scholarly journals Contractility of the epididymal duct - function, regulation and potential drug effects

Reproduction ◽  
2018 ◽  
Author(s):  
Vera Elfgen ◽  
Andrea Mietens ◽  
Marco Mewe ◽  
Thorben Hau ◽  
Ralf Middendorff
Keyword(s):  
Smooth Muscle ◽  
Clinical Practice ◽  
Side Effects ◽  
Male Fertility ◽  
Vas Deferens ◽  
Drug Effects ◽  
Potential Drug ◽  
Regulation Of Contraction ◽  
Contraction And Relaxation ◽  
Epididymal Duct

During their transit through the epididymis, spermatozoa mature and acquire motility and fertilizing capacity. The smooth muscle cells (SMCs) of the epididymal duct are thought to be responsible for the adequate transport of spermatozoa. Thus, precise regulation of SMC function also represents a prerequisite for sperm maturation thereby contributing to male fertility. In this review we would like to highlight various aspects of epididymal SMC function and discuss several angles with respect to regulation of contraction and relaxation. Different to the vas deferens, where disturbed SMC pathways resulting in male infertility could be defined, comparable information is missing in the epididymis. We therefore include some vas deferens data which could also be useful for a better understanding of epididymal SMC function. Furthermore, we would like to draw attention to drugs used in clinical practice and their potential (side) effects on contractions in the epididymis.

scholarly journals Phosphorylated HSP20 modulates the association of thin-filament binding proteins: caldesmon with tropomyosin in colonic smooth muscle

2010 ◽  
Vol 299 (5) ◽  
pp. G1164-G1176 ◽  
Author(s):  
Sita Somara ◽  
Robert R. Gilmont ◽  
Saranyaraajan Varadarajan ◽  
Khalil N. Bitar
Keyword(s):  
Smooth Muscle ◽  
Thin Filament ◽  
Muscle Activation ◽  
Molecular Signaling ◽  
Phosphorylation State ◽  
Filament Dynamics ◽  
Physiological Relevance ◽  
Regulation Of Contraction ◽  
Shock Proteins ◽  
Contraction And Relaxation

Small heat shock proteins HSP27 and HSP20 have been implicated in regulation of contraction and relaxation in smooth muscle. Activation of PKC-α promotes contraction by phosphorylation of HSP27 whereas activation of PKA promotes relaxation by phosphorylation of HSP20 in colonic smooth muscle cells (CSMC). We propose that the balance between the phosphorylation states of HSP27 and HSP20 represents a molecular signaling switch for contraction and relaxation. This molecular signaling switch acts downstream on a molecular mechanical switch [tropomyosin (TM)] regulating thin-filament dynamics. We have examined the role of phosphorylation state(s) of HSP20 on HSP27-mediated thin-filament regulation in CSMC. CSMC were transfected with different HSP20 phosphomutants. These transfections had no effect on the integrity of actin cytoskeleton. Cells transfected with 16D-HSP20 (phosphomimic) exhibited inhibition of acetylcholine (ACh)-induced contraction whereas cells transfected with 16A-HSP20 (nonphosphorylatable) had no effect on ACh-induced contraction. CSMC transfected with 16D-HSP20 cDNA showed significant decreases in 1) phosphorylation of HSP27 (ser78); 2) phosphorylation of PKC-α (ser657); 3) phosphorylation of TM and CaD (ser789); 4) ACh-induced phosphorylation of myosin light chain; 5) ACh-induced association of TM with HSP27; and 6) ACh-induced dissociation of TM from caldesmon (CaD). We thus propose the crucial physiological relevance of molecular signaling switch (phosphorylation state of HSP27 and HSP20), which dictates 1) the phosphorylation states of TM and CaD and 2) their dissociations from each other.

Man am I Stoned, I think! The role of experience and side effects in the perception of drug effects

1972 ◽  
Author(s):  
Cornelis Bakker ◽  
Albert S. Carlin ◽  
Robert Heaton ◽  
Reese T. Jones ◽  
Theodore X. Barber
Keyword(s):  
Side Effects ◽  
Drug Effects

Recent Advances in the Development of Antimicrobial Peptides (AMPs): Attempts for Sustainable Medicine?

2018 ◽  
Vol 25 (21) ◽  
pp. 2503-2519 ◽  
Author(s):  
Anne Kokel ◽  
Marianna Torok
Keyword(s):  
Side Effects ◽  
Antimicrobial Peptides ◽  
Potential Drug ◽  
Green Technologies ◽  
Specific Antibodies ◽  
Structural Modifications ◽  
Drug Candidates ◽  
Induce Resistance ◽  
Conventional Antibiotics

Background: Since the first isolation of antimicrobial peptides (AMPs) they have attracted extensive interest in medicinal chemistry. However, only a few AMP-based drugs are currently available on the market. Despite their effectiveness, biodegradability, and versatile mode of action that is less likely to induce resistance compared to conventional antibiotics, AMPs suffer from major issues that need to be addressed to broaden their use. Notably, AMPs can lack selectivity leading to side effects and cytotoxicity, and also exhibit in vivo instability. Several strategies are being actively considered to overcome the limitations that restrain the success of AMPs. Methods: In the current work, recent strategies reported for improving AMPs in the context of drug design and delivery were surveyed, and also their possible impact on patients and the environment was assessed. Results: As a major advantage AMPs possess an easily tunable skeleton offering opportunities to improve their properties. Strategic structural modifications and the beneficial properties of cyclic or branched AMPs in term of stability have been reported. The conjugation of AMPs with nanoparticles has also been explored to increase their in vivo stability. Other techniques such as the coupling of AMPs with specific antibodies aim to increase the selectivity of the potential drug towards the target. These strategies were evaluated for their effect on the environment highlighting green technologies. Conclusion: Although further research is needed taking into account both environmental and human health consequences of novel AMPs, several of these compounds are promising drug candidates for use in sustainable medicine.

Recent Advances in the Rational Drug Design Based on Multi-target Ligands

2020 ◽  
Vol 27 (28) ◽  
pp. 4720-4740 ◽  
Author(s):  
Ting Yang ◽  
Xin Sui ◽  
Bing Yu ◽  
Youqing Shen ◽  
Hailin Cong
Keyword(s):  
Drug Resistance ◽  
Clinical Practice ◽  
Side Effects ◽  
Drug Design ◽  
Rational Drug Design ◽  
Health Conditions ◽  
Pharmacokinetic Parameters ◽  
Single Target ◽  
Rational Drug ◽  
Huge Challenge

Multi-target drugs have gained considerable attention in the last decade owing to their advantages in the treatment of complex diseases and health conditions linked to drug resistance. Single-target drugs, although highly selective, may not necessarily have better efficacy or fewer side effects. Therefore, more attention is being paid to developing drugs that work on multiple targets at the same time, but developing such drugs is a huge challenge for medicinal chemists. Each target must have sufficient activity and have sufficiently characterized pharmacokinetic parameters. Multi-target drugs, which have long been known and effectively used in clinical practice, are briefly discussed in the present article. In addition, in this review, we will discuss the possible applications of multi-target ligands to guide the repositioning of prospective drugs.

Development of a brief questionnaire (ICQ-S) to monitor inhaled corticosteroid side-effects in clinical practice

Allergy ◽  
2014 ◽  
Vol 69 (3) ◽  
pp. 372-379 ◽  
Author(s):  
J. M. Foster ◽  
S. Schokker ◽  
R. Sanderman ◽  
D. S. Postma ◽  
T. van der Molen
Keyword(s):  
Clinical Practice ◽  
Side Effects ◽  
Inhaled Corticosteroid

scholarly journals Safety of hydroxychloroquine and darunavir or lopinavir in COVID-19 infection

2020 ◽  
Author(s):  
Etienne Meriglier ◽  
Claire Rivoisy ◽  
Mojgan Hessamfar ◽  
Noelle Bernard ◽  
Ines Aureau ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cohort Study ◽  
Clinical Practice ◽  
Combination Therapy ◽  
Observational Cohort Study ◽  
Potential Drug ◽  
Clinical Evaluations ◽  
History Of ◽  
Observational Cohort ◽  
Ecg Abnormalities

Abstract Background Combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir has been suggested as an approach to improve the outcome of patients with moderate/severe COVID-19 infection. Objectives To examine the safety of combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. Methods This was an observational cohort study of patients hospitalized for COVID-19 pneumonia treated with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. Clinical evaluations, electrocardiograms and the pharmacokinetics of hydroxychloroquine, darunavir and lopinavir were examined according to clinical practice and guidelines. Results Twenty-one patients received hydroxychloroquine with lopinavir/ritonavir (median age 68 years; 10 males) and 25 received hydroxychloroquine with darunavir/ritonavir (median age 71 years; 15 males). During treatment, eight patients (17.4%) developed ECG abnormalities. Ten patients discontinued treatment, including seven for ECG abnormalities a median of 5 (range 2–6) days after starting treatment. All ECG abnormalities reversed 1–2 days after interrupting treatment. Four patients died within 14 days. ECG abnormalities were significantly associated with age over 70 years, coexisting conditions (such as hypertension, chronic cardiovascular disease and kidney failure) and initial potential drug interactions, but not with the hydroxychloroquine concentration. Conclusions Of the patients with COVID-19 who received hydroxychloroquine with lopinavir or darunavir, 17% had ECG abnormalities, mainly related to age or in those with a history of cardiovascular disease.

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