574 research outputs found
How do medical students learn about SDH in the community? A qualitative study with a realist approach
No full textThe need to learn social determinants of health (SDH) is increasing in disparate societies, but educational interventions are complex and learning mechanisms are unclear. Therefore, this study used a realist approach to identify SDH learning patterns, namely context (C), mechanism (M), and outcomes (O) in communities. A 4-week clinical practice program was conducted for 5th- and 6th-year medical students in Japan. The program included SDH lectures and group activities to explore cases linked to SDH in the community. The medical students' structural reflection reports for learning SDH were thematically analyzed through CMO perspectives. First, medical students anticipated the concept of SDH and participated in a community in which a social model was central. They then transformed their perspective through observational learning and explanations from role models. Second, medical students’ confrontation of contradictions in the medical model triggered integrated explanations of solid facts. Third, conceptual understanding of SDH was deepened through comparison and verbalization of concrete experiences in multiple regions. Fourth, empathy for lay people was fostered by participating from a non-authoritative position, which differed from that in medical settings. Medical students can learn about the connections between society and medicine through four types of SDH learning patterns.</p
Preferential MGMT hypermethylation in SDH-deficient wild-type GIST
No full textAIMS: Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (SDHx). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by SDHx inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation. Epigenetic silencing of the DNA repair gene MGMT has proven utility as a positive predictor of the therapeutic efficacy of the alklyating drug temozolomide (TMZ) in tumours such as glioblastoma multiforme. The aim of this study was to examine MGMT promoter methylation status in a large cohort of GIST. METHODS: MGMT methylation analysis was performed on 65 tumour samples including 47 wtGIST (33 SDH-deficient wtGIST and 11 SDH preserved wtGIST) and 21 tyrosine kinase (TK) mutant GIST. RESULTS: MGMT promoter methylation was detected in 8 cases of SDH-deficient (dSDH) GIST but in none of the 14 SDH preserved wild-type GIST or 21 TK mutant GIST samples analysed. Mean MGMT methylation was significantly higher (p 0.0449) and MGMT expression significantly lower (p<0.0001) in dSDH wtGIST compared with TK mutant or SDH preserved GIST. No correlation was identified between SDHx subunit gene mutations or SDHC epimutation status and mean MGMT methylation levels. CONCLUSION: MGMT promoter hypermethylation occurs exclusively in a subset of dSDH wtGIST. Data from this study support testing of tumour MGMT promoter methylation in patients with dSDH wtGIST to identify those patients who may benefit from most from TMZ therapy
Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis
No full textSuccinate dehydrogenase (SDH) is a heterotetrameric nuclear-encoded complex responsible for the oxidation of succinate to fumarate in the tricarboxylic acid cycle. Loss-of-function mutations in any of the SDH genes are associated with cancer formation. However, the impact of SDH loss on cell metabolism and the mechanisms enabling growth of SDH-defective cells are largely unknown. Here, we generated Sdhb-ablated kidney mouse cells and used comparative metabolomics and stable-isotope-labelling approaches to identify nutritional requirements and metabolic adaptations to SDH loss. We found that lack of SDH activity commits cells to consume extracellular pyruvate, which sustains Warburg-like bioenergetic features. We further demonstrated that pyruvate carboxylation diverts glucose-derived carbons into aspartate biosynthesis, thus sustaining cell growth. By identifying pyruvate carboxylase as essential for the proliferation and tumorigenic capacity of SDH-deficient cells, this study revealed a metabolic vulnerability for potential future treatment of SDH-associated malignancies
Natural history of hypertension subtypes in young and middle-age adults.
No full textBACKGROUND:
The evolution of hypertension (HT) subtypes in young-to-middle-age subjects is unclear.
METHODS:
We did a prospective study in 1,141 participants aged 18-45 years from the HARVEST study screened for stage 1 HT, and 101 nonhypertensive subjects of control during a median follow-up of 72.9 months.
RESULTS:
At baseline, 13.8% of the subjects were classified as having isolated systolic HT (ISH), 24.8% as having isolated diastolic HT (IDH), and 61.4% as having systolic-diastolic HT (SDH). All hypertensive groups developed sustained HT (clinic blood pressure > or =140/90 mm Hg from two consecutive visits occurring at least after > or =6 months of observation) more frequently than nonhypertensive subjects (P or =135/85 mm Hg, n = 798), odds ratios were 5.1 (95%CI 3.1-8.2), 5.6 (95%CI 3.2-9.8), and 3.3 (95%CI 1.7-6.3), respectively. In the fully adjusted logistic model, the risk of ambulatory HT was smaller for the ISH than the IDH (P = 0.049) or SDH (P = 0.053) individuals.
CONCLUSIONS:
The present results indicate that young-to-middle-age subjects with ISH have a smaller risk of developing ambulatory HT than either subjects with SDH or IDH. Whether antihypertensive treatment can be postponed for long periods of time in young subjects with mild elevations of clinic systolic BP and low global cardiovascular risk should be examined in further studies
Datasheet1_A cross-sectional study identifying disparities in serum metabolic profiles among hypertensive patients with ISH, IDH and SDH subtypes.doc
No full textBackgroundIt has been well acknowledged that disordered intestinal microflora and their fermented products play crucial role during the development of hypertension (HTN). Aberrant profiles of fecal bacteria have been documented in subjects with isolated systolic HTN (ISH) and isolated diastolic HTN (IDH) previously. Nevertheless, evidence regarding the association of metabolic products in the bloodstream with ISH, IDH and combined systolic and diastolic HTN (SDH) remains scarce.MethodsWe performed a cross-sectional study and conducted untargeted liquid chromatography-mass spectrometry (LC/MS) analysis on serum samples of 119 participants, including 13 subjects with normotension (SBP ResultsHere, the results showed clearly separated clusters in PLS-DA and OPLS-DA score plots for patients suffering from ISH, IDH and SDH when compared with normotension controls. The ISH group was characterized by elevated levels of 3,5-tetradecadien carnitine and notable reduction of maleic acid. While IDH patients were enriched with metabolites in L-lactic acid and depleted in citric acid. Stearoylcarnitine was identified to be specifically enriched in SDH group. The differentially abundant metabolites between ISH and controls were involved in tyrosine metabolism pathways, and in biosynthesis of phenylalanine for those between SDH and controls. Potential linkages between the gut microbial and serum metabolic signatures were detected within ISH, IDH and SDH groups. Furthermore, we found the association of discriminatory metabolites with the characteristics of patients.ConclusionOur findings demonstrate disparate blood metabolomics signatures across ISH, IDH and SDH, with differentially enriched metabolites and potential functional pathways identified, reveal the underlying microbiome and metabolome network in HTN subtypes, and provide potential targets for disease classification and therapeutic strategy in clinical practice.</p
Table2_A cross-sectional study identifying disparities in serum metabolic profiles among hypertensive patients with ISH, IDH and SDH subtypes.doc
No full textBackgroundIt has been well acknowledged that disordered intestinal microflora and their fermented products play crucial role during the development of hypertension (HTN). Aberrant profiles of fecal bacteria have been documented in subjects with isolated systolic HTN (ISH) and isolated diastolic HTN (IDH) previously. Nevertheless, evidence regarding the association of metabolic products in the bloodstream with ISH, IDH and combined systolic and diastolic HTN (SDH) remains scarce.MethodsWe performed a cross-sectional study and conducted untargeted liquid chromatography-mass spectrometry (LC/MS) analysis on serum samples of 119 participants, including 13 subjects with normotension (SBP ResultsHere, the results showed clearly separated clusters in PLS-DA and OPLS-DA score plots for patients suffering from ISH, IDH and SDH when compared with normotension controls. The ISH group was characterized by elevated levels of 3,5-tetradecadien carnitine and notable reduction of maleic acid. While IDH patients were enriched with metabolites in L-lactic acid and depleted in citric acid. Stearoylcarnitine was identified to be specifically enriched in SDH group. The differentially abundant metabolites between ISH and controls were involved in tyrosine metabolism pathways, and in biosynthesis of phenylalanine for those between SDH and controls. Potential linkages between the gut microbial and serum metabolic signatures were detected within ISH, IDH and SDH groups. Furthermore, we found the association of discriminatory metabolites with the characteristics of patients.ConclusionOur findings demonstrate disparate blood metabolomics signatures across ISH, IDH and SDH, with differentially enriched metabolites and potential functional pathways identified, reveal the underlying microbiome and metabolome network in HTN subtypes, and provide potential targets for disease classification and therapeutic strategy in clinical practice.</p
Table1_A cross-sectional study identifying disparities in serum metabolic profiles among hypertensive patients with ISH, IDH and SDH subtypes.doc
No full textBackgroundIt has been well acknowledged that disordered intestinal microflora and their fermented products play crucial role during the development of hypertension (HTN). Aberrant profiles of fecal bacteria have been documented in subjects with isolated systolic HTN (ISH) and isolated diastolic HTN (IDH) previously. Nevertheless, evidence regarding the association of metabolic products in the bloodstream with ISH, IDH and combined systolic and diastolic HTN (SDH) remains scarce.MethodsWe performed a cross-sectional study and conducted untargeted liquid chromatography-mass spectrometry (LC/MS) analysis on serum samples of 119 participants, including 13 subjects with normotension (SBP ResultsHere, the results showed clearly separated clusters in PLS-DA and OPLS-DA score plots for patients suffering from ISH, IDH and SDH when compared with normotension controls. The ISH group was characterized by elevated levels of 3,5-tetradecadien carnitine and notable reduction of maleic acid. While IDH patients were enriched with metabolites in L-lactic acid and depleted in citric acid. Stearoylcarnitine was identified to be specifically enriched in SDH group. The differentially abundant metabolites between ISH and controls were involved in tyrosine metabolism pathways, and in biosynthesis of phenylalanine for those between SDH and controls. Potential linkages between the gut microbial and serum metabolic signatures were detected within ISH, IDH and SDH groups. Furthermore, we found the association of discriminatory metabolites with the characteristics of patients.ConclusionOur findings demonstrate disparate blood metabolomics signatures across ISH, IDH and SDH, with differentially enriched metabolites and potential functional pathways identified, reveal the underlying microbiome and metabolome network in HTN subtypes, and provide potential targets for disease classification and therapeutic strategy in clinical practice.</p
Isolated systolic hypertension of young-to-middle-age individuals implies a relatively low risk of developing hypertension needing treatment when central blood pressure is low.
No full textOBJECTIVES: The clinical significance of isolated systolic hypertension (ISH) in the young is still controversial. Aim of the present study was to investigate whether prognosis of ISH in young-to-middle-age individuals differs according to central blood pressure (BP).
DESIGN: We studied 354 participants screened for stage 1 hypertension and 34 normotensive controls to determine which individuals developed hypertension needing drug therapy. Among the hypertensive patients, 67 had ISH and were divided according to whether their central SBP, measured with applanation tonometry, was above (ISH-high) or below (ISH-low) the median (120.5 mmHg). Large artery (C1) and small artery (C2) compliance were also measured.
RESULTS: Compared to normotensive individuals, ISH-high had decreased C1 (P = 0.02) and C2 (P = 0.01), and higher peripheral resistance (P = 0.01). In contrast, in ISH-low, all these variables were similar to those in normotensive individuals. During 9.5 years of follow-up, incident hypertension was more common among participants with systolic-diastolic hypertension (SDH) and ISH-high than the other two groups [odds ratio (OR) = 6.2, 95% confidence interval (CI) = 1.8-21.1, P = 0.003 for SDH; OR = 6.0, 95% CI = 1.5-24.0, P = 0.01 for ISH-high, versus normotensive individuals]. Among ISH-low, incidence of hypertension was only slightly higher than that in normotensive individuals (OR = 1.1, 95% CI 0.2-5.3, P = 0.90) and lower than that in ISH-high (P = 0.03). These associations remained significant when ambulatory BP was included in the models or when the 125 mmHg cut-off for central BP was used to identify ISH subgroups.
CONCLUSION: These data show that young-to-middle-age ISH individuals with low central BP have a lower risk of hypertension needing treatment than those with high central BP. These results are applicable mainly to male individuals
Petroselinum crispum subsp. root SDH
No full text3.4. P. crispum root SDH is regulated by metabolites of the phenylpropanoid pathway Because the shikimate pathway is absent in mammals, searching and designing inhibitors against enzymes of this pathway may lead to the development of antimicrobials (such as the bacterial Mycobacterium tuberculosis and Helicobacter pylori SDH) and antiparasitic (malaria parasite SDH) and herbicidal (plant SDH) agents, which are harmless to humans (Diaz-Quiroz et al., 2018). There are 3 strategies for identifying compounds with an inhibitory effect on a particular enzyme: i) analyzing substrate structural analogs (Baillie et al., 1972; Diaz and Merino, 1997; Fiedler and Schultz, 1985; Koshiba, 1978; Lemos Silva et al., 1985; Lourenco and Neves, 1984; Lourenco et al., 1991; Rothe, 1974), ii) screening thousands of compounds (Avitia-Dominguez et al., 2014; Han et al., 2006; Peek et al., 2014), and iii) searching for feedback inhibitors among products of the whole pathway. The first strategy has led to the discovery of the herbicide 2,4-dichlorphenoxy acetic acid (2, 4-D) (Diaz and Merino, 1997). Concurrently, several studies have demonstrated that PCA (possible byproduct of SDH) inhibits plant SDH (Diaz and Merino, 1997; Koshiba, 1978; Lemos Silva et al., 1985; Lourenco and Neves, 1984; Lourenco et al., 1991). In this study, we have shown that P. crispum SDH forms PCA in the irreversible reaction (Fig. 4). Using a screening strategy, different research groups have identified SDH inhibitors, for example, 5 novel Helicobacter pylori SDH inhibitors, including the natural product curcumin (Han et al., 2006), and polyphenolic inhibitors (epigallocatechin gallate and epicatechin gallate) of Pseudomonas putida and Arabidopsis thaliana SDH (Peek et al., 2014). A limited number of inhibition/activation studies have identified dihydroxybenzoic acid and its derivatives as SDH inhibitors (Fiedler and Schultz, 1985; Koshiba, 1978; Nandy and Ganguli, 1961), thus showing that SDH inhibitors are not limited to herbicides and organic reagents. In this study, we chose the third strategy to identify plant SDH inhibitors among the products of the phenylpropanoid pathway (representative compounds of simple phenols, flavonoid, stilbene, and polyphenols). The strongest P. crispum SDH inhibitor was tannic acid (Fig. 5). Tannins have strong astringent properties, which may induce complexation with enzymes and substrates (Tintino et al., 2016). They bind to proteins (by hydrophobic, hydrophilic, non-specific, and specific interactions), pigments, low-molecular-weight compounds, and metallic ions (Kato et al., 2017). In microorganisms, interactions between tannic acid and the cell membrane can affect its permeability through the inhibition of the efflux pump, which may be associated with an antimicrobial effect (Tintino et al., 2016). Furthermore, the potentially extracellular localization of tannic acid may contribute to this effect because leaf mesophyll cell walls are the typical site of origin and deposition of hydrolysable tannins in oak leaves (Grundhofer et al., 2001). Furthermore, in the outer peels of pomegranate (Punica granatum L.), SDHs play a role in controlling the biosynthesis of hydrolysable tannins (Habashi et al., 2019). Our results also showed that P. crispum SDH is inhibited at 0.15 and 0.19 mM IC 50 by caffeic acid and chlorogenic acid (with 2 and 5 hydroxyl groups in the structure), respectively. Chlorogenic acids are esters formed between caffeic acid and quinic acid, which are strong antioxidants found in many vegetable species and coffee beans (Colon and Nerin, 2016; Guo et al., 2014; Liang and Kitts, 2015; Niggeweg et al., 2004). In plants, chlorogenic acids serve as protecting compounds against stress, e.g., viral infection (Spoustova et al., 2015), or as feeding deterrents (Ikonen et al., 2001). The p -coumaric, t -ferulic, sinapic, syringic, and salicylic acids, all with only one hydroxyl group, were milder SDH inhibitors, with IC 50 above 5 mM, and they are not involved in regulation under physiological conditions. On the other hand, our preliminary results indicate the presence of 0.1 μM p -coumaric, 1.7 μM t -ferulic, and 0.5 μM chlorogenic acid in P. crispum roots (data not shown) and recently Derouich et al. (2020) published a wide scale of phenolic compounds (including chlorogenic acid as the most abundant and then p -coumaric, caffeic, gallic, ferulic, vanillic, and syringic acid) in aerial parts of P. crispum plants and discussed their high antioxidant power (Derouich et al., 2020). Considering the localization, simple phenolic compounds are probably not stored in plastids in huge amounts, modifications of cinnamic acid to p -coumaric, t -ferulic, and sinapic acid take place at the membranes of the endoplasmic reticulum, flavonoids are believed to be synthetized in the cytosol and stored in vacuoles (Kitamura, 2006) together with monolignols derivatives, which are synthesized in the cytosol with some enzymes exhibiting membrane attachment and the bulk of the monolignol pool is targeted to the apoplast for polymerization to lignin (Dixon and Barros, 2019). Salicylic acid is an important signal molecule; however, its concentration does not reach the value of the experimentally determined IC 50, even during stress (Belonoznikova et al., 2020). In their study, Belinsky and Davies (1961) concluded that the both carbonyl group at the C1 position and a hydroxyl group at the 4-OH position are significant determinants of ligand binding. This is true for syringic acid with IC 50 5.1 ± 1.0 mM. Tannic acid contains several hydroxyl groups on phenyl rings; thus, their hydroxyl groups may interact with the amino acid residue in the enzyme active center. Under non-stress conditions, plant SDH may be inhibited by some phenylpropanoid compounds. In our previous study, we found significant chlorogenic and quinic acid depletion in tobacco plants exposed to potyviral stress and heat shock (Hyskova et al., 2021). Such a depletion could in turn favor the shikimate pathway, producing precursors of defense compounds by enhancing SDH activity. Plant SDH inhibition by divalent metal ions, particularly Zn 2+ and Cu 2+, is known and correlated with the inactivation of functional sulfhydryl groups of SDH and also confirmed with the inhibition of plant SDH by p -chloromercuribenzoate which could be reversed by cysteine (Balinsky and Davies, 1961; Koshiba, 1978; Lourenco and Neves, 1984). SDH from P. crispum root was also inhibited by Zn 2+ and Cu 2+, particularly by Cu 2+ ions (Table 4).Published as part of Hýskova, Veronika, Belonozníkov, Katerina, Smeringaiova, Ingrida, Kavan, Daniel, Ingr, Marek & Ryslava, Helena, 2021, How is the activity of shikimate dehydrogenase from the root of Petroselinum crispum (parsley) regulated and which side reactions are catalyzed?, pp. 1-12 in Phytochemistry (112881) (112881) 190 on pages 8-9, DOI: 10.1016/j.phytochem.2021.112881, http://zenodo.org/record/827025
Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations
No full textThe tricarboxylic acid, or Krebs, cycle is central to the cellular metabolism of sugars, lipids, and amino acids; it fuels the mitochondrial respiratory chain for energy generation. In the past decade, mutations in the Krebs-cycle enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase have been documented to be causally involved in carcinogenesis. This review is focused on the relationship between SDH mutations and the carcinogenic phenotype. The succinate dehydrogenase complex catalyzes the oxidation of succinate to fumarate; mutations in its subunits SDHA, SDHB, SDHC, and SDHD, and in the assembly factor SDHAF2, result in syndromes with distinct tumor types, including pheochromocytoma/paraganglioma, gastrointestinal stromal tumor, and, less often, renal-cell carcinoma and pituitary adenoma. In this study we collected all previously reported SDH mutations with the aim of defining their nature and tumor spectrum. In addition, genotype-phenotype correlations as well as mechanisms of biallelic inactivation were analyzed in the SDH-deficient setting. Finally, we performed bioinformatics analysis using SIFT, Polyphen2, and Mutation Assessor to predict the functional impact of nonsynonymous mutations. The prediction of the latter was further compared with available SDHA and/or SDHB immunohistochemistry data
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