Publications by authors named "Babak Baban"

115 Publications

Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway.

Mol Psychiatry 2021 Apr 8. Epub 2021 Apr 8.

Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Chronic stress is a major risk factor in the pathophysiology of many neuropsychiatric disorders. Further, chronic stress conditions can promote neuroinflammation and inflammatory responses in both humans and animal models. Type I interferons (IFN-I) are critical mediators of the inflammatory response in the periphery and responsible for the altered mood and behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of IFN-I signaling in chronic stress-induced changes in neuroinflammation and behavior. Using the chronic restraint stress model, we found that chronic stress induces a significant increase in serum IFNβ levels in mice, and systemic blockade of IFN-I signaling attenuated chronic stress-induced infiltration of macrophages into prefrontal cortex and behavioral abnormalities. Furthermore, complement component 3 (C3) mediates systemic IFNβ-induced changes in neuroinflammation and behavior. Also, we found significant increases in the mRNA expression levels of IFN-I stimulated genes in the prefrontal cortex of depressed suicide subjects and significant correlation with C3 and inflammatory markers. Together, these findings from animal and human postmortem brain studies identify a crucial role of C3 in IFN-I-mediated changes in neuroinflammation and behavior under chronic stress conditions.
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http://dx.doi.org/10.1038/s41380-021-01065-6DOI Listing
April 2021

High Levels of Interferon-Alpha Expressing Macrophages in Human Breast Milk During SARS-CoV-2 Infection: A Case Report.

Breastfeed Med 2021 Mar 30. Epub 2021 Mar 30.

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA.

In addition to hand washing and wearing masks, social distancing and reducing exposure time to <15 minutes are the most effective measures against the spread of COVID-19. Unfortunately, three of these guidelines are very difficult, if not impossible, for nursing babies: they cannot wear masks, stay six feet away from the lactating breasts, nor consistently finish within 15 minutes while nursing. We report a case of a nursing mother with SARS-CoV-2 infection, documenting changes of immune cells and cytokines in breast milk with and without the infection. With Institutional Review Board (IRB) approval, we obtained expressed breast milk samples from a lactating mother before and during SARS-CoV-2 infection as documented by reverse transcription-PCR. Using flow cytometry analysis, we measured the immune cell profiles and expression of cytokines such as interferon alpha (IFNα) in milk leukocytes before and during infection. There was an eightfold increase in IFNα+ milk leukocytes, from 1% before SARS-CoV-2 infection to 8% when actively infected. The milk macrophages showed the highest increase in IFNα expression. Both T and B lymphocytes showed mild increase. Innate lymphoid cells, neutrophils, and natural killer cells showed no increase in IFNα expression and the dendritic cells actually showed a reduction. We document the presence and high expression of IFNα in the breast milk macrophages of a lactating mother with confirmed COVID-19, compared with her milk before the infection.
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http://dx.doi.org/10.1089/bfm.2020.0369DOI Listing
March 2021

Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer's Disease.

J Alzheimers Dis 2021 ;80(3):973-977

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA.

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.
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http://dx.doi.org/10.3233/JAD-210026DOI Listing
January 2021

Delayed Administration of Angiotensin Receptor (AT2R) Agonist C21 Improves Survival and Preserves Sensorimotor Outcomes in Female Diabetic Rats Post-Stroke through Modulation of Microglial Activation.

Int J Mol Sci 2021 Jan 29;22(3). Epub 2021 Jan 29.

Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30912, USA.

About 70% of stroke victims present with comorbid diseases such as diabetes and hypertension. The integration of comorbidities in pre-clinical experimental design is important in understanding the mechanisms involved in the development of stroke injury and recovery. We recently showed that administration of compound C21, an angiotensin II type 2 receptor agonist, at day 3 post-stroke improved sensorimotor outcomes by lowering neuroinflammation in diabetic male animals. In the current study, we hypothesized that a delayed administration of C21 would also lower chronic inflammation post-stroke in diabetic female animals. Young female diabetic rats were subjected to 1 h of middle cerebral artery occlusion (MCAO). Three days post-stroke, rats were administered C21 or vehicle in drinking water at a dose of 0.12 mg/kg/day for 4 weeks. The impact of C21 on microglial polarization was analyzed by flow cytometry in vivo and in vitro. Compound 21 treatment improved fine motor skills after MCAO through modulation of the microglia/macrophage inflammatory properties. In addition, C21 increased M2 polarization and reduced the M1:M2 ratio in vitro. In conclusion, delayed administration of C21 downregulates post-stroke inflammation in female diabetic animals. C21 may be a useful therapeutic option to lower neuro-inflammation and improve the post-stroke recovery in diabetes.
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http://dx.doi.org/10.3390/ijms22031356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866408PMC
January 2021

AMPK induces regulatory innate lymphoid cells after traumatic brain injury.

JCI Insight 2021 Jan 11;6(1). Epub 2021 Jan 11.

Department of Neurosurgery, and.

The CNS is regarded as an immunoprivileged organ, evading routine immune surveillance; however, the coordinated development of immune responses profoundly influences outcomes after brain injury. Innate lymphoid cells (ILCs) are cytokine-producing cells that are critical for the initiation, modulation, and resolution of inflammation, but the functional relevance and mechanistic regulation of ILCs are unexplored after acute brain injury. We demonstrate increased proliferation of all ILC subtypes within the meninges for up to 1 year after experimental traumatic brain injury (TBI) while ILCs were present within resected dura and elevated within cerebrospinal fluid (CSF) of moderate-to-severe TBI patients. In line with energetic derangements after TBI, inhibition of the metabolic regulator, AMPK, increased meningeal ILC expansion, whereas AMPK activation suppressed proinflammatory ILC1/ILC3 and increased the frequency of IL-10-expressing ILC2 after TBI. Moreover, intracisternal administration of IL-33 activated AMPK, expanded ILC2, and suppressed ILC1 and ILC3 within the meninges of WT and Rag1-/- mice, but not Rag1-/- IL2rg-/- mice. Taken together, we identify AMPK as a brake on the expansion of proinflammatory, CNS-resident ILCs after brain injury. These findings establish a mechanistic framework whereby immunometabolic modulation of ILCs may direct the specificity, timing, and magnitude of cerebral immunity.
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http://dx.doi.org/10.1172/jci.insight.126766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821592PMC
January 2021

Combination of C21 and ARBs with rhACE2 as a therapeutic protocol: A new promising approach for treating ARDS in patients with coronavirus infection.

Med J Islam Repub Iran 2020 14;34:120. Epub 2020 Sep 14.

Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.

Coronavirus disease 2019 (COVID-19) is caused by a new severe acute respiratory syndrome Coronavirus. COVID-19 patients are at risk for acute respiratory distress syndrome and death from respiratory failure. In this study the complete genome of the SARS-CoV-2 reference sequence, geologically isolated types, and Coronavirus related to human diseases were compared by the Molecular Phylogenetic Maximum Likelihood method. The secondary and tertiary structures of the main protease of SARS-CoV were defined as the most similar viruses to SARS-CoV-2, aligned with chimera software. Therefore, considering ineffective antiviral medications used for SARS-CoV and the importance of preventing acute respiratory distress syndrome as the main cause of mortality, 2 strategies were adopted to acquire the most effective drug combination. The results of phylogenic analysis showed that SARS-CoV is the most similar virus to SARS-CoV-2. The secondary structure and superimposing of tertiary structure did not show a significant difference between SARS and SARS-CoV-2 3C-like main protease and the root means square deviation between Cα atoms did not support the difference between the 2 protein structures. Thus, these 2 mechanisms were fostered in accordance with the correlation between acute respiratory distress syndrome-related Coronavirus, angiotensin-converting enzyme 2 on one side and the possible treatments for reducing the respiratory side effects on the other. The analysis of renin-angiotensin system as well as the tested drugs applied to acute respiratory distress syndrome cases, indicated that angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and C21 as nonpeptide agonist might possess a promising modality of treatment for acute respiratory distress syndrome. Furthermore, implementing recombinant human ACE2 as a competitive receptor might be an effective way to trap and chelate the SARS-CoV-2 particles. The data suggest that combination therapy of angiotensin II receptor blockers and C21 could be a potential pharmacologic regimen to control and reduce acute respiratory distress syndrome. Moreover, rhACE2 can be recommended as an effective protective antiviral therapy in the treatment of COVID-19 and its complications.
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http://dx.doi.org/10.34171/mjiri.34.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722962PMC
September 2020

Local delivery of simvastatin maintains tooth anchorage during mechanical tooth moving via anti-inflammation property and AMPK/MAPK/NF-kB inhibition.

J Cell Mol Med 2021 Jan 12;25(1):333-344. Epub 2020 Dec 12.

Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Simvastatin (SMV) could increase tooth anchorage during orthodontic tooth movement (OTM). However, previous studies on its bone-specific anabolic and anti-inflammation properties were based on static in vitro and in vivo conditions. AMPK is a stress-activated kinase that protects tissue against serious damage from overloading inflammation. Rat periodontal ligament cells (PDLCs) were subjected to a serial of SMV concentrations to investigate the optimization that promoted osteogenic differentiation. The PDLCs in static and/or tensile culturing conditions then received the proper concentration SMV. Related factors expression was measured by the protein array, real-time PCR and Western blot. The 0.05UM SMV triggered osteogenic differentiation of PDLCs. The inhibition of AMPK activation through a pharmacological approach (Compound C) caused dramatic decrease in osteogenic/angiogenic gene expression and significant increase in inflammatory NF-κB phosphorylation. In contrast, pharmacological activation of AMPK by AICAR significantly inhibited inflammatory factors expression and activated ERK1/2, P38 MAPK phosphorylation. Moreover, AMPK activation induced by SMV delivery significantly attenuated the osteoclastogenesis and decreased the expression of pro-inflammatory TNF-α and NF-κB in a rodent model of OTM. The current studies suggested that SMV could intrigue intrinsic activation of AMPK in PDLCs that promote attenuate the inflammation which occurred under tensile irritation through AMPK/MAPK/NF-kB Inhibition.
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http://dx.doi.org/10.1111/jcmm.16058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810950PMC
January 2021

Infections of the lung: a predictive, preventive and personalized perspective through the lens of evolution, the emergence of SARS-CoV-2 and its pathogenesis.

EPMA J 2020 Nov 13:1-21. Epub 2020 Nov 13.

Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA USA.

The long evolutionary battle between humans and pathogens has played an important role in shaping the current network of host-pathogen interactions. Each organ brings new challenges from the perspective of a pathogen to establish a suitable niche for survival while subverting the protective mechanisms of the host. Lungs, the organ for oxygen exchange, have been an easy target for pathogens due to its accessibility. The organ has evolved diverse capabilities to provide the flexibility required for an organism's health and at the same time maintain protective functionality to prevent and resolve assault by pathogens. The pathogenic invasions are strongly challenged by healthy lung architecture which includes the presence and activity of the epithelium, mucous, antimicrobial proteins, surfactants, and immune cells. Competitively, the pathogens in the form of viruses, bacteria, and fungi have evolved an arsenal of strategies that can over-ride the host's protective mechanisms. While bacteria such as () can survive in dormant form for years before getting active in humans, novel pathogens can wreak havoc as they pose a high risk of morbidity and mortality in a very short duration of time. Recently, a coronavirus strain SARS-CoV-2 has caused a pandemic which provides us an opportunity to look at the host manipulative strategies used by respiratory pathogens. Their ability to hide, modify, evade, and exploit cell's processes are key to their survival. While pathogens like have been infecting humans for thousands of years, SARS-CoV-2 has been the cause of the recent pandemic. Molecular understanding of the strategies used by these pathogens could greatly serve in design of predictive, preventive, personalized medicine (PPPM). In this article, we have emphasized on the clinically relevant evasive strategies of the pathogens in the lungs with emphasis on and SARS-CoV-2. The molecular basis of these evasive strategies illuminated through advances in genomics, cell, and structural biology can assist in the mapping of vulnerable molecular networks which can be exploited translationally. These evolutionary approaches can further assist in generating screening and therapeutic options for susceptible populations and could be a promising approach for the prediction, prevention of disease, and the development of personalized medicines. Further, tailoring the clinical data of COVID-19 patients with their physiological responses in light of known host-respiratory pathogen interactions can provide opportunities to improve patient profiling and stratification according to identified therapeutic targets.
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http://dx.doi.org/10.1007/s13167-020-00230-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661834PMC
November 2020

Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome.

J Cell Mol Med 2020 11 15;24(21):12869-12872. Epub 2020 Oct 15.

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, University, Augusta, GA, USA.

Considering lack of target-specific antiviral treatment and vaccination for COVID-19, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve COVID-19-infected patient outcomes. In a follow-up study to our recent findings indicating the potential of Cannabidiol (CBD) in the treatment of acute respiratory distress syndrome (ARDS), here we show for the first time that CBD may ameliorate the symptoms of ARDS through up-regulation of apelin, a peptide with significant role in the central and peripheral regulation of immunity, CNS, metabolic and cardiovascular system. By administering intranasal Poly (I:C), a synthetic viral dsRNA, while we were able to mimic the symptoms of ARDS in a murine model, interestingly, there was a significant decrease in the expression of apelin in both blood and lung tissues. CBD treatment was able to reverse the symptoms of ARDS towards a normal level. Importantly, CBD treatment increased the apelin expression significantly, suggesting a potential crosstalk between apelinergic system and CBD may be the therapeutic target in the treatment of inflammatory diseases such as COVID-19 and many other pathologic conditions.
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http://dx.doi.org/10.1111/jcmm.15883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686987PMC
November 2020

Neurological consequences of COVID-19: what have we learned and where do we go from here?

J Neuroinflammation 2020 Sep 30;17(1):286. Epub 2020 Sep 30.

Department of Neurosurgery, Medical College of Georgia, Augusta University, 1120 15th Street, 30912, Augusta, Georgia.

The coronavirus disease-19 (COVID-19) pandemic is an unprecedented worldwide health crisis. COVID-19 is caused by SARS-CoV-2, a highly infectious pathogen that is genetically similar to SARS-CoV. Similar to other recent coronavirus outbreaks, including SARS and MERS, SARS-CoV-2 infected patients typically present with fever, dry cough, fatigue, and lower respiratory system dysfunction, including high rates of pneumonia and acute respiratory distress syndrome (ARDS); however, a rapidly accumulating set of clinical studies revealed atypical symptoms of COVID-19 that involve neurological signs, including headaches, anosmia, nausea, dysgeusia, damage to respiratory centers, and cerebral infarction. These unexpected findings may provide important clues regarding the pathological sequela of SARS-CoV-2 infection. Moreover, no efficacious therapies or vaccines are currently available, complicating the clinical management of COVID-19 patients and emphasizing the public health need for controlled, hypothesis-driven experimental studies to provide a framework for therapeutic development. In this mini-review, we summarize the current body of literature regarding the central nervous system (CNS) effects of SARS-CoV-2 and discuss several potential targets for therapeutic development to reduce neurological consequences in COVID-19 patients.
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http://dx.doi.org/10.1186/s12974-020-01957-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525232PMC
September 2020

Cannabidiol Modulates Cytokine Storm in Acute Respiratory Distress Syndrome Induced by Simulated Viral Infection Using Synthetic RNA.

Cannabis Cannabinoid Res 2020 2;5(3):197-201. Epub 2020 Sep 2.

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA.

In the absence of effective antivirals and vaccination, the pandemic of COVID-19 remains the most significant challenge to our health care system in decades. There is an urgent need for definitive therapeutic intervention. Clinical reports indicate that the cytokine storm associated with acute respiratory distress syndrome (ARDS) is the leading cause of mortality in severe cases of some respiratory viral infections, including COVID-19. In recent years, cannabinoids have been investigated extensively due to their potential effects on the human body. Among all cannabinoids, cannabidiol (CBD) has demonstrated potent anti-inflammatory effects in a variety of pathological conditions. Therefore, it is logical to explore whether CBD can reduce the cytokine storm and treat ARDS. In this study, we show that intranasal application of Poly(I:C), a synthetic analogue of viral double-stranded RNA, simulated symptoms of severe viral infections inducing signs of ARDS and cytokine storm. The administration of CBD downregulated the level of proinflammatory cytokines and ameliorated the clinical symptoms of Poly I:C-induced ARDS. Our results suggest a potential protective role for CBD during ARDS that may extend CBD as part of the treatment of COVID-19 by reducing the cytokine storm, protecting pulmonary tissues, and re-establishing inflammatory homeostasis.
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http://dx.doi.org/10.1089/can.2020.0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480719PMC
September 2020

Factors Affecting the Composition of Expressed Fresh Human Milk.

Breastfeed Med 2020 09 20;15(9):551-558. Epub 2020 Aug 20.

Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.

Breast milk is considered the ideal and preferred feeding for all infants through the first 4-6 months of life. It provides many short and long-term benefits to the infant and mother. In the absence of breastfeeding, expressed breast milk is the best way to provide nutrition. In the United States, the majority of breastfeeding mothers express milk at some point during the course of lactation. Breast milk is a dynamic fluid and its content changes with duration of lactation and varies between and among women. Many factors such as maternal diet and medications affect the constituents of breast milk. In addition, method of breast milk expression, handling, and storage can also influence its contents.
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http://dx.doi.org/10.1089/bfm.2020.0195DOI Listing
September 2020

IL-10 treatment decreases blood pressure in male, but not female, spontaneously hypertensive rats.

Am J Physiol Renal Physiol 2020 09 20;319(3):F359-F365. Epub 2020 Jul 20.

Department of Physiology, Augusta University, Augusta, Georgia.

Interleukin-10 (IL-10) is an anti-inflammatory cytokine that induces nitric oxide (NO) production. IL-10 supplementation has been previously shown to lower blood pressure (BP) in male hypertensive mice, but the effect of exogenous IL-10 in hypertensive female rodents has not been studied. For the present study, we hypothesized that chronic infusion of IL-10 in hypertensive rats would lower BP concomitant with an increase in renal NO synthase (NOS) activity. Male and female spontaneously hypertensive rats (SHRs; 12 wk old) were randomized to receive IL-10 infusion by subcutaneous minipump (3.5 µg·kg·day) or serve as sham controls ( = 4-6 rats per treatment per sex). BP was measured by tail cuff before and after 2 wk of treatment. Renal T cells and IL-10 were measured by flow cytometry, and NOS activity was determined by conversion of radiolabeled arginine to radiolabeled citrulline. Female SHRs had greater IL-10 renal cells than male SHRs and greater expression of the IL-10 receptor at baseline. BP did not change in female SHRs treated with IL-10, but BP significantly decreased following IL-10 infusion in male SHRs. Contrary to our hypothesis, NOS enzymatic activity decreased with IL-10 treatment in the renal inner medulla and cortex of both sexes. Renal regulatory T cells also decreased in both sexes after IL-10 treatment. In conclusion, despite male SHRs having less IL-10 and IL-10 receptor expression in the kidney compared with female SHRs, exogenous IL-10 selectively decreased BP only in male SHRs. Furthermore, our data suggest that exogenous IL-10-induced decreases in BP in male SHRs are not dependent on upregulating renal NOS activity.
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http://dx.doi.org/10.1152/ajprenal.00206.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509288PMC
September 2020

EPS8 phosphorylation by Src modulates its oncogenic functions.

Br J Cancer 2020 09 9;123(7):1078-1088. Epub 2020 Jul 9.

Department of Oral Biology and Diagnostic Sciences, Augusta University, Augusta, GA, USA.

Background: EPS8 is a scaffolding protein that regulates proliferation, actin dynamics and receptor trafficking. Its expression is increased in cancer, enhancing mitogenesis, migration and tumorigenesis. Src phosphorylates EPS8 at four tyrosine residues, although the function is unknown. Here we investigated the pro-oncogenic role of EPS8 tyrosine phosphorylation at Src target sites in HNSCC.

Methods: Plasmids expressing EPS8 Src-mediated phosphorylation site mutants (Y485F, Y525F, Y602F, Y774F and all four combined [FFFF]) were expressed in cells containing a normal endogenous level of EPS8. In addition, cells were treated with dasatinib to inhibit Src activity. EPS8 downstream targets were evaluated by western blotting. Wound closure, proliferation, immunofluorescence and tumorgenicity assays were used to investigate the impact of phenylalanine mutations on EPS8 biological functions.

Results: FOXM1, AURKA, and AURKB were decreased in cells expressing FFFF- and Y602F-EPS8 mutants, while cells harbouring the Y485F-, Y525F- and Y774F-EPS8 mutants showed no differences compared to controls. Consistent with this, dasatinib decreased the expression of EPS8 targets. Moreover, Y602F- and FFFF-EPS8 mutants reduced mitogenesis and motility. Strikingly though, FFFF- or Y602F-EPS8 mutants actually promoted tumorigenicity compared with control cells.

Conclusions: Phosphorylation of EPS8 at Y602 is crucial for signalling to the cell cycle and may provide insight to explain reduced efficacy of dasatinib treatment.
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http://dx.doi.org/10.1038/s41416-020-0976-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525440PMC
September 2020

Targeting the endocannabinoid system: a predictive, preventive, and personalized medicine-directed approach to the management of brain pathologies.

EPMA J 2020 Jun 15;11(2):217-250. Epub 2020 Apr 15.

Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA USA.

Cannabis-inspired medical products are garnering increasing attention from the scientific community, general public, and health policy makers. A plethora of scientific literature demonstrates intricate engagement of the endocannabinoid system with human immunology, psychology, developmental processes, neuronal plasticity, signal transduction, and metabolic regulation. Despite the therapeutic potential, the adverse psychoactive effects and historical stigma, cannabinoids have limited widespread clinical application. Therefore, it is plausible to weigh carefully the beneficial effects of cannabinoids against the potential adverse impacts for every individual. This is where the concept of "personalized medicine" as a promising approach for disease prediction and prevention may take into the account. The goal of this review is to provide an outline of the endocannabinoid system, including endocannabinoid metabolizing pathways, and will progress to a more in-depth discussion of the therapeutic interventions by endocannabinoids in various neurological disorders.
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http://dx.doi.org/10.1007/s13167-020-00203-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272537PMC
June 2020

Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury.

Sci Adv 2020 May 29;6(22):eaax8847. Epub 2020 May 29.

Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized patients with TBI die from secondary pathological processes that develop during supervised care. Neutrophils, which orchestrate innate immune responses, worsen TBI outcomes via undefined mechanisms. We hypothesized that formation of neutrophil extracellular traps (NETs), a purported mechanism of microbial trapping, exacerbates acute neurological injury after TBI. NET formation coincided with cerebral hypoperfusion and tissue hypoxia after experimental TBI, while elevated circulating NETs correlated with reduced serum deoxyribonuclease-1 (DNase-I) activity in patients with TBI. Functionally, Toll-like receptor 4 (TLR4) and the downstream kinase peptidylarginine deiminase 4 (PAD4) mediated NET formation and cerebrovascular dysfunction after TBI. Last, recombinant human DNase-I degraded NETs and improved neurological function. Thus, therapeutically targeting NETs may provide a mechanistically innovative approach to improve TBI outcomes without the associated risks of global neutrophil depletion.
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http://dx.doi.org/10.1126/sciadv.aax8847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259928PMC
May 2020

Greater T Regulatory Cells in Females Attenuate DOCA-Salt-Induced Increases in Blood Pressure Versus Males.

Hypertension 2020 06 27;75(6):1615-1623. Epub 2020 Apr 27.

From the Departments of Physiology (K.M.B., G.R.C., E.E.G., M.A., J.B.M., R.M., M.W.B., J.C.S.), Medical College of Georgia at Augusta University, GA.

Hypertension is the most common risk factor for cardiovascular disease, causing over 18 million deaths a year. Although the mechanisms controlling blood pressure (BP) in either sex remain largely unknown, T cells play a critical role in the development of hypertension. Further evidence supports a role for the immune system in contributing to sex differences in hypertension. The goal of the current study was to first, determine the impact of sex on the renal T-cell profiles in DOCA-salt hypertensive males and females and second, test the hypothesis that greater numbers of T regulatory cells (Tregs) in females protect against DOCA-salt-induced increases in BP and kidney injury. Male rats displayed greater increases in BP than females following 3 weeks of DOCA-salt treatment, although increases in renal injury were comparable between the sexes. DOCA-salt treatment resulted in an increase in proinflammatory T cells in both sexes; however, females had more anti-inflammatory Tregs than males. Additional male and female DOCA-salt rats were treated with anti-CD25 to decrease Tregs. Decreasing Tregs significantly increased BP only in females, thereby abolishing the sex difference in the BP response to DOCA-salt. This data supports the hypothesis that Tregs protect against the development of hypertension and are particularly important for the control of BP in females.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225054PMC
June 2020

Regulation of Innate Lymphoid Cells in Acute Kidney Injury: Crosstalk between Cannabidiol and GILZ.

J Immunol Res 2020 25;2020:6056373. Epub 2020 Feb 25.

Department of Oral Biology and Diagnostic Sciences, The Dental College of Georgia, Augusta University, Augusta, Georgia 30912-1128.

Innate lymphoid cells (ILCs) have emerged as largely tissue-resident archetypal cells of the immune system. We tested the hypotheses that renal ischemia-reperfusion injury (IRI) is a contributing factor to polarization of ILCs and that glucocorticoid-induced leucine zipper (GILZ) and cannabidiol regulate them in this condition. Mice subjected to unilateral renal IRI were treated with the following agents before restoration of renal blood flow: cannabidiol, DMSO, transactivator of transcription- (TAT-) GILZ, or the TAT peptide. Thereafter, kidney cells were prepared for flow cytometry analyses. Sham kidneys treated with either cannabidiol or TAT-GILZ displayed similar frequencies of each subset of ILCs compared to DMSO or TAT, respectively. Renal IRI increased ILC1s and ILC3s but reduced ILC2s compared to the sham group. Cannabidiol or TAT-GILZ treatment of IRI kidneys reversed this pattern as evidenced by reduced ILC1s and ILC3s but increased ILC2s compared to their DMSO- or TAT-treated counterparts. While TAT-GILZ treatment did not significantly affect cells positive for cannabinoid receptors subtype 2 (CB2+), cannabidiol treatment increased frequency of both CB2+ and GILZ-positive (GILZ+) cells of IRI kidneys. Subsequent studies showed that IRI reduced GILZ+ subsets of ILCs, an effect less marked for ILC2s. Treatment with cannabidiol increased frequencies of each subset of GILZ+ ILCs, but the effect was more marked for ILC2s. Indeed, cannabidiol treatment increased CB2+ GILZ+ ILC2s. Collectively, the results indicate that both cannabidiol and GILZ regulate ILC frequency and phenotype, in acute kidney injury, and that the effects of cannabidiol likely relate to modulation of endogenous GILZ.
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http://dx.doi.org/10.1155/2020/6056373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060850PMC
September 2020

Visceral adipose NLRP3 impairs cognition in obesity via IL-1R1 on CX3CR1+ cells.

J Clin Invest 2020 04;130(4):1961-1976

Department of Neuroscience and Regenerative Medicine.

Induction of the inflammasome protein cryopyrin (NLRP3) in visceral adipose tissue (VAT) promotes release of the proinflammatory cytokine IL-1β in obesity. Although this mechanism contributes to peripheral metabolic dysfunction, effects on the brain remain unexplored. We investigated whether visceral adipose NLRP3 impairs cognition by activating microglial IL-1 receptor 1 (IL-1R1). After observing protection against obesity-induced neuroinflammation and cognitive impairment in NLRP3-KO mice, we transplanted VAT from obese WT or NLRP3-KO donors into lean recipient mice. Transplantation of VAT from a WT donor (TRANSWT) increased hippocampal IL-1β and impaired cognition, but VAT transplants from comparably obese NLRP3-KO donors (TRANSKO) had no effect. Visceral adipose NLRP3 was required for deficits in long-term potentiation (LTP) in transplant recipients, and LTP impairment in TRANSWT mice was IL-1 dependent. Flow cytometric and gene expression analyses revealed that VAT transplantation recapitulated the effects of obesity on microglial activation and IL-1β gene expression, and visualization of hippocampal microglia revealed similar effects in vivo. Inducible ablation of IL-1R1 in CX3CR1-expressing cells eliminated cognitive impairment in mice with dietary obesity and in transplant recipients and restored immunoquiescence in hippocampal microglia. These results indicate that visceral adipose NLRP3 impairs memory via IL-1-mediated microglial activation and suggest that NLRP3/IL-1β signaling may underlie correlations between visceral adiposity and cognitive impairment in humans.
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http://dx.doi.org/10.1172/JCI126078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108893PMC
April 2020

Maternal milk ILCs and adaptive immune cells populate neonatal organs.

Cell Mol Immunol 2020 06 19;17(6):665-667. Epub 2019 Dec 19.

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA.

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http://dx.doi.org/10.1038/s41423-019-0350-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264251PMC
June 2020

Delayed Administration of Angiotensin II Type 2 Receptor (AT2R) Agonist Compound 21 Prevents the Development of Post-stroke Cognitive Impairment in Diabetes Through the Modulation of Microglia Polarization.

Transl Stroke Res 2020 08 3;11(4):762-775. Epub 2019 Dec 3.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Ave. MSC, Charleston, SC, 908, USA.

A disabling consequence of stroke is cognitive impairment, occurring in 12%-48% of patients, for which there is no therapy. A critical barrier is the lack of understanding of how post-stroke cognitive impairment (PSCI) develops. While 70% of stroke victims present with comorbid diseases such as diabetes and hypertension, the limited use of comorbid disease models in preclinical research further contributes to this lack of progress. To this end, we used a translational model of diabetes to study the development of PSCI. In addition, we evaluated the application of compound 21 (C21), an angiotensin II Type 2 receptor agonist, for the treatment of PSCI by blinding the treatment assignment, setting strict inclusion criteria, and implementing a delayed administration time point. Diabetes was induced by a high-fat diet (HFD) and low-dose streptozotocin (STZ) combination. Control and diabetic rats were subjected to 1 h middle cerebral artery occlusion (MCAO) or sham surgery. Adhesive removal task (ART) and two-trial Y-maze were utilized to test sensorimotor and cognitive function. Three days post-stroke, rats that met the inclusion criteria were administered C21 or vehicle in drinking water at a dose of 0.12 mg/kg/day for 8 weeks. Samples from freshly harvested brains were analyzed by flow cytometry and immunohistochemistry (IHC). Diabetes exacerbated the development of PSCI and increased inflammation and demyelination. Delayed administration of C21 3 days post-stroke reduced mortality and improved sensorimotor and cognitive deficits. It also reduced inflammation and demyelination through modulation of the M1:M2 ratio in the diabetic animals.
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http://dx.doi.org/10.1007/s12975-019-00752-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266715PMC
August 2020

Necrosis Contributes to the Development of Hypertension in Male, but Not Female, Spontaneously Hypertensive Rats.

Hypertension 2019 12 28;74(6):1524-1531. Epub 2019 Oct 28.

From the Department of Physiology, Medical College of Georgia (M.A., O.R., E.E.G., J.B.M., P.O., M.W.B., J.C.S.), Augusta University.

Necrosis is a pathological form of cell death that induces an inflammatory response, and immune cell activation contributes to the development and maintenance of hypertension. Necrosis was measured in kidney, spleen, and aorta of 12- to 13-week-old male and female SHRs (spontaneously hypertensive rats); male SHRs had greater renal necrotic cell death than female SHRs. Because male SHRs have a higher blood pressure (BP) and a more proinflammatory T-cell profile than female SHRs, the current studies tested the hypothesis that greater necrotic cell death in male SHRs exacerbates increases in BP and contributes to the proinflammatory T-cell profile. Male and female SHRs were randomized to receive vehicle or Necrox-5-a cell permeable inhibitor of necrosis-from 6 to 12 weeks of age or from 11 to 13 weeks of age. In both studies, Necrox-5 decreased renal necrosis and abolished the sex difference. Treatment with Necrox-5 beginning at 6 weeks of age attenuated maturation-induced increases in BP in male SHR; BP in female SHR was not altered by Necrox-5 treatment. Necrox-5 decreased proinflammatory renal T cells in both sexes, although sex differences were maintained. Administration of Necrox-5 for 2 weeks in SHR with established hypertension resulted in a small but significant decrease in BP in males with no effect in females. These results suggest that greater necrotic cell death in male SHR exacerbates maturation-induced increases in BP with age contributing to sex differences in BP. Moreover, although necrosis is proinflammatory, it is unlikely to explain sex differences in the renal T-cell profile.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854325PMC
December 2019

Niacin Ameliorates Neuro-Inflammation in Parkinson's Disease via GPR109A.

Int J Mol Sci 2019 Sep 14;20(18). Epub 2019 Sep 14.

Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.

In this study, we used macrophage RAW264.7 cells to elucidate the molecular mechanism underlying the anti-inflammatory actions of niacin. Anti-inflammatory actions of niacin and a possible role of its receptor GPR109A have been studied previously. However, the precise molecular mechanism of niacin's action in reducing inflammation through GPR109A is unknown. Here we observed that niacin reduced the translocation of phosphorylated nuclear kappa B (p-NF-κB) induced by lipopolysaccharide (LPS) in the nucleus of RAW264.7 cells. The reduction in the nuclear translocation in turn decreased the expression of pro-inflammatory cytokines IL-1β, IL-6 in RAW264.7 cells. We observed a decrease in the nuclear translocation of p-NF-κB and the expression of inflammatory cytokines after knockdown of GPR109A in RAW264.7 cells. Our results suggest that these molecular actions of niacin are mediated via its receptor GPR109A (also known as HCAR2) by controlling the translocation of p-NF-κB to the nucleus. Overall, our findings suggest that niacin treatment may have potential in reducing inflammation by targeting GPR109A.
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http://dx.doi.org/10.3390/ijms20184559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770365PMC
September 2019

Whole Body Vibration-Induced Omental Macrophage Polarization and Fecal Microbiome Modification in a Murine Model.

Int J Mol Sci 2019 Jun 26;20(13). Epub 2019 Jun 26.

Veterinary Preventive Medicine, Ohio State University, College of Veterinary Medicine, Columbus, OH 43210, USA.

Human nutrient metabolism, developed millions of years ago, is anachronistic. Adaptive features that offered survival advantages are now great liabilities. The current dietary pattern, coupled with massively reduced physical activities, causes an epidemic of obesity and chronic metabolic diseases, such as type 2 diabetes mellitus. Chronic inflammation is a major contributing factor to the initiation and progression of most metabolic and cardiovascular diseases. Among all components of an innate immune system, due to their dual roles as phagocytic as well as antigen-presenting cells, macrophages play an important role in the regulation of inflammatory responses, affecting the body's microenvironment and homeostasis. Earlier studies have established the beneficial, anti-inflammatory effects of whole body vibration (WBV) as a partial exercise mimetic, including reversing the effects of glucose intolerance and hepatic steatosis. Here for the first time, we describe potential mechanisms by which WBV may improve metabolic status and ameliorate the adverse consequences through macrophage polarization and altering the fecal microbiome.
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http://dx.doi.org/10.3390/ijms20133125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651746PMC
June 2019

Diabetic Stroke Promotes a Sexually Dimorphic Expansion of T Cells.

Neuromolecular Med 2019 12 13;21(4):445-453. Epub 2019 Jun 13.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Ave. MSC 908, Charleston, SC, 29425, USA.

We recently reported that diabetes negates the cerebrovascular protection typically seen in adult female rats resulting in cognitive impairment, which is worsened by increased parenchymal bleeding and edema after ischemic stroke. Although women experience more severe diabetes and suffer from a higher rate of diabetic complications, including stroke and cognitive impairment, underlying mechanisms contributing to sex differences are limited. Emerging evidence suggests interleukin (IL)-17 contributes to cerebrovascular pathologies: (1) high salt diet-mediated expansion of IL-17-producing T cells (Th17) in the gut microbiome promotes cerebrovascular dysfunction and cognitive impairment in male mice, (2) increased IL-17-producing γδTCR cells exacerbates stroke injury in male mice, and (3) IL-17 promotes rupture of cerebral aneurysms in female mice. Based on these premises, we investigated the potential involvement of IL-17-producing inflammatory cells in cerebrovascular dysfunction and post-stroke vascular injury in diabetes by measuring intestinal, circulating, or cerebral T cell profiles as well as in plasma IL-17 in both sexes. Cell suspensions prepared from naive or stroked (3 days after stroke) diabetic and control rats were analyzed by flow cytometry, and IL-17 levels were measured in plasma using ELISA. Diabetes deferentially promoted the expansion of cerebral Th17 cells in females. In response to stroke, diabetes had a sexually dimorphic effect on the expansion of numerous T cell profiles. These results suggest that a better understanding of the role of IL-17-producing cells in diabetes may identify potential avenues in which the molecular mechanisms contributing to these sex differences can be further elucidated.
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http://dx.doi.org/10.1007/s12017-019-08554-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884673PMC
December 2019

Innate immunity and oral microbiome: a personalized, predictive, and preventive approach to the management of oral diseases.

EPMA J 2019 Mar 25;10(1):43-50. Epub 2019 Feb 25.

2Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912-1128 USA.

Three recent advances in immunology, genetics, and microbiology have ushered in a new era in the continued efforts to better understand and treat oral diseases, moving ever closer to the three Ps of modern healthcare: personalized, predictive, and preventive medicine (PPPM). The discovery of now 15 subtypes of innate lymphoid cells, the refinement of DNA sequencing, and culture-independent characterization of the entire microbial community begin to reveal this complex adaptive network. All these advances warrant a systematic review as they have changed and will continue to change dental medicine. We will update dental professionals on these advances as related to oral diseases and associated pathologies in other organ systems such as premature labor, arthrosclerosis, and cancer. The five objectives are:Introduce the concept of microbiota and microbiomeExplain how we study microbiota and microbiomeDescribe the types and functions of innate lymphoid cellsInventory the unique demands of the oral cavityProvide a heuristic model to integrate the aboveConclusions and expert recommendations.
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http://dx.doi.org/10.1007/s13167-019-00163-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459445PMC
March 2019

Stem cells and tooth regeneration: prospects for personalized dentistry.

EPMA J 2019 Mar 7;10(1):31-42. Epub 2019 Jan 7.

Department of Oral Biology and Diagnostic Sciences; CL-2134, Dental College of Georgia, Augusta University, Augusta, GA 30912-1128 USA.

Over the last several decades, a wealth of information has become available regarding various sources of stem cells and their potential use for regenerative purposes. Given the intense debate regarding embryonic stem cells, much of the focus has centered around application of adult stem cells for regenerative engineering along with other relevant aspects including use of growth factors and scaffolding materials. The more recent discovery of tooth-derived stem cells has sparked much interest in their application to regenerative dentistry to treat and alleviate the most prevalent oral diseases-i.e., dental caries and periodontal diseases. Also exciting is the advent of induced pluripotent stem cells, which provides the means of using patient-derived somatic cells for their creation, and their eventual application for generation of the dental complex. Thus, evolving developments in the field of regenerative dentistry indicate the prospect of constructing "custom-made" tooth and supporting structures thereby fostering the realization of "personalized dentistry." On the other hand, others have explored the possibility of augmenting endogenous regenerative capacity through utilization of small molecules to regulate molecular signaling mechanisms that mediate regeneration of tooth structure. This review is focused on these aspects of regenerative dentistry in view of their relevance to personalized dentistry.
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http://dx.doi.org/10.1007/s13167-018-0156-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459449PMC
March 2019

The circadian expression of osteogenic factors in periodontal tissue loading mechanical force: new concepts of the personalized orthodontic care.

EPMA J 2019 Mar 18;10(1):13-20. Epub 2019 Feb 18.

1Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Qiaokou District, Wuhan, 430030 Hubei China.

Objective: The need for orthodontic treatment continues to increase. Strategies that shorten the treatment course and reduce discomfort are most welcome in clinic. Circadian rhythm plays important role in various physiological processes, including bone formation. This study intended to depict a possible circadian releasing property of the osteogenic factors within the periodontal tissue during orthodontic treatment, which may direct a more efficient and satisfactory orthodontic treatment to the patient.

Methods: Primary periodontal ligament cells (PDLCs) were obtained from the Sprague-Dawley (SD) rats. An equibiaxial strain value of 12% was applied on rat PDLCs (rPDLCs). After 2 h stimuli of 10 M dexamethasone (DX), the osteogenic genes' expressions were detected by real-time polymerase chain reaction (RT-PCR) at Zeitgeber times 0, 4, 8, 12, 16, 20, and 24. An orthodontic appliance was placed on 45 SD rats. Animals were maintained under 12-h light/dark periods and euthanized at 9 time points over the diurnal cycle. The orthodontic sensitive tissues of the mesial root of the maxillary first molar were collected for RT-PCR and immunohistological assay.

Results: The rPDLCs displayed typical fibroblastic spindle shape, and subcultured steadily in vitro. Induced by DX, the mRNA expression of Col-1, OPN, and IBSP within the loaded/unloaded rPDLCs oscillated as that of the main clock gene Per-1. The osteogenic genes' expressions as well as the protein releases sustained a circadian oscillation trend in vivo.

Conclusions: This study indicates the existence of a circadian rhythm of the osteogenic factors within the orthodontic sensitive tissues, which highlights the importance of precise timing of force loading in further orthodontic treatment. Thus, a periodicity pattern of orthodontic traction at night may prove a more efficient tooth movement while minimizing the treatment window and discomfort complains.
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http://dx.doi.org/10.1007/s13167-019-0161-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459461PMC
March 2019

Generation of Fam83h knockout mice by CRISPR/Cas9-mediated gene engineering.

J Cell Biochem 2019 Feb 3. Epub 2019 Feb 3.

Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.

Family with sequence similarity 83 member H (FAM83H) protein-coding geneplay an essential role in the structural organization, calcification of developing enamel, and keratin cytoskeleton disassembly by recruiting Casein kinase 1 alpha (CSNK1A1) to keratin filaments. In this study, we have applied CRISPR Cas9 nickase (D10A) to knockout (KO) the Fam83h gene in NMRI outbred mice. We generated homozygous Fam83h KO mice ( Fam83h ) through a premature termination codon, which was validated by Sanger sequencing in F0 generation. Next, we also bred the FAM83H KO for two generations. Reverse-transcription polymerase chain reaction and Western blot analysis approved the Fam83h KO mice. The Fam83h KO mice had evidence of normal morphology at the cervical loops, secretory and maturation stages, and mandibular molars. In comparison with the normal wild-type mice ( Fam83h ), the F2 homozygous KO ( Fam83h ) had sparse, scruffy coats with small body size and decreased general activity. Also, they had the natural reproductive ability and natural lifespan. In addition, delay in opening the eyes and dry eyes among infant mice were seen. The F1 heterozygous mice looked comparable to the normal wild-type mice ( Fam83h ), which showed autosomal recessive inheritance of these phenotypes. The KO of FAM83H had controversial effects on the development of teeth and the formation of enamel. The phenotype defect in dental development and the enamel formation were seen in three mice among four generations. It can be concluded that null FAM83H in outbred mice not only showed the reported phenotypes in null inbred mouse but also showed normal lifespan and reproductive ability; dental deficiency in three homozygous mice; and the symptoms that were similar to the symptoms of dry eye syndrome and curly coat dog syndrome in all four evaluated KO generations.
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http://dx.doi.org/10.1002/jcb.28381DOI Listing
February 2019