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The Gut Microbiome, Metformin, and Aging

Induri, Sri Nitya Reddy; Kansara, Payalben; Thomas, Scott C; Xu, Fangxi; Saxena, Deepak; Li, Xin
Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's mechanisms of action remain elusive. The gut typically harbors thousands of bacterial species, and as the concentration of metformin is much higher in the gut as compared to plasma, it is plausible that microbiome-drug-host interactions may influence the functions of metformin. Detrimental perturbations in the aging gut microbiome lead to the activation of the innate immune response concomitant with chronic low-grade inflammation. With the effectiveness of metformin in diabetes and antiaging varying among individuals, there is reason to believe that the gut microbiome plays a role in the efficacy of metformin. Metformin has been implicated in the promotion and maintenance of a healthy gut microbiome and reduces many age-related degenerative pathologies. Mechanistic understanding of metformin in the promotion of a healthy gut microbiome and aging will require a systems-level approach. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see for revised estimates.
PMID: 34449247
ISSN: 1545-4304
CID: 4989152

Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice

Wang, Lixiang; Li, Xin; Hanada, Yuki; Hasuzawa, Nao; Moriyama, Yoshinori; Nomura, Masatoshi; Yamamoto, Ken
Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.
PMID: 34290349
ISSN: 2399-3642
CID: 5018012

Protective Measures against COVID-19: Dental Practice and Infection Control

Induri, Sri Nitya Reddy; Chun, Yunah Caroline; Chun, Joonmo Christopher; Fleisher, Kenneth E; Glickman, Robert S; Xu, Fangxi; Ioannidou, Efthimia; Li, Xin; Saxena, Deepak
The onset of the Coronavirus 2019 (COVID-19) pandemic has challenged the worldwide healthcare sector, including dentistry. The highly infectious nature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and risk of transmission through aerosol generating procedures has profoundly impacted the delivery of dental care services globally. As dental practices with renewed infection control strategies and preventive measures are re-opening in the "new normal" period, it is the responsibility of healthcare professionals to constantly analyze new data and limit the spread of COVID-19 in dental care settings. In the light of new variants of SARS-CoV-2 rapidly emerging in different geographic locations, there is an urgent need to comply more than ever with the rigorous public health measures to mitigate COVID-19 transmission. The aim of this article is to provide dental clinicians with essential information regarding the spread of SARS-CoV-2 virus and protective measures against COVID-19 transmission in dental facilities. We complied and provided guidance and standard protocols recommended by credible national and international organizations. This review will serve as an aid to navigating through this unprecedented time with ease. Here we reviewed the available literature recommended for the best current practices that must be taken for a dental office to function safely and successfully.
PMID: 34200036
ISSN: 2227-9032
CID: 4936982

Progranulin promotes bone fracture healing via TNFR pathways in mice with type 2 diabetes mellitus

Ding, Yuanjing; Wei, Jianlu; Hettinghouse, Aubryanna; Li, Guangfei; Li, Xin; Einhorn, Thomas A; Liu, Chuan-Ju
Type 2 diabetes mellitus (T2DM) significantly increases bone fragility and fracture risk. Progranulin (PGRN) promotes bone fracture healing in both physiological and type 1 diabetic conditions. The present study aimed to investigate the role of PGRN in T2DM bone fracture healing. MKR mice (with an FVB/N genetic background) were used as the T2DM model. Drill-hole and Bonnarens and Einhorn models were used to investigate the role of PGRN in T2DM fracture healing in vivo. Primary bone marrow cells were isolated for molecular and signaling studies, and reverse transcription-polymerase chain reaction, immunohistochemical staining, and western blotting were performed to assess PGRN effects in vitro. PGRN mRNA and protein expression were upregulated in the T2DM model. Local administration of recombinant PGRN effectively promoted T2DM bone fracture healing in vivo. Additionally, PGRN could induce anabolic metabolism during endochondral ossification through the TNFR2-Akt and Erk1/2 pathways. Furthermore, PGRN showed anti-inflammatory activity in the T2DM bone regeneration process. These findings suggest that local administration of exogenous PGRN may be an alternative strategy to support bone regeneration in patients with T2DM. Additionally, PGRN might hold therapeutic potential for other TNFR-related metabolic disorders.
PMID: 33543485
ISSN: 1749-6632
CID: 4776682

Genome-wide association study identifies 48 common genetic variants associated with handedness

Cuellar-Partida, Gabriel; Tung, Joyce Y; Eriksson, Nicholas; Albrecht, Eva; Aliev, Fazil; Andreassen, Ole A; Barroso, Inês; Beckmann, Jacques S; Boks, Marco P; Boomsma, Dorret I; Boyd, Heather A; Breteler, Monique M B; Campbell, Harry; Chasman, Daniel I; Cherkas, Lynn F; Davies, Gail; de Geus, Eco J C; Deary, Ian J; Deloukas, Panos; Dick, Danielle M; Duffy, David L; Eriksson, Johan G; Esko, Tõnu; Feenstra, Bjarke; Geller, Frank; Gieger, Christian; Giegling, Ina; Gordon, Scott D; Han, Jiali; Hansen, Thomas F; Hartmann, Annette M; Hayward, Caroline; Heikkilä, Kauko; Hicks, Andrew A; Hirschhorn, Joel N; Hottenga, Jouke-Jan; Huffman, Jennifer E; Hwang, Liang-Dar; Ikram, M Arfan; Kaprio, Jaakko; Kemp, John P; Khaw, Kay-Tee; Klopp, Norman; Konte, Bettina; Kutalik, Zoltan; Lahti, Jari; Li, Xin; Loos, Ruth J F; Luciano, Michelle; Magnusson, Sigurdur H; Mangino, Massimo; Marques-Vidal, Pedro; Martin, Nicholas G; McArdle, Wendy L; McCarthy, Mark I; Medina-Gomez, Carolina; Melbye, Mads; Melville, Scott A; Metspalu, Andres; Milani, Lili; Mooser, Vincent; Nelis, Mari; Nyholt, Dale R; O'Connell, Kevin S; Ophoff, Roel A; Palmer, Cameron; Palotie, Aarno; Palviainen, Teemu; Pare, Guillaume; Paternoster, Lavinia; Peltonen, Leena; Penninx, Brenda W J H; Polasek, Ozren; Pramstaller, Peter P; Prokopenko, Inga; Raikkonen, Katri; Ripatti, Samuli; Rivadeneira, Fernando; Rudan, Igor; Rujescu, Dan; Smit, Johannes H; Smith, George Davey; Smoller, Jordan W; Soranzo, Nicole; Spector, Tim D; Pourcain, Beate St; Starr, John M; Stefánsson, Hreinn; Steinberg, Stacy; Teder-Laving, Maris; Thorleifsson, Gudmar; Stefánsson, Kári; Timpson, Nicholas J; Uitterlinden, André G; van Duijn, Cornelia M; van Rooij, Frank J A; Vink, Jaqueline M; Vollenweider, Peter; Vuoksimaa, Eero; Waeber, Gérard; Wareham, Nicholas J; Warrington, Nicole; Waterworth, Dawn; Werge, Thomas; Wichmann, H-Erich; Widen, Elisabeth; Willemsen, Gonneke; Wright, Alan F; Wright, Margaret J; Xu, Mousheng; Zhao, Jing Hua; Kraft, Peter; Hinds, David A; Lindgren, Cecilia M; Mägi, Reedik; Neale, Benjamin M; Evans, David M; Medland, Sarah E
Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
PMID: 32989287
ISSN: 2397-3374
CID: 4881222

Microbial population shift and metabolic characterization of silver diamine fluoride treatment failure on dental caries

Paul, Bidisha; Sierra, Maria A; Xu, Fangxi; Crystal, Yasmi O; Li, Xin; Saxena, Deepak; Ruff, Ryan Richard
The objective of this pilot study was to describe the microbial profiles present in the plaque and saliva of children who continued to develop new carious lesions following treatment with silver diamine fluoride ("nonresponders") compared to caries active, caries-free, and children immediately receiving SDF treatment for untreated caries in order to identify potential microbial differences that may relate to a re-incidence of caries. Saliva and plaque samples from infected and contralateral sites were obtained from twenty children who were either caries free, had active carious lesions, were caries active and received SDF treatment immediately before sampling, or had previously received SDF treatment and developed new caries. In total, 8,057,899 Illumina-generated sequence reads from 60 samples were obtained. Reads were processed using the Quantitative Insights Into Microbial Ecology pipeline. Group differences were assessed using Analysis of Variance Models and Tukey Honest Significant Differences. To identify significant taxa between treatment groups, Linear discriminant analysis Effect Size (LefSe) and Analysis of Differential Abundance Taking Sample Variation Into Account were used. Differential abundant analysis indicated that members of the Lachnospiraceae family were significantly enriched in non-responders and the genus Tannerella and species Granulicatella adiances were also highly abundant in this group. LefSe analysis between non-responders and SDF-treated groups revealed that genera Leptotrichia and Granulicatella were enriched in non-responders. We observed the highest abundance of phosphotransferase system and lowest abundance of lipopolysaccharide synthesis in non-responders. The microbiome in dental biofilms is responsible for initiation and progression of dental caries. SDF has been shown to be effective in arresting the progression carious lesions, in part due to its antimicrobial properties. Findings suggest that the differential abundance of select microbiota and specific pathway functioning in individuals that present with recurrent decay after SDF treatment may contribute to a potential failure of silver diamine fluoride to arrest dental caries. However, the short duration of sample collection following SDF application and the small sample size emphasize the need for further data and additional analysis.
PMID: 33720954
ISSN: 1932-6203
CID: 4817462

Vaping, SARS-CoV-2, and Multisystem Inflammatory Syndrome: A Perfect Storm [Review]

Brar, Esha; Saxena, Anish; Dukler, Claudia; Xu, Fangxi; Saxena, Deepak; Cheema Brar, Preneet; Guo, Yuqi; Li, Xin
ISSN: 2296-2360
CID: 4892412

Cross talk between drug-resistant epilepsy and the gut microbiome

Holmes, Manisha; Flaminio, Zia; Vardhan, Mridula; Xu, Fangxi; Li, Xin; Devinsky, Orrin; Saxena, Deepak
One-third of epilepsy patients have drug-resistant epilepsy (DRE), which is often complicated by polydrug toxicity and psychiatric and cognitive comorbidities. Advances in understanding the microbiome and gut-brain-axis are likely to shed light on epilepsy pathogenesis, anti-seizure medication (ASM) resistance, and potential therapeutic targets. Gut dysbiosis is associated with inflammation, blood-brain barrier disruption, and altered neuromodulators. High-throughput and metagenomic sequencing has advanced the characterization of microbial species and functional pathways. DRE patients show altered gut microbiome composition compared to drug-sensitive patients and healthy controls. The ketogenic and modified Atkins diets can reduce seizures in some patients with DRE. These low-carbohydrate dietary therapies alter the taxonomic and functional composition of the gut microbiome, and composition varies between diet responders and nonresponders. Murine models suggest that specific phyla are necessary to confer efficacy from the diet, and antibiotic treatment may eliminate efficacy. The impact of diet might involve alterations in microbiota, promotion of select microbial interactions, and variance in brain neurotransmitter levels that then influence seizures. Understanding the mechanics of how diet manipulates seizures may suggest novel therapies. Most ASMs act on neuronal transmission via effects on ion channels and neurotransmitters. However, ASMs may also assert their effects via the gut microbiota. In animal models, the microbiota composition (eg, abundance of certain phyla) can vary with ASM active drug metabolites. Given the developing understanding of the gut microbiome in DRE, probiotics are another potential therapy. Probiotics alter the microbiota composition, and small studies suggest that these supplements can reduce seizures in some patients. DRE has enormous consequences to patients and society, and the gut microbiome holds promise as a potential therapeutic target. However, the exact mechanism and recognition of which patients are likely to be responders remain elusive. Further studies are warranted.
PMID: 33140419
ISSN: 1528-1167
CID: 4655972

Identification of Differentially Methylated Regions Associated with a Knockout of SUV39H1 in Prostate Cancer Cells

Yan, Wenbo; Guo, Yuqi; Xu, Fangxi; Saxena, Deepak; Li, Xin
Epigenetic alterations, such as histone methylations, affect the pathogenesis of tumors including prostate cancer (PCa). Previously, we reported that metformin reduced SUV39H1, a histone methyltransferase of H3 Lys9, to inhibit the migration of PCa cells. Since histone methylation is functionally linked to DNA methylation, we speculate that the knockout of the SUV39H1 gene will affect the genomic DNA methylation profile to regulate PCa cell migration and invasion. The genome-wide DNA methylation level is lower in SUV39H1 knockout (KO) cells than wild-type (WT) ones. However, the methylation levels in functional regions of CpG Islands (CGI), 5' untranslated region (UTR5), and exon regions are higher in KO cells than WT cells. Analysis of differentially methylated regions (DMRs) identified 1241 DMR genes that have differential methylation on CG sites when comparing the KO and WT samples. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes Pathways analysis showed that knockout of SUV39H1 affects gene sets and pathways that are heavily involved in cell shapes, cell recognition, adhesion, motility, and migration. Our study suggests that SUV39H1 plays an important role in PCa migration via the epigenetic regulation of methylation on CG sites, and is a novel and legitimate target to inhibit PCa cell migration.
PMID: 33066102
ISSN: 2073-4425
CID: 4642782

E-cigarettes use in the United States: reasons for use, perceptions, and effects on health

Sapru, Sakshi; Vardhan, Mridula; Li, Qianhao; Guo, Yuqi; Li, Xin; Saxena, Deepak
BACKGROUND:Many researchers claim electronic cigarettes (e-cigarettes) to be a breakthrough invention for tobacco users that aspires to curb their addiction to conventional cigarettes. Claimed to be safer by their promoters, these smokeless devices have become increasingly popular since their arrival on the market among users of all ages, especially adolescents. This paper investigated the trends in e-cigarette usage since the time it arrived in the United States, highlighting the highest surge that has occurred in adolescent e-cigarette use. It also aimed to understand the reasons and perceptions behind the ever-increasing use of e-cigarettes by adolescents. MAIN BODY/UNASSIGNED:With the advent of e-cigarettes and common positive perceptions regarding their use, we are at risk of reversing the years of efforts regarding tobacco control and instead advance towards a new addiction with currently unknown long-term health hazards. There is substantial data showing a significant increase of e-cigarette users in the United States, especially among adolescents. The aim of this review was to explore the reasons behind this widespread increase in the use of e-cigarettes among the teenage population in the US and also to uncover the common perceptions about these new electronic delivery systems. In addition, this review attempted to summarize health benefits and hazards associated with e-cigarette use as it crucial to have the right information among its users regarding the health effects of e-cigarette use. CONCLUSION/CONCLUSIONS:E-cigarettes are more appealing than c-cigarettes for a variety of reasons, including cost, choice of different flavors, ease of accessibility, and use and impact of social media. There are also different perceptions among e-cigarette users, including both adolescents and adults. The former group may use them because of the sense of fashion associated with this novel device, and the latter might intend to quit conventional/combustible cigarettes (c-cigarettes) by switching to e-cigarettes. However, it is important to note that e-cigarettes are a recent phenomenon; therefore, there is a lack of many long-term studies that can identify future health risks associated with e-cigarette use. We need more detailed studies that focus on the long-term health effects of e-cigarette use. Moreover, with the ever-increasing usage of e-cigarettes by adolescents (10 and 19 years), it is very important that e-cigarettes be incorporated into the current tobacco-free laws and ordinances. We conclude by stating that e-cigarettes need stronger regulations to prevent youth access and use.
PMID: 33032554
ISSN: 1471-2458
CID: 4640812