Faculty Bibliography

Neuropathic pain and neuropsychiatric symptoms are common complications reported by the traumatic brain injury (TBI) population. Although a growing body of research has indicated the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for the management of neurological and psychiatric disorders, little evidence has been presented to support the effects of rTMS on neuropathic pain and neuropsychiatric symptoms in patients with TBI in all age groups. In addition, a better understanding of the potential factors that might influence the therapeutic effect of rTMS is necessary. The objective of this preregistered systematic review and meta-analysis was to quantify the effects of rTMS on physical and psychological symptoms in individuals with TBI. We systematically searched six databases for randomized controlled trials (RCTs) of rTMS in TBI patients reporting pain and neuropsychiatric outcomes published until March 20, 2022. The mean difference (MD) with 95% confidence intervals (CIs) was estimated separately for outcomes to understand the mean effect size. Twelve RCTs with 276 TBI patients were ultimately selected from 1605 records for systematic review, and 11 of the studies were included in the meta-analysis. Overall, five of the included studies showed a low risk of bias. The effects of rTMS on neuropathic pain were statistically significant (MD = -1.00, 95% CI -1.76 to -0.25, P = 0.009), with high heterogeneity (I ² = 76%). A significant advantage of 1 Hz rTMS over the right dorsolateral prefrontal cortex (DLPFC) in improving depression (MD = -6.52, 95% CI -11.58 to -1.46, P = 0.01) was shown, and a significant improvement was noted in the Rivermead Post-Concussion Symptoms Questionnaire-13 (RPQ-13) scores of mild TBI patients after rTMS (MD = -5.87, 95% CI -10.63 to -1.11, P = 0.02). However, no significance was found in cognition measurement. No major adverse events related to rTMS were reported. Moderate evidence suggests that rTMS can effectively and safely improve neuropathic pain, while its effectiveness on depression, postconcussion symptoms, and cognition is limited. More trials with a larger number of participants are needed to draw firm conclusions. This trial is registered with PROSPERO (PROSPERO registration number: CRD42021242364.

Prostate cancer is the most frequently diagnosed cancer in males and its development and progression remains an important area of study. Recently, long non-coding RNAs (lncRNAs) have been evidenced as key players in cancer pathogenesis. Specifically, dysregulation of long non-coding RNA (lncRNA) expression has shown to affect tumor proliferation and metastasis, acting as either tumor suppressors or oncogenes. However, its specific mechanisms and functions in prostate cancer remain unclear. This review provides an overview of currently available information on prostate cancer-related lncRNAs, including GAS5, GAS-007, MEG3, PCA3, PCAT14, PCAT1, PVT1, UCA1, SChLAP1, MALAT1, HOTAIR, and NEAT1. Notable tumor growth inhibitors include GAS5 and MEG3. GAS5 is evidenced to interfere with the AKT/MTOR signaling pathway through targeting microRNA mir-103. MEG3, however, is proposed to inhibit the cycle, sponge miR-9-5p, and induce gene silencing. PCAT1, PVT1, and UCA1 are important tumor growth promoters. PCAT1 is indicated to be a transcriptional repressor, a mir-145-5P sponge, and a P13K/AKT pathway activator. Studies suggest that PVT1 acts via microRNA targeting and regulating proliferating cell nuclear antigen. UCA1 may sponge miR-204 and miR-331-3p as well as regulate myosin VI. Thorough understanding of these lncRNAs may elucidate new aspects of prostate cancer pathology and serve a pivotal role in developing novel diagnostic and prognostic techniques.

Periodontitis, a chronic, inflammatory disease, induces systemic inflammation and contributes to the development of neurodegenerative diseases. The precise etiology of the most common neurodegenerative disorders, such as sporadic Alzheimer's, Parkinson's diseases and multiple sclerosis (AD, PD, and MS, respectively), remains to be revealed. Chronic neuroinflammation is a well-recognized component of these disorders, and evidence suggests that systemic inflammation is a possible stimulus for neuroinflammation development. Systemic inflammation can lead to deleterious consequences on the brain if the inflammation is sufficiently severe or if the brain shows vulnerabilities due to genetic predisposition, aging, or neurodegenerative diseases. It has been proposed that periodontal disease can initiate or contribute to the AD pathogenesis through multiple pathways, including key periodontal pathogens. Dysbiotic oral bacteria can release bacterial products into the bloodstream and eventually cross the brain-blood barrier; these bacteria can also cause alterations to gut microbiota that enhance inflammation and potentially affect brain function via the gut-brain axis. The trigeminal nerve has been suggested as another route for connecting oral bacterial products to the brain. PD and MS are often preceded by gastrointestinal symptoms or aberrant gut microbiome composition, and alterations in the enteric nervous system accompany the disease. Clinical evidence has suggested that patients with periodontitis are at a higher risk of developing PD and MS. This nexus among the brain, periodontal disease, and systemic inflammation heralds new ways in which microglial cells, the main innate immune cells, and astrocytes, the crucial regulators of innate and adaptive immune responses in the brain, contribute to brain pathology. Currently, the lack of understanding of the pathogenesis of neurodegeneration is hindering treatment development. However, we may prevent this pathogenesis by tackling one of its possible contributors (periodontitis) for systemic inflammation through simple preventive oral hygiene measures.

Electronic cigarettes (e-cigs) have become prevalent as an alternative to conventional cigarette smoking, particularly in youth. E-cig aerosols contain unique chemicals which alter the oral microbiome and promote dysbiosis in ways we are just beginning to investigate. We conducted a 6-month longitudinal study involving 84 subjects who were either e-cig users, conventional smokers, or nonsmokers. Periodontal condition, cytokine levels, and subgingival microbial community composition were assessed, with periodontal, clinical, and cytokine measures reflecting cohort habit and positively correlating with pathogenic taxa (e.g., Treponema, Saccharibacteria, and Porphyromonas). α-Diversity increased similarly across cohorts longitudinally, yet each cohort maintained a unique microbiome. The e-cig microbiome shared many characteristics with the microbiome of conventional smokers and some with nonsmokers, yet it maintained a unique subgingival microbial community enriched in Fusobacterium and Bacteroidales (G-2). Our data suggest that e-cig use promotes a unique periodontal microbiome, existing as a stable heterogeneous state between those of conventional smokers and nonsmokers and presenting unique oral health challenges. IMPORTANCE Electronic cigarette (e-cig) use is gaining in popularity and is often perceived as a healthier alternative to conventional smoking. Yet there is little evidence of the effects of long-term use of e-cigs on oral health. Conventional cigarette smoking is a prominent risk factor for the development of periodontitis, an oral disease affecting nearly half of adults over 30 years of age in the United States. Periodontitis is initiated through a disturbance in the microbial biofilm communities inhabiting the unique space between teeth and gingival tissues. This disturbance instigates host inflammatory and immune responses and, if left untreated, leads to tooth and bone loss and systemic diseases. We found that the e-cig user's periodontal microbiome is unique, eliciting unique host responses. Yet some similarities to the microbiomes of both conventional smokers and nonsmokers exist, with strikingly more in common with that of cigarette smokers, suggesting that there is a unique periodontal risk associated with e-cig use.

In this issue of Cancer Cell, Aftab et al. identify a pro-inflammatory cytokine, IL-33, that is released as a chemoattractant for type 2 immune cells in response to the intratumoral mycobiome. Depletion of fungi or deletion of IL-33 in cancer cells significantly decreases pancreatic ductal adenocarcinoma (PDAC) tumor progression and increases survival.

The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically Bacteroidetes species. Targeting Bacteroidetes with oral antibiotics reduced hepatic immune cells by ~90%, prevented APC maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of Bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial - glycosphingolipid - NKT - CCL5 axis that underlies hepatic immunity.

The effect of electronic cigarette (e-cigarette) smoking, especially its long-term impact on oral health, is poorly understood. Here, we conducted a longitudinal clinical study with two study visits, 6 months apart, to investigate the effect of e-cigarette use on the bacterial community structure in the saliva of 101 periodontitis patients. Our data demonstrated that e-cigarette use altered the oral microbiome in periodontitis patients, enriching members of the Filifactor, Treponema, and Fusobacterium taxa. For patients at the same periodontal disease stage, cigarette smokers and e-cigarette smokers shared more similarities in their oral bacterial composition. E-cigarette smoking may have a similar potential as cigarette smoking at altering the bacterial composition of saliva over time, leading to an increase in the relative abundance of periodontal disease-associated pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum. The correlation analysis showed that certain genera, such as Dialister, Selenomonas, and Leptotrichia in the e-cigarette smoking group, were positively correlated with the levels of proinflammatory cytokines, including IFN-γ, IL-1β, and TNF-α. E-cigarette use was also associated with elevated levels of proinflammatory cytokines such as IFN-γ and TNF-α, which contribute to oral microbiome dysbiosis and advanced disease state. This article is protected by copyright. All rights reserved.

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 http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Succinate is a metabolite in the tricarboxylic acid cycle (TCA) which plays a central role in mitochondrial activity. Excess succinate is known to be transported out of the cytosol, where it activates a succinate receptor (SUCNR1) to enhance inflammation through macrophages in various contexts. In addition, the intracellular role of succinate beyond an intermediate metabolite and prior to its extracellular release is also important to the polarization of macrophages. However, the role of succinate in microglial cells has not been characterized. Lipopolysaccharide (LPS) stimulates the elevation of intracellular succinate levels. To reveal the function of intracellular succinate associated with LPS-stimulated inflammatory response in microglial cells, we assessed the levels of ROS, cytokine production and mitochondrial fission in the primary microglia pretreated with cell-permeable diethyl succinate mimicking increased intracellular succinate. Our results suggest that elevated intracellular succinate exerts a protective role in the primary microglia by preventing their conversion into the pro-inflammatory M1 phenotype induced by LPS. This protective effect is SUCNR1-independent and mediated by reduced mitochondrial fission and cellular ROS production.