Biomedical subjects

Michael Sohn

Publications and source records attributed to Michael Sohn.

9 recordsLinked to original sources

PubMed2026

Longitudinal development of infant oral ecosystem: salivary metabolomic, bacteriome, and virome dynamics in early infancy.

This prospective cohort study investigated the longitudinal development of the salivary bacteriome, virome, and metabolome during early infancy. We assessed the associations between oral bacteria, viruses, and metabolites from 10 mother-infant dyads, with oral samples collected at 1 and 2 years of age. Forty saliva and plaque samples underwent untargeted metabolomic analysis, and infant saliva samples underwent metagenomic sequencing. Maternal salivary and plaque metabolomic profiles remained largely stable, whereas infant profiles were clearly separated from maternal profiles and changed with age. Notably, infant dental plaque metabolism underwent more substantial changes from year 1 to year 2 than saliva, with age-dependent metabolite shifts mainly involving energy, amino acid, nucleotide, and lipid metabolic pathways. Our findings also revealed significant developmental shifts in salivary bacteriome, virome, and functional pathway profiles during early childhood. The most abundant oral bacteria in early life, comprising over 75% of total abundance, included Veillonella, Streptococcus, Rothia, Prevotella, Neisseria, and Actinomyces species. While human viruses like Roseolovirus were detected, bacteriophages constituted the majority of the virome. Comparing infants at year 1 and year 2, we identified differentially abundant bacteria, viruses, metabolic functional pathways, and specific metabolites. We observed associations between bacteria and viruses, noting that these cross-kingdom relationships attenuated as infants grew. The study results underscore the complex and dynamic development of the oral microbiome, virome, and metabolome during early childhood.IMPORTANCEThe human oral cavity undergoes substantial microbial and metabolic development during early childhood, yet the temporal changes in the infant oral ecosystem remain incompletely understood. In this study, we longitudinally profiled the salivary metabolome, bacteriome, and virome of infants at 1 and 2 years of age. We demonstrated that the infant oral metabolome undergoes substantial developmental shifts, particularly in pathways related to energy, amino acid, and lipid metabolism; whereas maternal metabolic profiles remained stable over the same period. Furthermore, our results revealed the dynamic assembly of infant salivary virome and bacteriome and their associations with the functional pathways and metabolites. These findings provide new insights into the complex and dynamic development of the oral microbiome, virome, and metabolome in early infancy.

bacteriome↗

PubMed2005

Biochemistry and pharmacology of novel anthranilic acid derivatives activating heme-oxidized soluble guanylyl cyclase.

The heme-enzyme soluble guanylyl cyclase (sGC) is an ubiquitous NO receptor, which mediates NO downstream signaling by the generation of cGMP. We studied the mechanism of action of the anthranilic acid derivatives 5-chloro-2-(5-chloro-thiophene-2-sulfonylamino-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide sodium salt (HMR1766) (proposed international nonproprietary name, ataciguat sodium) and 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (S3448) as a new class of sGC agonists. Both compounds activated different sGC preparations (purified from bovine lung, or crude from human corpus cavernosum) in a concentration-dependent and quickly reversible fashion (EC50 = 0.5-10 microM), with mixed-type activation kinetics. Activation of sGC by these compounds was additive to activation by NO donors, but instead of being inhibited, it was potentiated by the heme-iron oxidants 1H-[1,2,4]-oxdiazolo[3,4-a]quinoxalin-1-one (ODQ) and 4H-8-bromo-1,2,4-oxadiazolo(3,4-d) benz(b)(1,4)oxazin-1-one (NS2028), suggesting that the new compounds target the ferric heme sGC isoform. Protoporphyrin IX acted as a competitive activator, and zinc-protoporphyrin IX inhibited activation of heme-oxidized sGC by HMR1766 and S3448, whereas heme depletion of sGC by Tween 20 treatment reduced activation. Both compounds increased cGMP levels in cultured rat aortic smooth muscle cells; induced vasorelaxation of isolated endothelium-denuded rat aorta, porcine coronary arteries, and human corpus cavernosum (EC50 1 to 10 microM); and elicited phosphorylation of the cGMP kinase substrate vasodilator-stimulated phosphoprotein at Ser239. HMR1766 intravenous bolus injection decreased arterial blood pressure in anesthetized pigs. All of these pharmacological responses to the new compounds were enhanced by ODQ and NS2028. Our findings suggest that HMR1766 and S3448 preferentially activate the NO-insensitive heme-oxidized form of sGC, which exists to a variable extent in vascular tissues, and is a pharmacological target for these new vasodilator drugs.

Animals↗

PubMed2005

Cyclic AMP-specific and cyclic GMP-specific phosphodiesterase isoenzymes in human cavernous arteries--immunohistochemical distribution and functional significance.

OBJECTIVES: It has been well established that male erectile dysfunction is frequently associated with vascular diseases. The normal function of cavernous arteries is considered a prerequisite to maintain sufficient blood flow to the trabecular spaces in order to enable penile erection. Contractility of cavernous arteries is regulated by the peripheral autonomic nervous system and endogenous factors released from the endothelial cell layer. A significant increase of blood flow in the central cavernous arteries is the initial event leading to penile tumescence and rigidity. Besides the significance of the nitric oxide/cyclic guanosine monophosphate (cGMP)-mediated mechanisms, the cyclic AMP (cAMP) signalling pathway is also involved in the regulation of tone of the erectile tissue, and interactions between cGMP- and cAMP-mediated mechanisms have been demonstrated. The aim of the present study was to investigate by means of immunohistochemistry the presence of the phosphodiesterase (PDE) isoenzymes 3, 4 (cAMP-specific PDEs) and 5 (cGMP-specific PDE) in thin sections of human central cavernous arteries (HCA) and their functional significance in the mechanism of vessel tone regulation. METHODS: Functional experiments were performed using circular segments of HCA and strip preparations of the human corpus cavernosum (HCC). Relaxant effects induced by the cumulative addition of the PDE inhibitors milrinone (PDE3 inhibitor), rolipram (PDE4 inhibitor) and sildenafil (PDE5 inhibitor; 0.01, 0.1, 1 and 10 M) were studied in preparations of HCA and HCC challenged by 1 M norepinephrine (NE). Moreover, immunohistochemistry was carried out in order to evaluate the expression of PDE3, PDE4 and PDE5 in thin sections of HCA. RESULTS: Milrinone, rolipram and sildenafil dose-dependently reversed the NE-induced tension of the isolated vascular segments and HCC strips with sildenafil being the most effective drug. Neither rolipram nor milrinone reached an EC50 value. Abundant immunoreactivities specific for PDE3, PDE4 and PDE5 were observed in the entire smooth musculature of the wall of HCA and resistance arteries. In addition, immunoreactivity for PDE4 was also detected in the cytoplasm of endothelial cells lining the cavernous arteries. CONCLUSIONS: The cGMP-dependent relaxation of cavernous arteries is not only dependent on the normal function of the peripheral autonomic nervous system but also on the functional integrity of the vascular endothelium. The expression of the cGMP-specific PDE5 and the ability of the PDE5 inhibitor sildenafil to reverse the adrenergic tension of isolated segments of HCA underline the important role of the NO/cGMP pathway in the control of smooth muscle tone of human trabecular smooth musculature and penile cavernous arteries. Our results also suggest a significance of the cAMP-dependent signaling mechanisms in the regulation of tension of central HCAs. The present findings are also in support of the hypothesis of interactions between the cGMP- and cAMP-mediated signaling pathways in HCAs. Further investigations are indicated in order to outline potential differences between central HCAs and helicine resistance arteries. This may help to understand better the relations between structural and functional changes in the penile erectile tissue in patients with cardiovascular diseases and endothelial dysfunction.

Arteries↗

PubMed2005

Sleep investigations in erectile dysfunction.

Regarding the aetiology of erectile dysfunction, beside numerous organic causes in many cases psychological factors play an important role. The pathophysiological mechanisms underlying the so-called psychogenic erectile dysfunction are not yet understood. Based on a neurobiological approach to psychogenic erectile dysfunction, polysomnographic investigations were carried out with the aim of identifying possible alterations of the sleep EEG. 24 male patients with psychogenic erectile dysfunction without detectable organic factors or other mental disorders were studied in the sleep laboratory, as well as an age-matched control group without sexual dysfunctions. Beside a reduction of sleep efficacy, the most prominent finding was a shortening of REM latency in the patients compared to the controls. Moreover, spectral analysis revealed a reduced theta power for all sleep stages and a reduced delta power for stage II and slow wave sleep in the patients. The findings support the point of view that psychogenic erectile dysfunction is an organic disorder of the brain. The sleep EEG abnormalities may reflect dysregulations in limbic structures which are suggested to be involved in the pathophysiology of sexual dysfunctions. As these alterations had also been reported for other mental disorders, particularly depression, they appear to be non-specific biological abnormalities for different psychiatric syndromes, including psychogenic erectile dysfunction.

Adult↗

PubMed2004

Interactions between cGMP- and cAMP-pathways are involved in the regulation of penile smooth muscle tone.

Nitric oxide (NO)/cyclic GMP (cGMP)-mediated mechanisms have a pivotal function in reducing the tone of the penile smooth musculature during normal erectile responses. The cyclic AMP (cAMP) signaling pathway is also involved in the adjustment of smooth muscle contractility, and suggestions for interactions between cGMP- and cAMP-mediated mechanisms have been presented. Using activators of the cGMP- or the cAMP-pathway, as well as inhibitors of protein kinase A (PKA; cAMP-dependent kinase) and protein kinase G (PKG; cGMP-dependent kinase), the present study was undertaken to further delineate the functional relation between these pathways in the penis. In addition, the distribution of PKA and some cAMP-binding phosphodiesterases (cAMP-PDEs) were investigated in human erectile tissue. Functional experiments were performed on isolated human corpus cavernosum (HCC). The effects of an inhibitor of the PKA, Rp-8CPT-cAMPS (10 microM), or the PKG, Rp-8-pCPT-cGMPS (10 microM), on relaxation induced by the cumulative administration of sodium nitroprusside (SNP), forskolin, sildenafil or tadalafil (IC351) were studied in preparations of HCC precontracted with 1 microM norepinephrine (NE). Using immunohistochemical procedures, the presence of immunoreactivity for cAMP-PDEs PDE3, PDE4, and PDE4A, as well as for PKA was investigated in specimens of HCC from which preparations were also used in the functional experiments. Forskolin, SNP, sildenafil, and IC 351 dose-dependently reversed NE-induced tension of isolated HCC preparations. The relaxing effects of SNP were significantly attenuated by Rp-8-pCPT-cGMPS, but not by Rp-8CPT-cAMPS. In contrast, relaxation induced by forskolin, sildenafil and tadalafil were significantly reversed by both Rp-8-pCPT-cGMPS and Rp-8CPT-cAMPS. Abundant immunoreactivity for PDE3 and PKA was observed in the corpus cavernosum smooth muscle cells. Immunoreactivity for PDE4 was also detected in the smooth musculature and in the cytoplasm of endothelial cells lining the cavernous sinusoids, as well as in nerve fibres interspersing the trabecular stroma. The present results support the hypothesis of interactions between cGMP- and cAMP-mediated signals in the HCC, and suggest that the effects of inhibitors of PDE5 on isolated erectile tissue may also partly or indirectly include actions of the cAMP second messenger system. The exact mechanism by which such an interaction occurs is not clear, but it may involve altered activity of the cGMP-inhibited PDE3 brought about by a change in the intracellular levels of cGMP by the inhibition of PDE5. This will in turn lead to increasing levels of cAMP, facilitating the interaction of cAMP with the PKA. The immunoreactivity specific for PDE3, PDE4, PDE4A and PKA registered in HCC section is also in support of an important role for the cAMP/PKA-system for penile smooth muscle function.

Adult↗

PubMed2004

Cytotoxicity of different intracavernous vasoactive drugs on cultured endothelial cells of human corpus cavernosum penis.

OBJECTIVES: To investigate the cytotoxic effect of prostaglandin E(1) (PGE(1)), a standard combination of papaverine/phentolamine, and a triple mixture of these agents on human cavernosal endothelial cells using a cell culture model. The endothelial layer of the corpus cavernosum plays an important role in signal transduction of penile erection and is directly exposed to vasoactive agents after intracavernous injection for erectile dysfunction. METHODS: Primary endothelial cells were obtained from the corpus cavernosum of 13 potent patients undergoing penile surgery. Cultured cells were exposed for 30 minutes to physiologic dilutions of 20 microg PGE(1), 30 mg papaverine/1 mg phentolamine, or the same dosages of the triple mixture of these agents, each dissolved in 5 to 50 mL sodium chloride. Lactate dehydrogenase release as a cytotoxicity marker was measured 6 hours after drug exposure, and the total cell metabolic activity was quantified after 48 hours with a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)-based assay. Additionally, the amount of viable cells was identified with a dual fluorescent staining procedure. RESULTS: The initial release of lactate dehydrogenase was elevated up to 3.2-fold in the concentrated papaverine/phentolamine and triple mixture group compared with PGE(1) and the control. After 48 hours, the papaverine-containing formulations led to a significant dose-dependent decrease in the viable cell count and metabolic activity of the cultures that was not noticed with PGE(1). CONCLUSIONS: These in vitro data strongly suggest an unfavorable effect of vasoactive agents containing papaverine on cavernosal endothelial cells. Before fibrotic changes of the smooth muscle stroma, the functionally important endothelium of the corpus cavernosum might suffer significantly from intracavernous injection therapy. Therefore, papaverine should no longer be used for this indication.

Alprostadil↗

PubMed2004

The penile implant for erectile dysfunction.

INTRODUCTION: Penile prostheses, introduced as the first effective organic treatment for erectile dysfunction over three decades ago, have an important role in the treatment of erectile dysfunction when other nonprosthetic treatment options have proven unsatisfactory. Although they are the least chosen and most invasive treatment option, they have the highest satisfaction rate of all available ED options and provide a predictable and reliable result. AIM: To provide recommendations/guidelines concerning state-of-the-art knowledge for utilization of the penile prosthesis in the management of men with erectile dysfunction. METHODS: An International Consultation in collaboration with the major sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a 2-year period. There were 10 experts from seven countries concerning the Penile Implant for Erectile Dysfunction. MAIN OUTCOME MEASURE: Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation and debate. RESULTS: Recommendations/guidelines for penile prosthesis (hydraulic, semi-rigid and soft silicone) insertion for management of men with erectile dysfunction were updated. Consensed issues included: criteria for patient selection, informed consent procedures, strategies for preoperative preparation, operative incisions/technical considerations and outcome results in terms of patient satisfaction and device survival. Updated information was reviewed concerning therapies for device failures, device insertion in scarred corporal bodies and strategies for managing implant infections. CONCLUSIONS: There is a need for more research in developing management strategies for insertion of penile prostheses in men with ED.

Consensus↗

PubMed2003

Androgen and estrogen receptors in the human corpus cavernosum penis: immunohistochemical and cell culture results.

Despite the central and peripheral effects of androgens on the nervous system, the local effects of androgens in the corpus cavernosum penis and their importance for erectile function is still unclear. In this study corpus cavernosum biopsies of eight adult potent patients, aged 19-63 years, undergoing penile deviation surgery (group A) and 12 patients undergoing male-to-female transsexual surgery (group B) were immunostained for nuclear androgen and estrogen-alpha receptors. Additionally, primary corpus cavernosum endothelial cell cultures were obtained from six transsexual patients and exposed to testosterone, dihydrotestosterone, estradiol and progesterone likewise for 7 days. Total cell count was performed and cell metabolic activity was measured by a tetrazolium salt-based assay. Androgen and estrogen-alpha receptors were detected in stromal as well as in endothelial cells. Of all cell nuclei, 74.9% (SD 16.4) in group A and 63.5% (SD 17.1) in group B were positively stained for androgen receptors. The respective percentage of estrogen receptors was 11% (SD 9.5) and 21.2% (SD 12.6). An age-dependent difference in receptor distribution was not observed in either group. In the cell culture system only cultures exposed to testosterone and dihydrotestosterone showed a dose-dependent increase of cell metabolic activity compared to the cultures supplemented with estradiol and progesterone. The significant and age-independent high androgen and low estrogen-alpha receptor distribution found in both groups suggests a possible peripheral effect of androgens at the level of the corpus cavernosum penis in adult humans. This is supported by the observed effect of testosterone and dihydrotestosterone on cell count and endothelial cell metabolism in our cell culture system. The role of estrogens remains unclear.

Adult↗

PubMed2002

In vitro effects of a novel class of nitric oxide (NO) donating compounds on isolated human erectile tissue.

OBJECTIVES: The discovery of nitric oxide (NO) as one of the major effectors in penile erectile function has led to the development of various drugs which are able to elevate intracellular levels of cGMP. Recently, a novel class of NO donors have been developed, exemplified by S-nitroso-glutathione (GSNO) and S-nitroso-N-acetylcysteine-ethylester (SNACET), as well as compounds combining both phosphodiesterase inhibitory and NO donating activity, such as NCX 911 (sildenafil nitrate). In our study, we assessed the effects of GSNO, SNACET and NCX 911 on adrenergic tension and electrically induced relaxation of isolated human corpus cavernosum (HCC) and the in vitro formation of cGMP. Effects were compared to those of sodium nitroprusside (SNP) and sildenafil citrate. MATERIALS AND METHODS: Using the organ bath technique, drug effects were investigated on norepinephrine-induced tension and electrically induced relaxation of HCC. HCC strips were exposed to increasing concentrations of the compounds (0.01/0.1-10/100 microM) and the accumulation of cGMP was determined by means of a radioimmunoassay. RESULTS: Relaxation of HCC induced by means of electrical field stimulation (EFS) was abolished by tetrotodoxin, guanylyl cyclase inhibitor ODQ and nitric oxide synthase inhibitor L-NNA. Adrenergic tension of HCC strips was dose-dependently reversed by the drugs. The rank order of potency was: SNP > GSNO > NCX911 > sildenafil > SNACET. Compounds also dose-dependently increased EFS-induced amplitudes of relaxation (SNP > NCX911 > sildenafil > SNACET/GSNO). Relaxing effects of the drugs were paralleled by an increase in tissue levels of cGMP. CONCLUSION: Our results provide a rationale for future use of NCX 911 and S-nitrosothiols in the pharmacotherapy of erectile dysfunction (ED). Since the compounds are assumed to exert no considerable hemodynamic effects, they might be developed into new oral treatments for ED.

Adult↗