palestine: A Report of 200 Cases

Abstract: Purpose: Prove that Computed Tomography (CT) is a more effective diagnostic tool for diagnosing Coronavirus Disease 2019 (COVID-19) in comparison with Reverse Transcription Polymerase Chain Reaction (RT-PCR) due to its higher sensitivity. Methods and materials: A total of 200 cases that had records of chest CT scans and RT-PCR tests were collected from Palestinian governmental hospitals from September to November 2020. Results: CT indicated COVID-19 in 62.5% of sample population (125 of 200) whereas RT-PCR indicated COVID-19 in 37.5% (75 of 200) cases. A P-value of 0.028 signifies the existence of a relationship between gender and CT sensitivity. Conclusion: High resolution computed tomography (HRCT) of the chest is a more rapid, sensitive, and effective tool than the current gold standard (RT-PCR); therefore, should be considered a primary diagnostic method for COVID-19.

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight

Abstract: From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.

Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses.

Abstract: For thousands of years, Cannabis sativa has been utilized as a medicine and for recreational and spiritual purposes. Phytocannabinoids are a family of compounds that are found in the cannabis plant, which is known for its psychotogenic and euphoric effects; the main psychotropic constituent of cannabis is Δ9-tetrahydrocannabinol (Δ9-THC). The pharmacological effects of cannabinoids are a result of interactions between those compounds and cannabinoid receptors, CB1 and CB2, located in many parts of the human body. Cannabis is used as a therapeutic agent for treating pain and emesis. Some cannabinoids are clinically applied for treating chronic pain, particularly cancer and multiple sclerosis-associated pain, for appetite stimulation and anti-emesis in HIV/AIDS and cancer patients, and for spasticity treatment in multiple sclerosis and epilepsy patients. Medical cannabis varies from recreational cannabis in the chemical content of THC and cannabidiol (CBD), modes of administration, and safety. Despite the therapeutic effects of cannabis, exposure to high concentrations of THC, the main compound that is responsible for most of the intoxicating effects experienced by users, could lead to psychological events and adverse effects that affect almost all body systems, such as neurological (dizziness, drowsiness, seizures, coma, and others), ophthalmological (mydriasis and conjunctival hyperemia), cardiovascular (tachycardia and arterial hypertension), and gastrointestinal (nausea, vomiting, and thirst), mainly associated with recreational use. Cannabis toxicity in children is more concerning and can cause serious adverse effects such as acute neurological symptoms (stupor), lethargy, seizures, and even coma. More countries are legalizing the commercial production and sale of cannabis for medicinal use, and some for recreational use as well. Liberalization of cannabis laws has led to increased incidence of toxicity, hyperemesis syndrome, lung disease cardiovascular disease, reduced fertility, tolerance, and dependence with chronic prolonged use. This review focuses on the potential therapeutic effects of cannabis and cannabinoids, as well as the acute and chronic toxic effects of cannabis use on various body systems.

Determinants of persistent post-COVID-19 symptoms: value of a novel COVID-19 symptom score

Abstract: Being a newly emerging disease, little is known about its long-lasting post-COVID-19 consequences. The aim of this work is to assess the frequency, patterns, and determinants of persistent post-COVID-19 symptoms and to evaluate the value of a proposed novel COVID-19 symptom score. Patients with confirmed COVID-19 in a hospital-based registry were included in a cross-sectional study (the hospitals including Assiut University Hospital, Assiut Chest Hospital, Aswan University Hospital, and Aswan Specialized Hospital). The patient demographics, comorbid disorders, the mean duration since the onset of the symptoms, history of hospital or ICU admittance, and the treatment taken during the acute state, as well as symptom score before and after convalescence, were recorded. The most frequent constitutional and neurological symptoms were myalgia (60.0%), arthralgia (57.2%), restriction of daily activities (57.0%), and sleeping troubles (50.9%), followed by anorexia (42.6%), chest pain (32.6%), gastritis (32.3%), cough (29.3%), and dyspnea (29.1%). The mean total score of acute stage symptoms was 31.0 ± 16.3 while post-COVID 19 symptom score was 13.1 ± 12.6 (P 18 to predict occurrence of post-COVID-19 symptoms. COVID-19 can present with a diverse spectrum of long-term post-COVID-19 symptoms. Increased acute phase symptom severity and COVID-19 symptom score > 18 together with the presence of any comorbid diseases increase the risk for persistent post-COVID-19 manifestations and severity.

Recent advances in waste-recycled nanomaterials for biomedical applications: Waste-to-wealth

Abstract: Global overpopulation, industrial expansion, and urbanization have generated massive amounts of wastes. This is considered as a significant worldwide challenge that requires an urgent solution. Additionally, remarkable advances in the field of biomedicine have impacted the entire spectrum of healthcare and medicine. This has paved the way for further refining of the outcomes of biomedical strategies toward early detection and treatment of different diseases. Various nanomaterials (NMs) have been dedicated to different biomedical applications including drug delivery, vaccinations, imaging modalities, and biosensors. However, toxicity is still the main factor restricting their use. NMs recycled from different types of wastes present a pioneering approach to not only avoid hazardous effects on the environment, but to also implement circular economy practices, which are crucial to attain sustainable growth. Moreover, recycled NMs have been utilized as a safe, yet revolutionary alternative with outstanding potential for many biomedical applications. This review focuses on waste recycled NMs, their synthesis, properties, and their potential for multiple biomedical applications with special emphasis on their role in the early detection and control of multiple diseases. Their pivotal therapeutic actions as antimicrobial, anticancer, antioxidant nanodrugs, and vaccines will also be outlined. The ongoing advancements in the design of recycled NMs are expanding their diagnostic and therapeutic roles for diverse biomedical applications in the era of precision medicine.

Effects of Social Media Use on Psychological Well-Being: A Mediated Model.

Abstract: The growth in social media use has given rise to concerns about the impacts it may have on users' psychological well-being. This paper's main objective is to shed light on the effect of social media use on psychological well-being. Building on contributions from various fields in the literature, it provides a more comprehensive study of the phenomenon by considering a set of mediators, including social capital types (i.e., bonding social capital and bridging social capital), social isolation, and smartphone addiction. The paper includes a quantitative study of 940 social media users from Mexico, using structural equation modeling (SEM) to test the proposed hypotheses. The findings point to an overall positive indirect impact of social media usage on psychological well-being, mainly due to the positive effect of bonding and bridging social capital. The empirical model's explanatory power is 45.1%. This paper provides empirical evidence and robust statistical analysis that demonstrates both positive and negative effects coexist, helping to reconcile the inconsistencies found so far in the literature.

Classification, Toxicity and Bioactivity of Natural Diterpenoid Alkaloids.

Abstract: Diterpenoid alkaloids are natural compounds having complex structural features with many stereo-centres originating from the amination of natural tetracyclic diterpenes and produced primarily from plants in the Aconitum, Delphinium, Consolida genera. Corals, Xenia, Okinawan/Clavularia, Alcyonacea (soft corals) and marine sponges are rich sources of diterpenoids, despite the difficulty to access them and the lack of availability. Researchers have long been concerned with the potential beneficial or harmful effects of diterpenoid alkaloids due to their structural complexity, which accounts for their use as pharmaceuticals as well as their lousy reputation as toxic substances. Compounds belonging to this unique and fascinating family of natural products exhibit a broad spectrum of biological activities. Some of these compounds are on the list of clinical drugs, while others act as incredibly potent neurotoxins. Despite numerous attempts to prepare synthetic products, this review only introduces the natural diterpenoid alkaloids, describing ‘compounds’ structures and classifications and their toxicity and bioactivity. The purpose of the review is to highlight some existing relationships between the presence of substituents in the structure of such molecules and their recognised bioactivity.

Knowledge and attitudes among dental students about COVID-19 and its precautionary measures: A cross-sectional study

Abstract: Objective: This study aims to evaluate students' knowledge and attitudes about COVID-19 and its precautionary measures. Methods: A cross-sectional study was conducted among dental students in their clinical practice years in two Palestinian universities. An online questionnaire was sent out using students' in mid-May, 2020. The questionnaire assessed students self-reported knowledge about the COVID-19, and students' attitudes towards providing clinical care during the pandemic. Results : A total of 305 dental students completed the questionnaire. Fifty-nine percent (n = 180) reported having updated training on infection control measures in dental settings and 29% (n = 89) reported having attended a training course regarding COVID-19. Eighty-two percent of students (n = 250) preferred to avoid working with suspected COVID-19 patients. Almost 89% (n = 269) admitted fear of transmitting the virus to their families. This fear was related to their perception that using regular standard precautions is unsafe in dealing with COVID-19 patients and their perception of their schools' preparedness to update infection prevention measures (χ 2 = 50.45, p 2 = 9.77, p = 0.021). Conclusion : Students in this sample are aware of COVID-19 and its precautionary measures. Adherence to new, stricter infection control protocols and periodic orientation of students to these protocols are ways to guarantee a safer environment for both patients and students.

Knowledge of cervical cancer risk factors among Palestinian women: a national cross-sectional study.

Abstract: BACKGROUND High awareness of cervical cancer (CC) risk factors is important to decrease the morbidity and mortality associated with CC. This study aimed to assess the knowledge level of Palestinian women about CC risk factors and to determine the factors associated with good knowledge. METHODS This was a national cross-sectional study. Adult women from hospitals, primary healthcare centers, and public spaces of 11 governorates in Palestine were recruited using a stratified convenience sampling. A translated-into-Arabic version of the validated CC awareness measure (CeCAM) was used to assess the knowledge about the 11 CC risk factors. For each correctly identified risk factor, the participant was given one point. The total score was calculated and was categorized into three categories: poor knowledge (0-3), fair knowledge (4-7), and good knowledge (8-11). RESULTS A total of 7223 participants completed the Arabic CeCAM (response rate = 89.3%) and 7058 questionnaires were included in the final analysis: 2655 from the Gaza Strip and 4403 from the West Bank and Jerusalem. Participants recruited from the Gaza Strip were younger, getting lower monthly incomes, and with less chronic diseases than participants recruited from the West Bank and Jerusalem. The most frequently identified risk factor was 'having a weakened immune system' (n = 5458, 77.3%) followed by 'infection with a sexually transmitted infection' (n = 5388, 76.3%). The least identified risk factor was 'having many children' (n = 1597, 22.6%). Only 1670 women (23.7%) had good knowledge of CC risk factors. Women living in the Gaza Strip were more likely than women living in the West Bank and Jerusalem to have good knowledge (25.2% vs 22.7%). Completing a secondary or diploma degree, being employed, and having a monthly income of ≥ 1450 NIS (around $450) were all associated with lower likelihood of having good knowledge of CC risk factors. Conversely, knowing someone with cancer was associated with higher likelihood of having good knowledge. CONCLUSION The overall awareness of CC risk factors was low. There is a substantial need to establish educational programs to promote Palestinian women's awareness of CC.

Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations

Abstract: We thank C. Thai, A. Sanchez, T. Chevez, A. Nunez and M. V. Robles for their help with tissue collection and clinical information from the women participating in our study. We also thank M. Miyano for assistance with immunofluorescence images, M. Basam for help with coding, and our patient advocates S. Samson and S. Preto for providing much needed context. Funding was provided by: DOD CDMRP (BC141351 Era of Hope Scholar Award and BC181737), Hilton-Ludwig Foundation and City of Hope Center for Cancer and Aging to M.A.L.; National Institutes of Health/National Cancer Institute (NIH/NCI) grants (nos. R01CA237602, U01CA244109, R33AG059206 and R01EB024989 to M.A.L. and nos. R01CA170851, P20CA24619, R01CA192914 and U01CA189283 to V.E.S.) and NCI Cancer Metabolism Training Program Postdoctoral Fellowship T32CA221709 to R.W.S. Research reported in this publication included work performed in the Integrative Genomics and Bioinformatics, Analytical Cytometry, and Biomarker Analysis and Validation Cores supported by the NCI of the NIH under grant no. P30CA033572. M.R.S. and J.C.G. are supported by US Department of Energy under contract no. DE-AC02-05CH11231. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Clinical Profile of COVID-19 Patients Presenting with Uveitis – A Short Case Series

Abstract: Purpose To present the clinical features of anterior, intermediate and posterior uveitis in patients with COVID-19 and to increase the awareness of the treating physicians to refer patients with COVID-19 who have eye symptoms for ophthalmic exam, in order to diagnose as early as possible and prevent vision-threatening complications. Methods Retrospective observational case reports. Results We report three cases of COVID-19 patients who developed uveitis during or after the course of their sickness with COVID-19. All patients underwent a detailed eye examination, relevant history and investigations did not prove any other cause of uveitis. Conclusion This report presents novel data on the course of subjects with uveitis during the COVID-19 pandemic. Intermediate and posterior uveitis warrant further evaluation with differential diagnosis supported by laboratory tests due to the association with systemic diseases and risk of permanent vision loss. Iridocyclitis, intermediate, and posterior uveitis treatment should be guided by ophthalmologists, particularly uveitis specialists, when possible.

Bi-allelic truncating mutations in VWA1 cause neuromyopathy.

Abstract: The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders. Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model. Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder. We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent. Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.

Knowledge of ovarian cancer symptoms among women in Palestine: a national cross-sectional study.

Abstract: Introduction Ovarian cancer (OC) is often diagnosed at advanced stages. This study aimed to assess the Palestinian women's knowledge about OC symptoms and determine the factors associated with having good knowledge. Methods A cross-sectional study was conducted from July 2019 to March 2020 in the two main areas of Palestine: the West Bank and Jerusalem as well as the Gaza Strip. A translated-into-Arabic version of the validated OC awareness measure (OCAM) was utilized for data collection. Stratified convenience sampling was used to recruit adult women attending hospitals, primary healthcare centers, and public spaces at 11 governorates. The knowledge level was categorized into three categories based on the number of symptoms recognized: poor (0 to 4), fair (5 to 8), and good (9 to 11). Results Of 6095 approached, 5618 participants completed the Arabic OCAM (response rate = 92.1%).A total of 5411 questionnaires were included in the analysis: 2278 from the Gaza Strip and 3133 from the West Bank and Jerusalem. Participants living in the West Bank and Jerusalem were older, of higher monthly income, and with more chronic diseases than those living in the Gaza Strip. The most frequently identified symptoms were 'extreme generalized fatigue' (n = 3821, 70.6%), 'unexplained weight loss' (n = 3607, 66.7%), and 'increased abdominal size on most days' (n = 3252, 60.1%). On the other hand, the least recognized symptoms were 'feeling full persistently' (n = 1553, 28.7%) and 'difficulty eating on most days' (n = 1971, 36.4%). Only 943 participants (17.4%) displayed good knowledge of OC symptoms. Participants from the Gaza Strip had a higher likelihood than participants from the West Bank and Jerusalem to have a good level of knowledge (21.0% vs. 14.8%). Being married, knowing someone with cancer, and visiting hospitals were all associated with a higher likelihood of having good knowledge level. However, living in the West Bank and Jerusalem was associated with a lower likelihood of having good knowledge. Conclusion The overall knowledge of OC symptoms in this study was low. Educational interventions are needed to improve Palestinian women's knowledge about OC symptoms.

The role of 5-lipoxygenase in the pathophysiology of COVID-19 and its therapeutic implications.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, known as coronavirus disease 2019 (COVID-19) causes cytokine release syndrome (CRS), leading to acute respiratory distress syndrome (ARDS), acute kidney and cardiac injury, liver dysfunction, and multiorgan failure Although several studies have discussed the role of 5-lipoxygenase (5-LOX) in viral infections, such as influenzae and SARS, it remains unexplored in the pathophysiology of COVID-19 5-LOX acts on free arachidonic acid (AA) to form proinflammatory leukotrienes (LTs) Of note, numerous cells involved with COVID-19 (eg, inflammatory and smooth muscle cells, platelets, and vascular endothelium) widely express leukotriene receptors Moreover, 5-LOX metabolites induce the release of cytokines (eg, tumour necrosis factor-α [TNF-α], interleukin-1α [IL-1α], and interleukin-1β [IL-1β]) and express tissue factor on cell membranes and activate plasmin Since macrophages, monocytes, neutrophils, and eosinophils can express lipoxygenases, activation of 5-LOX and the subsequent release of LTs may contribute to the severity of COVID-19 This review sheds light on the potential implications of 5-LOX in SARS-CoV-2-mediated infection and the anticipated therapeutic role of 5-LOX inhibitors

Knowledge of Palestinian women about cervical cancer warning signs: a national cross- sectional study.

Abstract: Timely presentation and diagnosis of cervical cancer (CC) are crucial to decrease its mortality especially in low- and middle-income countries like Palestine. This study aimed to evaluate the knowledge of Palestinian women about CC warning signs and determine the factors associated with good knowledge. This was a national cross-sectional study conducted between July 2019 and March 2020 in Palestine. Stratified convenience sampling was used to recruit adult women from hospitals, primary healthcare centers, and public spaces of 11 governorates. A translated-into-Arabic version of the validated CC awareness measure (CeCAM) was used to assess women’s knowledge of 12 CC warning signs. Of 8086 approached, 7223 participants completed the CeCAM (response rate = 89.3%). A total of 7058 questionnaires were included in the analysis: 2655 from the Gaza Strip and 4403 from the West Bank and Jerusalem (WBJ). The median age [interquartile range] for all participants was 34.0 [24.0, 42.0] years. Participants recruited from the WBJ were older, getting higher monthly income, and having more chronic diseases than those recruited from the Gaza Strip. The most frequently identified warning sign was ‘vaginal bleeding after menopause’ (n = 5028, 71.2%) followed by ‘extreme generalized fatigue’ (n = 4601, 65.2%) and ‘unexplained weight loss’ (n = 4578, 64.9%). Only 1934 participants (27.4%) demonstrated good knowledge of CC warning signs. Participants from the Gaza Strip were slightly more likely than participants from the WBJ to have a good level of knowledge. Factors associated with having good knowledge included having a bachelor or postgraduate degree, being married, divorced, or widowed as well as knowing someone with cancer. The overall awareness of CC warning signs was low. Educational interventions are needed to increase Palestinian women’s awareness of CC warning signs.

The Prevalence of Temporomandibular Disorders and Dental Attrition Levels in Patients with Posterior Crossbite and/or Deep Bite: A Preliminary Prospective Study.

Abstract: Background. The prevalence of various temporomandibular disorders (TMD) and the severity of attrition in patients with either bilateral or unilateral deep bite and/or posterior crossbite has not been established, nor has the effect of one year of orthodontic treatment on TMD. Methods. Of 310 patients presenting with suspected TMD, 160 were diagnosed with various TMD and 150 were TMD-free. Diagnosis was according to the Axis I of the Diagnostic Criteria for TMD. All participants underwent a dental examination, and 100 patients were reevaluated after one year of orthodontic treatment. Fisher’s exact test and the proportion test with Bonferroni’s correction were used for the categorical univariate analysis. Results. There was a significant association ( ) between deep bite and dental attrition (wear), but not between crossbite and/or deep bite in patients diagnosed with either painful TMD or disc displacement. The risk of sustaining painful TMD when crossbite presented simultaneously on the anterior and the posterior dentition was 2.625-fold greater than when it presented with a normal bite, although this difference was not significant ( ) due to the lack of statistical power. There was no significant sex-related association between the occurrence of either painful TMD or disc displacement. A reduction in TMD findings was demonstrated after one year of treatment, but no statistical power was reached due to the small sample size. Conclusions. Deep bite may be related to dental wear but not to pain from TMD and/or disc displacement. Only crossbite that presents simultaneously on the anterior and the posterior dentition (mixed X-bite) may have some effect on the level of pain in TMD, but not on in the prevalence of disc displacement. Confirmation of these conclusions by well-designed studies on larger patient groups is warranted. There was a clinically significant improvement in TMD findings after one year of treatment.

Challenges Facing Family Caregivers of Children With Disabilities During COVID-19 Pandemic in Palestine.

Abstract: Background:COVID-19 has caused great changes in all aspects of life which affected all people especially vulnerable groups such as children with disabilities (CWD) and their families.Objective:This...

External locus-of-control partially mediates the association between cumulative trauma exposure and posttraumatic stress symptoms among adolescents from diverse background

Abstract: Locus of control (LOC) is a modifiable mediator of symptoms of posttraumatic stress disorder (PTSD) among traumatized individuals and a potential target of intervention. Compared with studies invol...

Bed Bugs (Hemiptera: Cimicidae) Population Diversity and First Record of Cimex hemipterus in Paris.

Abstract: Cimex lectularius and C. hemipterus are blood-sucking insects with a long history of presence in human communities. We investigated the molecular diversity of the bed bug population of Paris and its suburb cities using cytochrome oxidase 1 (CO1) sequencing. A total of 1211 specimens belonging to different life stages were collected from 62 infested human dwellings in Paris (13 out of 20 arrondissements) and the surrounding cities (18 cities). Morphological determination and COI sequencing of 132 specimens demonstrated C. lectularius as the predominant species and, surprisingly, the presence of C. hemipterus in four infested areas of Paris and its suburb cities. Neighbor-joining tree and network analyses depicted the presence of two C. lectularius populations. Most samples from Paris and its suburb cities clustered in a major clade. The second population encompasses specimens from Paris (arrondissements 11 and 19) and its suburb cities (e.g., Bobigny, Pantin, and Montreuil) that clustered with Hungary, Czechia, and Finland. This is the second evidence for C. hemipterus infestation in France and the third in Europe, which challenges the classic pattern of C. hemipterus dispersion and implies sympatric occurrence of C. lectularius and C. hemipterus. Since Paris is one of the most popular tourist destinations in the world, our observations shed light on bed bugs’ dispersal dynamic and may help future vector control strategies.

Association between posterior crossbite and/or deep bite and temporomandibular disorders among Palestinian adolescents: A sex comparison.

Abstract: Objective: To assess the prevalence of temporomandibular disorders (TMDs) and posterior crossbite and/or deep bite and any possible association between them.Methods: One thousand-nineteen adolescen...

Enzyme Models-From Catalysis to Prodrugs.

Abstract: Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.

Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency

Abstract: Cytochrome-c-oxidase (COX) subunit 4 (COX4) plays important roles in the function, assembly and regulation of COX (mitochondrial respiratory complex 4), the terminal electron acceptor of the oxidative phosphorylation (OXPHOS) system. The principal COX4 isoform, COX4-1, is expressed in all tissues, whereas COX4-2 is mainly expressed in the lungs, or under hypoxia and other stress conditions. We have previously described a patient with a COX4-1 defect with a relatively mild presentation compared to other primary COX deficiencies, and hypothesized that this could be the result of a compensatory upregulation of COX4-2. To this end, COX4-1 was downregulated by shRNAs in human foreskin fibroblasts (HFF) and compared to the patient’s cells. COX4-1, COX4-2 and HIF-1α were detected by immunocytochemistry. The mRNA transcripts of both COX4 isoforms and HIF-1 target genes were quantified by RT-qPCR. COX activity and OXPHOS function were measured by enzymatic and oxygen consumption assays, respectively. Pathways were analyzed by CEL-Seq2 and by RT-qPCR. We demonstrated elevated COX4-2 levels in the COX4-1-deficient cells, with a concomitant HIF-1α stabilization, nuclear localization and upregulation of the hypoxia and glycolysis pathways. We suggest that COX4-2 and HIF-1α are upregulated also in normoxia as a compensatory mechanism in COX4-1 deficiency.