Alternative approaches for the treatment of Asthma and COPD: Focus on Cell-based therapies, Epigenetics, and Gene silencing approaches

Despite many organized health initiatives and critically acclaimed guidelines for proper management of asthma therapy, there is still a large population of severe asthmatics having an uncontrolled disease. Severe persistent asthma, characterized by chronic airway inflammation, increased eosinophils and serum IgE is currently managed by using inhaled corticosteroids. It is quite challenging to get the best treatment guidelines for bronchial asthma in severe asthmatics, particularly in the presence of steroid resistance and the non-responsiveness to β-agonists. For that purpose, other methodologies are required to reverse the uncontrolled airway remodeling in steroid-resistant severe asthma. These advanced alternative approaches should be able to treat asthma symptoms and to improve the inflammatory conditions underlying characteristic pathological features of asthma. The current review focuses and summarizes the alternative approaches used in severe asthma patients. Agents targeting inflammatory cytokines, phosphodiesterase inhibitors, antibodies, oligonucleotides, stem cells, and target drug delivery using gene silencing, offer promise in treating severe asthma.Keywords: Asthma; COPD; Therapies; Epigenetics; Gene silencin

Salvia reflexa (Lamiaceae): a new record for Pakistan

Salvia reflexa Hornem., a member of the New World subgenus Calosphace, ranges from North America to southern South America, Australia, New Zealand, South Africa and Afghanistan in Asia, and still continues to expand its range. Here we report further range expansion for S. reflexa into the tribal areas of Pakistan and hypothesize that it has been introduced from Afghanistan. This represents a new record for the flora of Pakistan

Rainwater harvesting scenarios and its prospective in Pakistan

Water is a precious commodity and water scarcity has become a serious issue in many parts of the world, especially in dense urban areas. Water resources are under increasing stress due to continuous population growth, agricultural development, urbanization, and industrialization. The gap between water demand and supply has also increased in recent years. This has resulted in increasing pressure on underground water resources as well as the depletion of groundwater aquifers at an alarming rate. Thus there is a growing need to explore viable methods and techniques to manage water availability, especially in urban areas. The objective of the current study was to determine the potential for rainwater harvesting (RWH) in the twin cities of Islamabad and Riwalpindi. We evaluated its suitability to supplement the water supply as well as contribute to groundwater recharge and flood control efforts. This could in turn help to overcome water demand, could potentially recharge depleting groundwater resources and could result in the development of a currently untapped additional water source for urban hubs

Synthesis and Characterization of TiO2-Water Nanofluids

Nanofluids made of TiO2 and multiwalled carbon nanotubes are the focus of our study. Using TiO2 and water as the basic fluids, nanofluids were created in 100 : 0, 75 : 25, and 50 : 50 proportions. Carbon nanotubes (CNTs) were disseminated into these base fluids of three types at 0.125, 0.25, and 0.5 percentages. Over the course of two months, the change of zeta potential is monitored to assess the stability of the dispersion. XRD analysis and SEM and TEM analysis are carried out for TiO2 nanofluids. Nanoparticles were analyzed using EDAX analysis to identify their composition. SEM examination was used to investigate the morphology for TiO2 nanoparticles. Particles of TiO2 produced in this manner seemed to have an average diameter of 27 nm. Nanofluids have a poor stability, which is the most important aspect of employing them, although most studies did not focus on this. When it comes to nanofluids, this study is unique in that it provides an in-depth look of surface modification approaches that have been employed by researchers to address these issues, as well as an evaluation of their stability over two months. Solubility is improved by acid treatment of CNTs, which results in functional groups on the surface of CNTs

Homozygosity mapping and whole exome sequencing provide exact diagnosis of Cohen syndrome in a Saudi family

Background: Cohen syndrome (CS) is a rare multi-system autosomal recessive disorder with a high prevalence in the Finnish population. Clinical features of Finnish-type CS are homogeneous, however, in non-Finnish populations, CS diagnosis is challenging due to broad phenotypic variability. Methods: We studied a consanguineous family having three affected individuals with clinical features of severe intellectual disability and global developmental delay. Clinical diagnosis of the phenotype could not be established based on the features. Therefore, whole genome SNP genotyping and whole exome sequencing (WES) were performed on DNA samples from affected and unaffected family members. Results: Homozygosity mapping identified a shared loss of heterozygosity region on chromosome 8q22.1-q22.3 and WES data analysis revealed an insertion-deletion (indel) mutation (c.11519_11521delCAAinsT) in the VPS13B gene. The indel is predicted to cause a frameshift resulting in a premature termination of the VPS13B protein (NP_060360.3:p.Pro3840Leufs*2). Conclusion: VPS13B encodes a giant transmembrane protein called vacuolar protein sorting 13 homolog B. VPS13B is known to play a role in the glycosylation of Golgi proteins and in endosomal-lysosomal trafficking. Moreover, it is thought to function in vesicle mediated transport and sorting of proteins within the cell. The mechanism by which abnormalities of the VPS13B protein lead to the phenotype of CS is currently unknown. Here, in this study, we successfully established a clinical diagnosis of CS cases from a family using genomic analyses. Clinical re-examination of the patients revealed characteristic ocular abnormalities. (C) 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved

Involvement of Muscarinic Receptors in Hypotensive and Diuretic Effects of Aqueous Soluble Fraction from Asphodelus tenuifolius Cav.

Background. Asphodelus tenuifolius Cav. (Asphodelaceae) is widely used in Pakistan traditional medicine as a hypotensive and diuretic agent. Despite the cardioprotective effects described for A. tenuifolius, the mechanisms involved in its probable hypotensive and diuretic effects have never been evaluated. Firstly, different extracts from A. tenuifolius seeds were obtained, and their antioxidant profiles and chemical constituents by LC-DAD-were determined, including molecular networking by the GNPS platform. Then, to evaluate changes in blood pressure, different groups of anesthetized normotensive rats were intravenously treated with the crude extract (AT-Cr, 1–50 mg/kg), aqueous (AS-AT, 1–25 mg/kg), n-butanol (BS-AT, 1–50 mg/kg), and dichloromethane fraction (DS-AT, 1–80 mg/kg). The diuretic effects of AT-Cr, AS-AT, BS-AT, and DS-AT at 100, 200, and 300 mg/kg, p.o. doses, were also evaluated in comparison with hydrochlorothiazide (HCTZ, 10 mg/kg, p.o). The urinary volume, sodium, potassium, and pH were estimated in the sample collected for 6 h from saline-loaded rats. Using pharmacological antagonists or inhibitors, we determine the involvement of acetylcholine, prostaglandins, and nitric oxide in A. tenuifolius-induced hypotensive and diuresis action. In addition, the activities of angiotensin-converting enzyme, erythrocyte carbonic anhydrase, and renal Na+/K+/ATPase were evaluated in vitro. Acute treatment with crude extract and fractions of A. tenuifolius exhibited significant hypotensive and diuretic potential in normotensive rats. However, AS-AT produced the most potent and significant dose-dependent hypotension and diuretic effects in normotensive rats. Previous treatment with atropine significantly reduced the hypotensive and diuretic action of AS-AT, but pretreatment with indomethacin or L-NAME did not affect these effects. Moreover, the 7-day treatment with AS-AT did not reduce activities of serum angiotensin-converting enzyme, erythrocyte carbonic anhydrase, and renal Na+/K+/ATPase. AS-AT showed four major compound node clusters, which included sugars, alkaloids, nucleoside, amino acid, and glycosylated flavonoids. This research supports and extends the traditional use of A. tenuifolius as a hypotensive and diuretic agent. The results showed that AS-AT from A. tenuifolius could present compounds responsible for hypotensive and diuretic activities through the activation of muscarinic receptors

Prevalence of UDP-glucuronosyltransferase polymorphisms (UGT1A6∗2, 1A7∗12, 1A8∗3, 1A9∗3, 2B7∗2, and 2B15∗2) in a

Glucuronidation is an important phase II pathway responsible for many endogenous substances and drug metabolism. The present work evaluated allele frequencies of certain UDP-glucuronosyl-transferases (UGT 1A6∗2, A7∗12, A8∗3, A9∗3, 2B7∗2, and 2B15∗2) in Saudi Arabians that could provide essential ethnic information. Blood samples from 192 healthy unrelated Saudi males of various geographic regions were collected. Genomic DNA was isolated and genotyping of various UGTs was carried out using polymerase chain reaction (PCR) followed by direct sequencing. For UGT1A6∗2 A/G genotype, the most common variant was the homozygous repeat (AA) and the most common allele was (A) with a frequency of 46.5% and 67.3%, respectively. Similarly, the most common variant for UGT1A7∗12 T/C genotype was the heterozygous repeat (TC) with a frequency of 78.7% while the mutant allele (C) was present in 60.6% of the study population. Both UGT1A8∗3 (G/A) and UGT1A9∗3 (T/C) showed only a wild homozygous pattern in all screened subjects. For UGT2B7∗2, the heterozygous repeat (TC) was found with a frequency of 57.3% and the alleles (A) showed a frequency of 50.8%. In contrast, for UGT2B15∗2 (G253T), the heterozygous repeat (TG) presented 62.3% of the subjects where the most common allele (G) was with a frequency of 66.2%. In conclusion, our data indicate that Saudis harbor some important UGT mutations known to affect enzyme activity. Additional studies are therefore, warranted to assess the clinical implications of these gene polymorphisms in this ethnic group

Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability

Premature ovarian failure (POF) is a genetically and phenotypically heterogeneous disorder that includes individuals with manifestations ranging from primary amenorrhea to loss of menstrual function prior to age 40. POF presents as hypergonadotropic hypogonadism and can be part of a syndrome or occur in isolation. Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism. The sisters were born to parents who are first cousins. SNP analysis and whole-exome sequencing revealed the presence of a pathogenic variant of the minichromosome maintenance 8 gene (MCM8, c.446C>G; p.P149R) located within a region of homozygosity that was present in the affected daughters but not in their unaffected sisters. Because MCM8 participates in homologous recombination and dsDNA break repair, we tested fibroblasts from the affected sisters for hypersensitivity to chromosomal breaks. Compared with fibroblasts from unaffected daughters, chromosomal break repair was deficient in fibroblasts from the affected individuals, likely due to inhibited recruitment of MCM8 p.P149R to sites of DNA damage. Our study identifies an autosomal recessive disorder caused by an MCM8 mutation that manifests with endocrine dysfunction and genomic instability