scholarly journals Proteomics-Based Retinal Target Engagement Analysis and Retina-Targeted Delivery of 17β-Estradiol by the DHED Prodrug for Ocular Neurotherapy in Males

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1392
Author(s):  
Katalin Prokai-Tatrai ◽  
Khadiza Zaman ◽  
Vien Nguyen ◽  
Daniel L. De La Cruz ◽  
Laszlo Prokai
Keyword(s):  
Targeted Delivery ◽  
Mitochondrial Respiratory Chain ◽  
Male Rat ◽  
Eye Drops ◽  
Target Engagement ◽  
Rat Retina ◽  
Beneficial Effects ◽  
17Β Estradiol ◽  
The Impact ◽  
First Time

We examined the impact of 17β-estradiol (E2) eye drops on the modulation of the proteome profile in the male rat retina. With discovery-driven proteomics, we have identified proteins that were regulated by our treatment. These proteins were assembled to several bioinformatics-based networks implicating E2’s beneficial effects on the male rat retina in a broad context of ocular neuroprotection including the maintenance of retinal homeostasis, facilitation of efficient disposal of damaged proteins, and mitochondrial respiratory chain biogenesis. We have also shown for the first time that the hormone’s beneficial effects on the male retina can be constrained to this target site by treatment with the bioprecursor prodrug, DHED. A large concentration of E2 was produced after DHED eye drops not only in male rat retinae but also in those of rabbits. However, DHED treatment did not increase circulating E2 levels, thereby ensuring therapeutic safety in males. Targeted proteomics focusing on selected biomarkers of E2’s target engagement further confirmed the prodrug’s metabolism to E2 in the male retina and indicated that the retinal impact of DHED treatment was identical to that of the direct E2 treatment. Altogether, our study shows the potential of topical DHED therapy for an efficacious and safe protection of the male retina without the unwanted hormonal side-effects associated with current estrogen therapies.

scholarly journals The Tardigrade Hypsibius Exemplaris as an Emerging Model to Study the Mitochondrial Alternative Oxidase at Animal Organismal Level

2020 ◽  
Author(s):  
Daria Grobys ◽  
Milena Roszkowska ◽  
Łukasz Kaczmarek ◽  
Wiesława Jarmuszkiewicz ◽  
Andonis Karachitos ◽  
...  
Keyword(s):  
Alternative Oxidase ◽  
Mitochondrial Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Complex Iii ◽  
Whole Body ◽  
Intact Specimen ◽  
Complex Iv ◽  
Animal Physiology ◽  
The Impact ◽  
First Time

Abstract Background: Mitochondrial alternative oxidase (AOX) is suggested to be present in mitochondria of most invertebrates but not vertebrates. Independently of the reason concerning the enzyme occurrence in animal mitochondria, expression of AOX in human mitochondria is regarded as a potential therapeutic strategy in treatment of mitochondrial diseases caused by the mitochondrial respiratory chain (MRC) deficiency or blockage. Undoubtedly, development of AOX expression-based therapy requires explanation of AOX contribution to animal physiology. Till now the relevant data has been obtained mainly due to heterologous AOX expression in cells and animals that do not have natively expressed AOX. We think that application of animals natively expressing AOX could importantly contribute to the research and therapy development. Because the available genomic and transcriptomic data suggests the presence of functional AOX protein in mitochondria of the tardigrade Hypsibius exemplaris, we decided to investigate the possibility of the animal application as a model for AOX activity analysis at organismal level.Results: We observed that H. exemplaris tolerance to the blockage of the MRC complexes III and/or IV was diminished in the presence of AOX inhibitor and the inhibitor-sensitive respiration enabled the tardigrade respiration under condition of the blockage. Furthermore, although detection of H. exemplaris AOX at protein level and pronounced oxygraphic registration of its activity required the MRC complex III and/or IV blockage, the obtained data indicated that AOX clearly contributed to the animal functioning, also in the absence of the blockage. Conclusions: According to our best knowledge we demonstrated, for the first time, that AOX activity of small aquatic invertebrates, represented by the studied tardigrade species, can be monitored by measurement of intact specimen whole-body respiration. Furthermore, it was also possible to monitor the impact of the MRC complex IV blockage on AOX expression level and AOX inhibition in the absence of the blockage on animal functioning. Thus, H. exemplaris could be applied as a whole-animal model suitable to study activity and expression regulation of natively expressed animal AOX.

17β-Estradiol synthesis in the adult male rat retina

2007 ◽  
Vol 85 (1) ◽  
pp. 166-172 ◽  
Author(s):  
C. Cascio ◽  
D. Russo ◽  
G. Drago ◽  
G. Galizzi ◽  
R. Passantino ◽  
...  
Keyword(s):  
Adult Male ◽  
Male Rat ◽  
Rat Retina ◽  
Adult Male Rat ◽  
17Β Estradiol ◽  
Estradiol Synthesis

scholarly journals Impact of Route of Estrogen Administration on Bone Turnover Markers in Oligoamenorrheic Athletes and Its Mediators

2018 ◽  
Vol 104 (5) ◽  
pp. 1449-1458 ◽  
Author(s):  
Vibha Singhal ◽  
Kathryn E Ackerman ◽  
Amita Bose ◽  
Landy Paola Torre Flores ◽  
Hang Lee ◽  
...  
Keyword(s):  
Bone Formation ◽  
Ethinyl Estradiol ◽  
Total Testosterone ◽  
Mineral Density ◽  
Beneficial Effects ◽  
17Β Estradiol ◽  
Turnover Markers ◽  
Pill Group ◽  
The Impact ◽  
Estrogen Administration

Abstract Objective Transdermal, but not oral, estrogen replacement improves bone mineral density (BMD) in athletes with oligoamenorrhea (OA). Our objective was to determine mechanisms that may explain the impact of route of estrogen administration on bone outcomes. Methods Seventy-three participants with OA between 14 and 25 years old received (i) a 17β-estradiol transdermal patch continuously with cyclic oral micronized progesterone (PATCH), (ii) a combined ethinyl estradiol and desogestrel pill (PILL), or (iii) no estrogen/progesterone (NONE) for 12 months. We evaluated morning fasting levels of a marker of bone formation [N-terminal propeptide of type 1 procollagen (P1NP)], a marker of bone resorption (N-telopeptide), IGF-1, insulinlike growth factor binding protein 3, total testosterone, estradiol, SHBG, sclerostin, preadipocyte factor-1 (Pref-1), brain-derived neurotrophic factor (BDNF), calcium, 25(OH) vitamin D, and PTH levels at baseline and 12 months. Results Groups did not differ for age, weight, exercise activity, or markers of bone formation at baseline. Over 12 months, P1NP decreased the most in the PILL group (P = 0.03) associated with a decrease in IGF-1 levels (r = 0.37; P = 0.003). Sclerostin, Pref-1, and BDNF decreased in the PATCH group over 12 months. PATCH had the greatest increases in estradiol (P ≤ 0.0001), and estradiol increases were associated with increases in bone density. Conclusion Transdermal 17β-estradiol given over 12 months does not cause the decrease in IGF-1 observed with oral ethinyl estradiol. It also leads to decreases in sclerostin, Pref-1, and BDNF, which may mediate the beneficial effects of estrogen.

scholarly journals Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 456
Author(s):  
Katalin Prokai-Tatrai ◽  
Vien Nguyen ◽  
Daniel L. De La Cruz ◽  
Rebecca Guerra ◽  
Khadiza Zaman ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Ex Vivo ◽  
Estrogen Therapy ◽  
Topical Administration ◽  
The Body ◽  
Female Rats ◽  
Full Potential ◽  
Eye Drops ◽  
17Β Estradiol

The purpose of this study was to explore retina-targeted delivery of 17β-estradiol (E2), a powerful neuroprotectant, by its bioprecursor prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) administered as eye drops in animal models. Compared to the parent hormone, DHED displayed increased transcorneal flux ex vivo both with and without the presence of 2-hydroxypropyl-β-cyclodextrin used as a penetration-enhancing excipient in rat, rabbit, and pig. In vitro, the prodrug also showed facile bioactivation to E2 in the retina but not in the cornea. After topical administration to rats and rabbits, peak DHED-derived E2 concentrations reached 13 ± 5 ng/g and 18 ± 7 ng/g in the retina of female rats and rabbits, respectively. However, the prodrug remained inert in the rest of the body and, therefore, did not cause increase in circulating hormone concentration, as well as wet uterine and anterior pituitary weights as typical markers of E2′s endocrine impact. Altogether, our studies presented here have demonstrated the premise of topical retina-selective estrogen therapy by the DHED prodrug approach for the first time and provide compelling support for further investigation into the full potential of DHED for an efficacious and safe ocular neurotherapy.

scholarly journals 17β-Estradiol Delivered in Eye Drops: Evidence of Impact on Protein Networks and Associated Biological Processes in the Rat Retina through Quantitative Proteomics

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 101 ◽  
Author(s):  
Laszlo Prokai ◽  
Khadiza Zaman ◽  
Vien Nguyen ◽  
Katalin Prokai-Tatrai
Keyword(s):  
Broad Spectrum ◽  
System Development ◽  
Nervous System Development ◽  
Brown Norway ◽  
Protein Networks ◽  
Eye Drops ◽  
Functional Protein ◽  
Rat Retina ◽  
17Β Estradiol ◽  
And Function

To facilitate the development of broad-spectrum retina neuroprotectants that can be delivered through topical dosage forms, this proteomics study focused on analyzing target engagements through the identification of functional protein networks impacted after delivery of 17β-estradiol in eye drops. Specifically, the retinae of ovariectomized Brown Norway rats treated with daily eye drops of 17β-estradiol for three weeks were compared to those of vehicle-treated ovariectomized control animals. We searched the acquired raw data against a composite protein sequence database by using Mascot, as well as employed label-free quantification to detect changes in protein abundances. Our investigation using rigorous validation criteria revealed 331 estrogen-regulated proteins in the rat retina (158 were up-regulated, while 173 were down-regulated by 17β-estradiol delivered in eye drops). Comprehensive pathway analyses indicate that these proteins are relevant overall to nervous system development and function, tissue development, organ development, as well as visual system development and function. We also present 18 protein networks with associated canonical pathways showing the effects of treatments for the detailed analyses of target engagements regarding potential application of estrogens as topically delivered broad-spectrum retina neuroprotectants. Profound impact on crystallins is discussed as one of the plausible neuroprotective mechanisms.

Relationship between big five personality model and abusive supervision

2019 ◽  
Vol 12 (2) ◽  
Author(s):  
Bibi Tahira ◽  
Naveed Saif ◽  
Muhammad Haroon ◽  
Sadaqat Ali
Keyword(s):  
Big Five ◽  
Abusive Supervision ◽  
State Universities ◽  
Big Five Personality ◽  
Big Five Model ◽  
The Impact ◽  
First Time ◽  
Supervisor Behavior ◽  
Moderating Role

The current study tries to understand the diverse nature of relationship between personality Big Five Model (PBFM) and student's perception of abusive supervision in higher education institutions of Khyber Pakhtoonkhwa Pakistan. Data was collected in dyads i.e. (supervisors were asked to rate their personality attributes while student were asked to rate the supervisor behavior) through adopted construct. For this purpose, data was collected from three government state universities and one Private Sector University. The focus was on MS/M.Phill and PhD student and their supervisors of the mentioned universities. After measuring normality and validity regression analysis was conducted to assess the impact of supervisor personality characteristics that leads to abusive supervision. Findings indicate interestingly that except agreeableness other four attributes of (PBFM) are play their role for abusive supervision. The results are novel in the nature as for the first time Neuroticism, openness to experience, extraversion and conscientiousness are held responsible for the abusive supervision. The study did not explore the demographic characteristics, and moderating role of organizational culture, justice and interpersonal deviances to understand the strength of relationship in more detail way. Keywords: Personality big five model, abusive supervision, HEIs

HBOT Application at Cases of Gingival Inflammation

2019 ◽  
Author(s):  
Ilma Robo
Keyword(s):  
Root Resorption ◽  
Periodontal Diseases ◽  
Therapeutic Effects ◽  
Clinical Effects ◽  
Gingival Inflammation ◽  
Beneficial Effects ◽  
New Therapeutic Approaches ◽  
Short Period ◽  
Mechanical Therapy ◽  
The Impact

The treatment of periodontal diseases, mainly of their origin, with the most common clinical manifestation in form of gingival inflammation, is manifold and powerful, including: mechanical therapy, antibiotic, antiseptic and various approaches to treatment, which are recommended to be used within a short period of time. New therapeutic approaches have been proven as alternative treatment to conventional therapy, or in combination with conventional therapies, to reduce the number of periodontopathic pathogens in gingival sulcus. HBOT has a detrimental effect on periodontal microorganisms, as well as beneficial effects on the healing of periodontal tissue, increasing oxygen pressure in gingival pockets. Our study is aimed at reviewing the current published literature on hyperbaric oxygen therapy and focuses on role of HBOT as a therapeutic measure for the individual with periodontal disease in general and for the impact on the recovery of gingival inflammation. HBOT and periodontal treatment together, reduce up to 99% of the gram-negative anaerobic load of subgingival flora. HBOT, significantly reduces subgingival anaerobic flora. Clinical effects in 2-year follow-up of treated patients are sensitive. Reduction of gingival hemorrhage indexes, depth of peritoneum, plaque index, occurs in cases of combination of HBOT and detraction. Reduced load persists up to 2 months after therapy. The significant increase in connective tissue removal starts at the end of 2nd week, to achieve the maximum in week 3-6 of application. HBOT used for re-implantation, stimulates the healing of periodontal membrane, pulp, prevents root resorption, healing of periodontal lining tissues. HBOT, significantly reduces the hemorrhage index with 1.2 value difference, 0.7mm probe depth, reduces gingival fluid by 2. HGH exposure is increased by gingival blood flow, with a difference of 2 in measured value. The therapeutic effects of HBOT in the value of the evaluation index can be saved up to 1-year post treatment.

The Influence of TRIPS Compliant Patent Laws on Indian Pharmaceutical Industry

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
Rupesh Rastogi ◽  
Virendra Kumar
Keyword(s):  
Pharmaceutical Industry ◽  
Patent Protection ◽  
Uruguay Round ◽  
Pharmaceutical Products ◽  
Trips Agreement ◽  
Patent Law ◽  
Patent Laws ◽  
The Impact ◽  
First Time ◽  
Indian Pharmaceutical Industry

The first legislation in India relating to patents was the Act VI of 1856. The Indian Patents and Design Act, 1911 (Act II of 1911) replaced all the previous Acts. The Act brought patent administration under the management of Controller of Patents for the first time. After Independence, it was felt that the Indian Patents & Designs Act, 1911 was not fulfilling its objective. Various comities were constituted to recommend, framing a patent law which can fulfill the requirement of Indian Industry and people. The Indian Patent Act of 1970 was enacted to achieve the above objectives. The major provisions of the act, provided for process, not the product patents in food, medicines, chemicals with a term of 14 years and 5-7 for chemicals and drugs. The Act enabled Indian citizens to access cheapest medicines in the world and paved a way for exponential growth of Indian Pharmaceutical Industry. TRIPS agreement, which is one of the important results of the Uruguay Round, mandated strong patent protection, especially for pharmaceutical products, thereby allowing the patenting of NCEs, compounds and processes. India is thereby required to meet the minimum standards under the TRIPS Agreement in relation to patents and the pharmaceutical industry. India’s patent legislation must now include provisions for availability of patents for both pharmaceutical products and processes inventions. The present paper examines the impact of change in Indian Patent law on Pharmaceutical Industry.

The impact of traditional plants and their secondary metabolites in the discovery of COVID-19 treatment

2020 ◽  
Vol 26 ◽  
Author(s):  
Shabana Bibi ◽  
Ayesha Sarfraz ◽  
Ghazala Mustafa ◽  
Zeeshan Ahmed ◽  
Muhammad Aurang Zeb ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Test System ◽  
Chemical Information ◽  
System Type ◽  
The Family ◽  
Comprehensive Search ◽  
Coronavirus Infection ◽  
The Impact ◽  
First Time ◽  
Plant Sources

Background: Coronavirus Disease-2019 belongs to the family of viruses which cause a serious pneumonia along with fever, breathing issues and infection of lungs for the first time in China and later spread worldwide. Objective: Several studies and clinical trials have been conducted to identify potential drugs and vaccines for Coronavirus Disease-2019. The present study listed natural secondary metabolites identified from plant sources with antiviral properties and could be safer and tolerable treatment for Coronavirus Disease-2019. Methods: A comprehensive search on the reported studies was conducted using different search engine such as Google scholar, SciFinder, Sciencedirect, Medline PubMed, and Scopus for the collection of research articles based on plantderived secondary metabolites, herbal extracts, and traditional medicine for coronavirus infections. Results: Status of COVID-19 worldwide and information of important molecular targets involved in COVID-19 is described and through literature search, is highlighted that numerous plant species and their extracts possess antiviral properties and studied with respect to Coronavirus treatments. Chemical information, plant source, test system type with mechanism of action for each secondary metabolite is also mentioned in this review paper. Conclusion: The present review has listed plants that have presented antiviral potential in the previous coronavirus pandemics and their secondary metabolites which could be significant for the development of novel and a safer drug which could prevent and cure coronavirus infection worldwide.

Individual and Combined Assessment of Ser680Asn FSH Receptor and FSHβ -211 G>T Gene Polymorphisms in Ovarian Response in IVF/ICSI Program

2020 ◽  
Vol 21 ◽  
Author(s):  
Elli Anagnostou ◽  
Alexia Kafkoutsou ◽  
Despina Mavrogianni ◽  
Ekaterini Domali ◽  
Evangelia Dimitroulia ◽  
...  
Keyword(s):  
Gene Polymorphism ◽  
Gene Polymorphisms ◽  
Ovarian Response ◽  
Greek Population ◽  
Control Group ◽  
Genotype Distribution ◽  
Β Subunit ◽  
Molecular Genetic Study ◽  
The Impact ◽  
First Time

Background: Molecular biology tools, such as the detection of single nucleotide polymorphisms (SNPs), have been considered to assist to the management of the ovarian stimulation protocols. Purpose: The aim of this study was to evaluate the impact of two polymorphisms, the Asn680Ser polymorphism of the FSHR gene, and the FSH β subunit (FSHβ) gene polymorphism -211 G>T, in a Greek population of women undergoing IVF/ICSI program in our center. In addition, a control group of fertile women was studied, to verify whether there are differences in the genotype distribution between fertile and infertile population for both polymorphisms, as the FSHβ gene polymorphism -211 G>T is studied for the first time in the Greek population. Results : The FSH β-211 G>T polymorphism, studied for the first time in the Greek infertile population, appears to be quite rare. When studying the two polymorphisms separately, statistically significant differences were obtained that concerned the LH levels. Discussion: According to the combination analysis of the two polymorphisms by the number of alleles, women with 2-3 polymorphic alleles needed more days of stimulation, but there were no differences in pregnancy rates. Conclusion: This molecular genetic study helps to elucidate whether the polygenic combination of the Asn680Ser and FSH β subunit -211 G>T gene polymorphisms is of additive value in the prediction of ovarian response to exogenous gonadotropins.

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