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Today, 12 Ιουλίου 2016, 4:19:58 μμ
Urinary Metabolomics Reveals Alterations of Aromatic Amino Acid Metabolism of Alzheimer’s Disease in the Transgenic CRND8 Mice
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with amyloid plaques accumulation as the key feature involved in its pathology. To date, however, the biochemical changes in AD have not been clearly characterized. Here, we present that urinary metabolomics based on high resolution mass spectrometry was employed for delineation of metabolic alterations in transgenic CRND8 mice. In this noninvasive approach, urinary metabolome reveals the biochemical changes in early onset of this AD mouse model. In virtue of comprehensive metabolite profiling and multivariate statistical analysis, a total of 73 differential metabolites of urine sample sets was identified in 12-week and 18-week transgenic mice compared to wild-type littermates, covering perturbations of aromatic amino acid metabolism, the Krebs cycle and one-carbon metabolism. Of particular interest is that divergent tryptophan metabolism, such as upregulation of serotonin pathway while downregulation of kynurenine pathway, was observed. Meanwhile, the accumulation of both N-acetylvanilalanine and 3-methoxytyrosine indicated aromatic L-amino acid decarboxylase deficiency. And the microbial metabolites derived from aromatic amino acid metabolism and drug-like phase II metabolic response via the glycine conjugation reactions were also highlighted, indicating that genetic modification in mouse brain not only alters genotype but also perturbs the gut microbiome. Together, our study demonstrated that the integrative approach employing mass spectrometry-based metabolomics and a transgenic mouse model for AD may provide new evidence for distinct metabolic signatures. The perturbations of metabolic pathways may have far-reaching implications for early diagnosis and intervention in AD.
A Systematic Review of Plant-Derived Natural Compounds for Anxiety Disorders
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Anxiety disorders are the most common mental illnesses affecting human beings. They range from panic to generalized anxiety disorders upsetting the well-being and psychosocial performance of patients. Several conventional anxiolytic drugs are being used which in turn results in several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being conducted by researchers. </p><p> The aim of the present study is to comprehensively review phytochemical compounds with well-established anxiolytic activities and their structure-activity relationships as well as neuropsychopharmacological aspects. </p><p> Results showed that phytochemicals like; alkaloids, flavonoids, phenolic acids, lignans, cinnamates, terpenes and saponins possess anxiolytic effects in a wide range of animal models of anxiety. The involved mechanisms include interaction with γ-aminobutyric acid (GABA)<sub>A</sub> receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine (5-HT)<sub>1A</sub> and 5-HT<sub>2A/C</sub> receptors, noradrenergic and dopaminergic systems, glycine and glutamate receptors, and κ-opioid receptor as well as cannabinoid (CB)1 and CB2 receptors. Phytochemicals also modulate the hypothalamo-pituitary-adrenal (HPA) axis, the levels of pro-inflammatory cytokines like interleukin (IL)-2, IL-6, IL-1β and tumor necrosis factor (TNF)-α, and improve brain derived neurotrophic factor (BDNF) levels. Transient receptor potential cation channel subfamily V (TRPV)3, nitric oxide cyclic guanosine monophosphate (NOcGMP) pathway and monoamine oxidase enzymes are other targets of phytochemicals with anxiolytic activity. </p><p> Taking together, these phytochemicals may be considered as supplements to conventional anxiolytic therapies in order to improve efficacy and reduce adverse effects. Further preclinical and clinical studies are still needed in order to recognize the structure-activity relationships, metabolism, absorption, and neuropsychopharmacological mechanisms of plantderived natural agents. </p><p>
Biomarker-Guided Strategy for Treatment of Autism Spectrum Disorder (ASD)
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Autism spectrum disorder (ASD) is a complex, life-long neurodevelopmental disorder currently affecting an estimated 1 out of 68 among children aged 8 y in the United States. ASD has complex genetic and epigenetic features that lead to the phenotype and there is no single genetic marker for the diagnosis. Therefore, the diagnosis for ASD is phenotype- based with no validated or credible laboratory tests available. Evidence-based treatments for ASD are limited. There is no FDA approved medical therapy that addresses either core ASD symptoms or pathophysiological processes associated with ASD. We outline herein, several ASD-associated basic physiological pathways that can be regulated by the small molecule phytochemical sulforaphane, as an example of a druggable small molecule target for which much in vitro, pre-clinical, and clinical evidence already exists: (1) redox metabolism/oxidative stress, (2) mitochondrial dysfunction, (3) immune dysregulation/neuroinflammation, (4) febrile illness and the heat shock response, and (5) synaptic dysfunction. Furthermore, we identify the biomarkers that can be used to assess the functioning of these pathways as well as suggesting how these biomarkers could guide novel treatment strategies to correct these biochemical abnormalities in order to improve core and associated symptoms of ASD.
Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Background: Preclinical studies have shown that lithium modifies pathological cascades implicated in certain neurodegenerative disorders, such as Alzheimer’s disease (AD), Huntigton`s disease (HD), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). A critical question is whether these pharmacodynamic properties of lithium translate into neurodegenerative diseases modifying effects in human subjects. Methods: We reviewed all English controlled clinical trials published in PubMed, PsycINFO, Embase, SCOPUS, ISI-Web with the use of lithium for the treatment of neurodegenerative disorders between July 2004 and July 2014. Results: Lithium showed evidence for positive effects on cognitive functions and biomarkers in amnestic mild cognitive impairment (aMCI, 1 study) and AD (2 studies), even with doses lower than those used for mood stabilisation. Studies of Li in HD, MSA and CSI did not show benefits of lithium. However, due to methodological limitations and small sample size, these studies may be inconclusive. Studies in ALS showed consistently negative results and presented evidence against the use of lithium for the treatment of this disease. Conclusion: In absence of disease modifying treatments for any neurodegenerative disorders, the fact that at least 3 studies supported the effect of lithium in aMCI/AD is noteworthy. Future studies should focus on defining the dose range necessary for neuroprotective effects to occur.
Personalized Treatment of Obsessive-Compulsive Disorder: Radiology, EEG, Pharmacogenetics and Biochemistry
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Background: Obsessive-compulsive disorder (OCD) is a common mental illness and a ubiquitous cause of disability. Approximately half of the patients with OCD only partially respond or do not respond at all to current ways of treatment. Even patients responding to treatment usually need high doses of medication and/or intense psychotherapy for a long time. It is obvious that therapeutic approaches to OCD need improving. In this article, we review the modalities of personalized medicine in OCD. </p><p> Methods: We conducted a search in PubMed (until June 2015) and Scopus (until June 2015) by using the following terms: “obsessive-compulsive disorder,” “personalized medicine,” “response prediction,” “pharmacogenetics,” “therapeutic drug monitoring,” “EEG,” “neuroimaging” and “serotonin.” The literature about neuroimaging including radiological techniques (positron emission tomography, single-photon emission tomography, functional and morphometric magnetic resonance imaging and magnetic resonance spectroscopy) and electroencephalography, therapeutic drug monitoring (measuring the plasma levels of drugs), pharmacogenetics (genes encoding cytochrome P450 enzymes, serotonin transporter, serotonin receptors, norepinephrine transporter, dopamine receptors, brain-derived neurotrophic factor [BDNF] and catechol-O-methyltransferase) and biochemistry (whole blood serotonin levels and neuroendocrine challenge tests) is investigated. </p><p> Results: Pre-treatment changes in glucose metabolism shown by radiological instruments might be related to response to medication. Increased alpha in EEG is predictive of good response whereas increased theta forecasts a poor response. BDNF, serotonin receptors and glutamatergic and serotonergic transmission have been found to be somewhat related to treatment response in OCD. Few studies on whole blood serotonin levels and hormone response to challenge with a serotonergic medication in patients seem to have a predictive value in OCD treatment. </p><p> Conclusion: Although the studies to elaborate a personalized treatment of OCD have produced some promising results, much more work is required to provide clinician with a reliable decision tree. </p><p>
Recent Advances Using Phosphodiesterase 4 (PDE4) Inhibitors to Treat Inflammatory Disorders: Animal and Clinical Studies
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Phosphodiesterase 4 (PDE4) inhibitors can be effective drugs for treating inflammation in different tissues/organs caused by conditions such as asthma, chronic obstructive pulmonary disease (COPD), psoriasis, and Alzheimer’s disease. It has been demonstrated that PDE4 inhibitors used for drug therapy provide some advantages over conventional formulations, including sensitivity to selective inhibitors, unique tissue distribution, and ease of oral administration. To date, the U.S. Food and Drug Administration (USFDA) had approved two PDE4 inhibitors, roflumilast (Daxas®, Daliresp®) and apremilast (Otezla®), for treating respective COPD and plaque psoriasis. Several pharmaceutical companies and academic laboratories continuously develop novel PDE4 inhibitors for clinical application. A concern pertaining to the development of PDE4 inhibitors is the high occurrence rate of side effects such as emesis, nausea, and headache. This review describes recent developments using PDE4 inhibitors for inflammation management. Special attention is paid to the use of PDE4 inhibitors in treating pulmonary and cutaneous inflammation. This review article focuses on issues related to animal and human studies. The action mode of the inhibitors is also addressed.
Oxidative Stress Genes, Antioxidants and Coronary Artery Disease in Type 2 Diabetes Mellitus
Today, 12 Ιουλίου 2016, 4:19:59 μμ
The worldwide increasing prevalence of obesity and sedentary lifestyle is the main cause of the rising incidence of T2DM. Due to chronic macrovascular and microvascular complications, T2DM represent a huge socioeconomic burden in the world. Oxidative stress is a key pathogenic mechanism implicated in diabetic coronary artery disease (CAD). Polymorphisms of oxidative stress genes are known to influence oxidative stress levels and are therefore thought to impact CAD pathogenesis. Identifying higher risk groups would be rational, since it would allow better sample selection and thus better results in antioxidant trials. In this review, we summarize the evidence of oxidative stress gene polymorphisms related to the pathogenesis of CAD. Moreover, we provide a review of antioxidants tested in subjects with CAD.
Metformin - The Drug for the Treatment of Autoimmune Diseases; A New Use of a Known Anti-Diabetic Drug
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Autoimmune diseases are characterized by the production of autoantibodies directed against specific organs of own organism. Additional common traits of autoimmune diseases are chronic inflammation due to generation of inflammatory mediators, and disorders of redox processes. The pathogenesis of autoimmune diseases is still unknown. Treatment is based only on relieving the symptoms and improving the quality of patients lives. Metformin, which is used in treatment of type 2 diabetes, has properties which are desirable for autoimmune disease therapy, including anti-inflammatory and antioxidant effects, and the ability to regenerate the endothelium.
GPR 120: The Potential Target for Obesity Treatment
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Background: G protein coupled receptor 120 (GPR120) is a class of receptors in the gastrointestinal tract (GIT) that is implicated in nutrient sensing and body weight regulation. Functions of GPR120 are thought to be mediated by the release of a group of hormones known as incretins, such as glucagon like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). </p><p> Methods: We have searched PubMed with the keywords "GPR120","GLP-1" and "obesity". Relevant studies were retrieved and included in the review. </p><p> Results: Recently, many exogenous compounds have been investigated in their role in the release of GLP-1 and in causing weight loss in obese rats. However, some results question the putative role of GPR120 in metabolic homeostasis. </p><p> Conclusion: Herein, we evaluate the potential use of GPR120 as a target receptor in obesity and found it to be ubiquitous throughout the GIT, with various functions in each site. In order to find the optimal drug, the role of GPR120 in each site needs to be defined and selectivity of the potential drug needs to be studied to ensure the success of this growing line of obesity management. </p><p>
Enzymology of Pyrimidine Metabolism and Neurodegeneration
Today, 12 Ιουλίου 2016, 4:19:59 μμ
It is well known that disorders of pyrimidine pathways may lead to neurological, hematological, immunological diseases, renal impairments, and association with malignancies. Nucleotide homeostasis depends on the three stages of pyrimidine metabolism: de novo synthesis, catabolism and recycling of these metabolites. </p><p> Cytidine and uridine, in addition to be used as substrates for pyrimidine nucleotide salvaging, also act as the precursors of cytidine triphosphate used in the biosynthetic pathway of both brain’s phosphatidylcholine and phosphatidylethanolamine via the Kennedy cycle. The synthesis in the brain of phosphatidylcholine and other membrane phosphatides can utilize, in addition to glucose, three compounds present in the blood stream: choline, uridine, and a polyunsaturated fatty acids like docosahexaenoic acid. </p><p> Some authors, using rat models, found that oral administration of two phospholipid precursors such as uridine and omega-3 fatty acids, along with choline from the diet, can increase the amount of synaptic membrane generated by surviving striatal neurons in rats with induced Parkinson’s disease. Other authors found that in hypertensive rat fed with uridine and choline, cognitive deficit resulted improved. Uridine has also been recently considered as a neuroactive molecule, because of its involvement in important neurological functions by improving memory, sleep disorders, anti-epileptic effects, as well as neuronal plasticity. Cytidine and uridine are uptaken by the brain via specific receptors and successively salvaged to the corresponding nucleotides. The present review is devoted to the enzymology of pyrimidine pathways whose importance has attracted the attention of several researchers investigating on the mechanisms underlying the physiopathology of brain. </p><p>
Placental Hypoxia Developed During Preeclampsia Induces Telocytes Apoptosis in Chorionic Villi Affecting The Maternal-Fetus Metabolic Exchange
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Telocytes (TC) are a new type of stromal cells initially found and studied in digestive and extra- digestive organs. These cells have a small cell body with 2 to 5 thin and extremely long cytoplasmic prolongations named telopodes. In recent years, TC have also been described in placental chorionic villi, located in a strategical position between the smooth muscle cells from fetal vessels and the myofibroblasts in the stromal villi. Unlike other organs, the placenta is not innervated and considering the strategic location of TC is has been postulated that TC function would be related to signal transduction mechanisms involved in the regulation of the fetal vessels blood flow, as well as in the shortening/lengthening of the chorionic villi, providing the necessary rhythmicity to the process of maternal/fetal metabolic exchange. Preeclampsia (PE) is a systemic syndrome that affects 4%–6% of pregnancies worldwide. It is characterized by a placental state of ischemia-hypoxia which triggers an oxidative stress stage with the concomitant production of reactive oxygen species (ROS) leading to an increase in the degree of placental apoptosis. Placental vascular tone is regulated by the vasodilator nitric oxide (NO) and, in PE cases, NO is diverted towards the formation of peroxynitrite, a powerful oxidative agent whose activity leads to an increase of placental apoptosis degree that compromises TC and myofibroblasts, a key feature we would like to emphasize in this work.
Communication from Tubular Epithelial Cells to Podocytes through Sirt1 and Nicotinic Acid Metabolism
Today, 12 Ιουλίου 2016, 4:19:59 μμ
We have recently published that tubular epithelial cells affect the podocyte epigenome though nicotinic acid metabolism in diabetic nephropathy (DN), and we have named this relationship “proximal tubule–podocyte communication”. In this review, we describe this novel mechanism in the early stage of DN, focusing on the function of renal tubular Sirt1 and Sirt1-related nicotinic acid metabolism. Mainly, we discuss the following three findings. First, we described the details of proximal tubule–podocyte communication. Second, we explained how Sirt1 regulates albuminuria via epigenetic mechanisms. This means that repeated high glucose stress triggers the initial changes in proximal tubules, which lead to the epigenetically irreversible glomerular damages. However, proximal tubular Sirt1 overexpression can rescue these changes. Our previous data indicated that the decrease in Sirt1 expression in proximal tubules caused the reduction in glomerular Sirt1 and the subsequent increase in glomerular Claudin-1. It seemed plausible that some humoral mediator is released from proximal tubules, migrates to podocytes and glomeruli, and affects Sirt1 expression in podocytes. Third, we mentioned a mediator connecting this communication, nicotinamide mononucleotide (NMN). We suggest the potential of Sirt1 or NMN as not only a therapeutic target but also as a prognostic marker of very early stage DN.
Population Studies of Association Between Lithium and Risk of Neurodegenerative Disorders
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Background: Lithium shows neuroprotective and neurotrophic effects in vitro and in vivo. Due to its involvement in hippocampal neurogenesis and the interaction with beta-amyloid and neurofibrillary tangle metabolism it has been hypothesized that lithium could have the potential to influence the development of dementia. Method: Using the PubMed database and cross-reference search strategies our aim was to specifically identify population (cohort or case-control) studies investigating the association between lithium and dementia. Results: Data from large cohort studies suggest an association between lithium treatment and dementia risk reduction or reduced dementia severity. Studies with smaller sample sizes yield more variable findings. Conclusions: Lithium may reduce the risk of dementia among middle-aged and older people. Beneficial lithium effects are possibly limited to specific types of neurodegenerative processes.
Sulforaphane Treatment of Young Men with Autism Spectrum Disorder
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders that begin in early childhood. They are characterized by differences in behavior and delays in communication and affect at least 1% of children. Observational studies have now confirmed that behaviors of a substantial percentage of children with autism tend to improve with the onset of febrile illness, which might be the downstream effects of altered metabolic pathways involving increased expression of heat shock proteins (HSP) and cellular stress responses. Sulforaphane, a phytochemical derived from a number of cruciferous vegetables, most notably broccoli sprouts, has metabolic effects that in some ways resemble that of fever. This review paper discusses this “fever effect” and the intracellular effects of sulforaphane as well as the results of our recent clinical trial of sulforaphane in young adults with autism. The accompanying review by Liu et al. describes the cellular actions of sulforaphane and potential biomarkers in the study of ASD.
A Possible Case of Bipolar Disorder Unmasked by Dextromethorphan in a 16-year-old Adolescent
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Background/Objective: Several case reports have described psychosis or mania in patients abusing dextromethorphan. In each of the cases of mania, the symptoms resolved rapidly after the dextromethorphan was metabolized. To our knowledge, no cases have been reported of an underlying diagnosis of bipolar disorder that has been revealed by abuse of dextromethorphan. This report describes such a possible case. </p><p> Method: We describe clinical observations and treatment of patient who received standard level of care for bipolar disorder. </p><p> Results: Our patient presented with symptoms of mania after ingesting 300 mg of dextromethorphan. His symptoms lasted for over one week after the dextromethorphan was out of his system, even after an antimanic agent was started. This is a significantly longer symptomatic period of time than has previously been reported in the literature. </p><p> Conclusions: While this case technically meets criteria for dextromethorphan-induced bipolar disorder according to DSM-5, we suggest that the prolonged course of symptoms may be more indicative of a primary bipolar disorder. We propose that this case might be more similar to the unmasking of bipolar symptoms by anti-depressant medications, which would be supported by the hypothesized acute anti-depressant effects of dextromethorphan. </p><p>
Editorial (Thematic Selection: Mitochondrial Dysfunction & Neurological Disorders)
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Editorial (Thematic Issue: New Therapeutic Targets for Autism Spectrum Disorders)
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Untapped Potential of Disordered Proteins in Current Druggable Human Proteome
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Current efforts in design and characterization of drugs often rely on the structure of their protein targets. However, a large fraction of proteins lack unique 3-D structures and exist as highly dynamic structural ensembles. These intrinsically disordered proteins are involved in pathogenesis of various human diseases and are highly abundant in eukaryotes. Based on a comprehensive analysis of the current druggable human proteome covering 12 drug classes and 18 major classes of drug targets we show a significant bias toward high structural coverage and low abundance of intrinsic disorder. We review reasons for this bias including widespread use of the structural information in various stages of drug development and characterization process and difficulty with attaining structures for the intrinsically disordered proteins. We also discuss future of intrinsically disordered proteins as drug targets. Given the overall high disorder content of the human proteome and current bias of the druggable human proteome toward structural proteins, it is inevitable that disordered proteins will have to raise up on the list of prospective drug targets. The protein disorder-assisted drug design can draw from current rational drug design techniques and would also need novel approaches that no longer rely on a unique protein structure.
mTOR, a Potential Target to Treat Autism Spectrum Disorder
Today, 12 Ιουλίου 2016, 4:19:59 μμ
Mammalian target of rapamycin (mTOR) is a key regulator in various cellular processes, including cell growth, gene expression, and synaptic functions. Autism spectrum disorder (ASD) is frequently accompanied by monogenic disorders, such as tuberous sclerosis complex, phosphatase and tensin homolog tumor hamartoma syndrome, neurofibromatosis 1, and fragile X syndrome, in which mTOR is hyperactive. Mutations in the genes involved in the mTOR-mediated signaling pathway have been identified in some cases of syndromic ASD. Evidences indicate a pathogenic role for hyperactive mTOR-mediated signaling in ASD associated with these monogenic disorders, and mTOR inhibitors are a potential pharmacotherapy for ASD. Abnormal synaptic transmission through metabotropic glutamate receptor 5 may underlie in a part of ASD associated with hyperactive mTOR-mediated signaling. In this review, the relationship between mTOR and ASD is discussed.
Effects of Yokukansan, a Japanese Kampo Medicine for Symptoms Associated Autism Spectrum Disorder
Today, 12 Ιουλίου 2016, 4:19:59 μμ
A neuropsychiatric syndrome, Autism spectrum disorder (ASD) is qualified via impairments in qualitative communication, social interaction, and stereotyped or restricted, repetitive patterns of behavior, interests, or activities. While all ASDs are considered to have qualitative deficits in social relatedness to others, many people with ASDs have other symptoms, including irritability (which includes aggression, self-injurious behavior, and severe tantrums). In order to decrease these behaviors, it is often helpful to make use of behavioral therapy. In addition, due to the intensity and severity of irritability, adjunctive medications are sometimes needed. Although many of the adjunctive medications have been tested and demonstrated to be useful in treating ASD, no clear standardized treatment has emerged. While the adjunctive medications have shown efficacy, the associated side effects have proven to be a barrier to their accepted use. A traditional Japanese medicine, Yokukansan (YKS), is composed of seven kinds of dried herbs and is widely clinically prescribed for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous systems. YKS may be safe and useful in treating dementia patients’ behavioral and psychological symptoms according to indications from recent studies. We introduce in this review, the ameliorative effects of YKS on Asperger's disorder in open-label studies and on ASDs including pervasive developmental disorder not otherwise specified (PDD-NOS). This review will suggest that YKS is well tolerated and effective for the treatment for subjects with ASD who have severe hyperactivity/noncompliance and irritability/agitation. Additionally, the serotonergic, glutamatergic, anti-inflammatory and neurogenesis effects are explored which are thought to be involved in the mechanisms underlying the efficacy of YKS.
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