Pyrroloquinoline-Quinone Is More than an Antioxidant: A Vitamin-Like Accessory Factor Important in Health and Disease Prevention

Pyrroloquinoline quinone (PQQ) is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. In addition, PQQ attenuates clinically relevant dysfunctions (e.g., those associated with ischemia, inflammation and lipotoxicity). PQQ is novel among biofactors that are not currently accepted as vitamins or conditional vitamins. For example, the absence of PQQ in diets produces a response like a vitamin–related deficiency with recovery upon PQQ repletion in a dose-dependent manner. Moreover, potential health benefits, such as improved metabolic flexibility and immuno-and neuroprotection, are associated with PQQ supplementation. Here, we address PQQ’s role as an enzymatic cofactor or accessory factor and highlight mechanisms underlying PQQ’s actions. We review both large scale and targeted datasets demonstrating that a neonatal or perinatal PQQ deficiency reduces mitochondria content and mitochondrial-related gene expression. Data are reviewed that suggest PQQ’s modulation of lactate acid and perhaps other dehydrogenases enhance NAD+–dependent sirtuin activity, along with the sirtuin targets, such as PGC-1α, NRF-1, NRF-2 and TFAM; thus, mediating mitochondrial functions. Taken together, current observations suggest vitamin-like PQQ has strong potential as a potent therapeutic nutraceutical.

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A Mechano-Activated Cell Reporter System as a Proxy for Flow-Dependent Endothelial Atheroprotection

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555218761101 ◽

2018 ◽

Vol 23 (8) ◽

pp. 869-876

Author(s):

Bendix R. Slegtenhorst ◽

Oscar R. Fajardo Ramirez ◽

Yuzhi Zhang ◽

Zahra Dhanerawala ◽

Stefan G. Tullius ◽

...

Keyword(s):

Vascular Endothelium ◽

Critical Role ◽

Green Fluorescence Protein ◽

Dependent Manner ◽

Reporter System ◽

Health And Disease ◽

Fluorescence Protein ◽

Biomechanical Stimuli ◽

Dose Dependent

The vascular endothelium plays a critical role in the health and disease of the cardiovascular system. Importantly, biomechanical stimuli generated by blood flow and sensed by the endothelium constitute important local inputs that are translated into transcriptional programs and functional endothelial phenotypes. Pulsatile, laminar flow, characteristic of regions in the vasculature that are resistant to atherosclerosis, evokes an atheroprotective endothelial phenotype. This atheroprotective phenotype is integrated by the transcription factor Kruppel-like factor-2 (KLF2), and therefore the expression of KLF2 can be used as a proxy for endothelial atheroprotection. Here, we report the generation and characterization of a cellular KLF2 reporter system, based on green fluorescence protein (GFP) expression driven by the human KLF2 promoter. This reporter is induced selectively by an atheroprotective shear stress waveform in human endothelial cells, is regulated by endogenous signaling events, and is activated by the pharmacological inducer of KLF2, simvastatin, in a dose-dependent manner. This reporter system can now be used to probe KLF2 signaling and for the discovery of a novel chemical-biological space capable of acting as the “pharmacomimetics of atheroprotective flow” on the vascular endothelium.

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The Escherichia coli Common Pilus and the Bundle-Forming Pilus Act in Concert during the Formation of Localized Adherence by Enteropathogenic E. coli

Journal of Bacteriology ◽

10.1128/jb.01539-08 ◽

2009 ◽

Vol 191 (11) ◽

pp. 3451-3461 ◽

Cited By ~ 51

Author(s):

Zeus Saldaña ◽

Ayşen L. Erdem ◽

Stephanie Schüller ◽

Iruka N. Okeke ◽

Mark Lucas ◽

...

Keyword(s):

Escherichia Coli ◽

Epithelial Cells ◽

Cultured Cells ◽

Dependent Manner ◽

Triple Mutant ◽

E Coli ◽

Accessory Factor ◽

Isogenic Mutants ◽

Dose Dependent ◽

Background Expression

ABSTRACT Although the bundle-forming pilus (BFP) of enteropathogenic Escherichia coli (EPEC) mediates microcolony formation on epithelial cells, the adherence of BFP-deficient mutants is significantly abrogated, but the mutants are still adherent due to the presence of intimin and possibly other adhesins. In this study we investigated the contribution of the recently described E. coli common pilus (ECP) to the overall adherence properties of EPEC. We found that ECP and BFP structures can be simultaneously observed in the course (between zero time and 7 h during infection) of formation of localized adherence on cultured epithelial cells. These two pilus types colocalized at different levels of the microcolony topology, tethering the adhering bacteria. No evidence of BFP disappearance was found after prolonged infection. When expressed from a plasmid present in nonadherent E. coli HB101, ECP rendered this organism highly adherent at levels comparable to those of HB101 expressing the BFP. Purified ECP bound in a dose-dependent manner to epithelial cells, and the binding was blocked with anti-ECP antibodies, confirming that the pili possess adhesin properties. An ECP mutant showed only a modest reduction in adherence to cultured cells due to background expression levels of BFP and intimin. However, isogenic mutants not expressing EspA or BFP were significantly less adherent when the ecpA gene was also deleted. Furthermore, a ΔespA ΔecpA double mutant (unable to translocate Tir and to establish intimate adhesion) was at least 10-fold less adherent than the ΔespA and ΔecpA single mutants, even in the presence of BFP. A Δbfp ΔespA ΔecpA triple mutant showed the least adherence compared to the wild type and all the isogenic mutant strains tested, suggesting that ECP plays a synergistic role in adherence. Our data indicate that ECP is an accessory factor that, in association with BFP and other adhesins, contributes to the multifactorial complex interaction of EPEC with host epithelial cells.

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Integrative Analysis to Uncover the Molecular Mechanisms of Caesalpinia sappan L. for Anti-Cancer Activity

Natural Product Communications ◽

10.1177/1934578x211039922 ◽

2021 ◽

Vol 16 (11) ◽

pp. 1934578X2110399

Author(s):

Bing Liu ◽

Hao Lian

Keyword(s):

Molecular Docking ◽

Large Scale ◽

Molecular Mechanisms ◽

The Cancer Genome Atlas ◽

Network Pharmacology ◽

Dependent Manner ◽

Genomic Databases ◽

Caesalpinia Sappan ◽

Dose Dependent

Objectives: Caesalpinia Sappan L. is a traditional Chinese medicine with a long history. Recent studies have confirmed that Sappan has an antitumor effect, but its specific mechanism is still unclear. Methods: In this study, we used network pharmacology to predict the target and signal pathway of Sappan. In addition, the Cancer Genome Atlas and cancer cell lines encyclopedia large-scale genomic databases were used to analyze the relationship between different subtypes of Akt. Based on molecular docking technology, the interaction mode between small molecule compounds and protein targets was explored. Finally, we studied the effect of Sappan on Akt protein expression by Western blot in vitro. Results: AKT1 and AKT2 were significantly expressed in breast cancer cells, but they were significantly different from AKT3. Finally, molecular docking analysis showed that (3R,5R)-1,3,4,5-tetrakis(((E)-3-(3,4-dihydroxyphenyl)acryloyl)oxy)cyclohexane-1-carboxylic acid had a very ideal binding mode with Akt. Subsequent experiments showed that Sappan extract could induce apoptosis of HepG2 cells in a dose-dependent manner, and down regulate the phosphorylation level of Akt protein thr308 in a dose-dependent manner. Conclusions: This study provides new ideas for Sappan's anticancer research through the strategy of system pharmacology.

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Association of arsenic exposure and cognitive impairment: a population-based cross-sectional study in China

10.21203/rs.3.rs-19627/v1 ◽

2020 ◽

Author(s):

Wang Xin ◽

Huang Xiaoyan ◽

Zhou Lu ◽

Chen Juan ◽

Zhang Xuxiang ◽

...

Keyword(s):

Risk Factor ◽

Cognitive Impairment ◽

Cognitive Function ◽

Large Scale ◽

Arsenic Exposure ◽

Public Health Issue ◽

Dependent Manner ◽

Cross Sectional ◽

Chronic Arsenic Exposure ◽

Dose Dependent

Abstract Background: Chronic arsenic exposure is a major public health issue worldwide. Previous studies explored the effects of arsenic exposure on cognitive impairment, but majority of previous studies focused on the effects on school children rather than adults. Moreover, few studies investigated the role of arsenic exposure in cognitive impairment process in a large scale in China.Methods: Aimed to evaluate the association between long-term exposure to arsenic and cognitive impairment in China, we designed a cross-sectional analytical study in which 1,556 adults from three locations around the Realgar Plant (Heshan Village, Wangyangqiao Community and Baiyangshan Village) were enrolled. Participants’ general cognitive function were evaluated by using a Chinese version of Mini-mental state Examination (MMSE). Internal arsenic exposure status of participants (hair arsenic concentrations) was measured by inductively coupled plasma-mass spectroscopy (ICP-MS), and external arsenic exposure status of participants was approximately evaluated by measuring the distance between the participants’ location to Realgar Plant.Results: In our study, we found that the prevalence of cognitive impairment in arsenic-endemic areas was 20.6%, which was significantly higher than the prevalence of cognitive impairment in China (14.5%). Hair arsenic concentrations and prevalence of arsenicosis in cognitive impaired group (CI) was significantly higher than those in cognitive normal group (CN) (P<0.05).Conclusions: Our analyses revealed that the distance away from Realgar Plant was positively correlated with MMSE scores, while inversely associated with the prevalence of cognitive impairment. In addition, we found that MMSE scores were decreased with the increasing hair arsenic concentrations in a dose-dependent manner. In two-level Logistic regression analysis, arsenicosis was still a risk factor for cognitive impairment (odds ratio (OR) =1.77, P<0.05) even after adjusting for potential confounding variables. Our results showed that chronic arsenic exposure decreased cognitive function in adults in a dose-dependent manner, and arsenicosis was a risk factor for cognitive impairment.

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Impact of occupational dust exposure on dermatologic symptoms among Korean workers

Toxicology and Industrial Health ◽

10.1177/0748233720964636 ◽

2020 ◽

Vol 36 (12) ◽

pp. 971-978

Author(s):

Seunghyun Lee ◽

Sang Ha Lee ◽

Wanhyung Lee

Keyword(s):

Large Scale ◽

Dust Exposure ◽

Exposure Level ◽

Dependent Manner ◽

Health Issues ◽

Multivariate Logistic Regression ◽

Work Related ◽

Major Route ◽

Occupational Dust Exposure ◽

Dose Dependent

Occupation-related dust exposure is common, especially with increased industrialization. While occupational dust-related health issues caused by inhalation or ingestion have been well studied, only a few studies have examined the dermatologic effects of occupational dust exposure. This study aimed to investigate the association between occupational dust exposure and dermatologic symptoms in Korean workers. Among the large-scale representative data from the fifth Korean Working Conditions Survey, 45,700 workers were selected for study. Occupational dust exposure level was categorized as none, moderate, and severe, and dermatologic symptoms were assessed using a questionnaire on health problems. We analyzed the association between occupational dust exposure and dermatologic symptoms using multivariate logistic regression. Risks of skin problems and work-related skin problems were significantly associated with the level of occupational dust exposure in a dose-dependent manner (odds ratio (95% confidence interval): moderate, 1.51 (1.14–2.01); severe, 2.39 (1.74–3.29) in general skin problems; moderate, 1.72 (1.22–2.42); severe, 3.06 (2.11–4.44) in work-related skin problems). We, thus, demonstrate an association between occupational dust exposure and skin problems. As skin absorption of dust is a major route of dust exposure at the workplace, it is necessary to determine the efficacy of continuous management of occupational dust exposure.

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Ketone Supplementation for Health and Disease

10.1093/med/9780190497996.003.0032 ◽

2016 ◽

Author(s):

Angela M. Poff ◽

Shannon L. Kesl ◽

Dominic P. D’Agostino

Keyword(s):

Treatment Compliance ◽

Practical Method ◽

Preliminary Evidence ◽

Metabolic Efficiency ◽

Therapeutic Effects ◽

Dependent Manner ◽

Health And Disease ◽

And Function ◽

Restrictive Diet ◽

Dose Dependent

Exogenous ketone supplements rapidly elevate blood ketones in a dose-dependent manner regardless of dietary intake, making them a practical method of inducing therapeutic ketosis for medical use. It is thought that ketone supplementation could be used as a stand-alone therapy, or as a way to further augment the therapeutic efficacy of the ketogenic diet. Ketone supplementation could increase treatment compliance by allowing many patients to maintain a more normal lifestyle with a less restrictive diet. The therapeutic effects of ketone supplementation are likely mediated in part by a stabilization of blood glucose and insulin levels, an increase in metabolic efficiency, and an inhibition of oxidative stress and inflammation. Ketone supplements may also serve as an effective preventative medicine due to their potential ability to protect and enhance mitochondrial health and function. Indeed, preliminary evidence suggests there are a number of conditions for which exogenous ketone supplementation may be beneficial.

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Purification and molecular characterization of recombinant rat betacellulin

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0270239 ◽

2001 ◽

Vol 27 (2) ◽

pp. 239-247 ◽

Cited By ~ 1

Author(s):

AJ Dunbar ◽

IK Priebe ◽

MP Sanderson ◽

C Goddard

Keyword(s):

Fusion Protein ◽

Large Scale ◽

Gel Filtration ◽

Factor Xa ◽

Dependent Manner ◽

3T3 Fibroblasts ◽

Reducing Conditions ◽

Dose Dependent ◽

Heparin Affinity

A method for the large scale expression and purification of rat betacellulin (BTC) from Escherichia coli has been developed using a cleavable fusion protein strategy. Insoluble fusion protein collected as inclusion bodies was dissolved in urea under reducing conditions, re-folded, and purified by gel filtration chromatography and C(4) RP-HPLC. Authentic rat BTC was obtained after proteolytic cleavage of the fusion protein with Factor Xa. Factor Xa cleaved an additional site within the BTC protein, generating a truncated isoform separable from full-length BTC by heparin-affinity chromatography. Recombinant rat BTC stimulated the proliferation of mouse Balb/c 3T3 fibroblasts and competed for binding to the ErbB1 receptor in a dose-dependent manner analogous to that of BTC purified from natural sources.

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Time-, Sex-, and Dose-Dependent Alterations of the Gut Microbiota by Consumption of Dietary Daikenchuto (TU-100)

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/7415975 ◽

2018 ◽

Vol 2018 ◽

pp. 1-18 ◽

Cited By ~ 5

Author(s):

Jun Miyoshi ◽

Kentaro Nobutani ◽

Mark W. Musch ◽

Daina L. Ringus ◽

Nathaniel A. Hubert ◽

...

Keyword(s):

Gut Microbiota ◽

Dependent Manner ◽

Herbal Medication ◽

Human Intestinal Microbiota ◽

Health And Disease ◽

Dietary Components ◽

Medication Efficacy ◽

Dose Dependent ◽

Withdrawal Effects ◽

Mouse Gut Microbiota

Medications or dietary components can affect both the host and the host’s gut microbiota. Changes in the microbiota may influence medication efficacy and interactions. Daikenchuto (TU-100), a herbal medication, comprised of ginger, ginseng, and Japanese pepper, is widely used in Japanese traditional Kampo medicine for intestinal motility and postoperative paralytic ileus. We previously showed in mice that consumption of TU-100 for 4 weeks changed the gut microbiota and increased bioavailability of bacterial ginsenoside metabolites. Since TU-100 is prescribed in humans for months to years, we examined the time- and sex-dependent effects of TU-100 on mouse gut microbiota. Oral administration of 1.5% TU-100 for 24 weeks caused more pronounced changes in gut microbiota in female than in male mice. Changes in both sexes largely reverted to baseline upon TU-100 withdrawal. Effects were time and dose dependent. The microbial profiles reverted to baseline within 4 weeks after withdrawal of 0.75% TU-100 but were sustained after withdrawal of 3% TU-100. In summary, dietary TU-100 changed mouse microbiota in a time-, sex-, and dose-dependent manner. These findings may be taken into consideration when determining optimizing dose for conditions of human health and disease with the consideration of differences in composition and response of the human intestinal microbiota.

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Inhibition of diphosphatidylglycerol synthesis by u.v. A radiations in N.C.T.C. 2544 human keratinocytes

Biochemical Journal ◽

10.1042/bj2990085 ◽

1994 ◽

Vol 299 (1) ◽

pp. 85-90 ◽

Cited By ~ 4

Author(s):

M Djavaheri-Mergny ◽

L Mora ◽

C Mazière ◽

M Auclair ◽

R Santus ◽

...

Keyword(s):

Arachidonic Acid ◽

Oleic Acid ◽

Human Keratinocytes ◽

Dependent Manner ◽

Phospholipid Synthesis ◽

Mitochondrial Inner Membrane ◽

Human Keratinocyte ◽

Mitochondrial Functions ◽

Keratinocyte Cell ◽

Dose Dependent

The effects of u.v. A radiations on phospholipid synthesis were studied in the N.C.T.C. 2544 human keratinocyte cell line, by using [14C]arachidonic acid, [14C]oleic acid or sodium [32P]orthophosphate as precursors. Cells were irradiated in Hanks' medium with 365 nm light at doses up to 19 J/cm2, and then phospholipid synthesis from the three precursors was studied. Under these conditions, only small alterations in the incorporation pattern of [14C]arachidonic into phospholipids [phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI)] were observed, for u.v. A irradiation doses up to 19 J/cm2. In contrast, with [14C]oleic acid as precursor, two additional spots were observed, which co-migrate with pure phosphatidylglycerol (PG) and diphosphatidylglycerol (DPG) standards. The incorporation of [14C]oleic acid into PG and DPG was decreased in a dose-dependent manner after u.v. A exposure, with about 50% and 75% decreases at 9.5 J/cm2 and 19 J/cm2 respectively. As for arachidonic acid incorporation, no significant differences in the synthesis of the major phospholipids (PC, PE, PI) were noted upon u.v. A exposure. The dramatic and selective decrease in PG and DPG syntheses was confirmed with [32P]orthophosphate as precursor. As DPG is a specific component of the mitochondrial inner membrane, it appears that one of the early kinds of damage induced by u.v. A irradiation could be the impairment of mitochondrial functions.

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