Publications by authors named "Tuo Shao"

39 Publications

Differentially expressed immune response genes in COVID-19 patients based on disease severity.

Aging (Albany NY) 2021 Mar 29;13. Epub 2021 Mar 29.

Fuyang Infectious Disease Clinical College of Anhui Medical University, Fuyang 236015, Anhui Province, P.R. of China.

Background: Dysregulated immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are thought to underlie the progression of coronavirus disease 2019 (COVID-19). We sought to further characterize host antiviral and cytokine gene expression in COVID-19 patients based on illness severity.

Methods: In this case-control study, we retrospectively analyzed 46 recovered COVID-19 patients and 24 healthy subjects (no history of COVID-19) recruited from the Second People's Hospital of Fuyang City. Blood samples were collected from each study participant for RNA extraction and PCR. We assessed changes in antiviral gene expression between healthy controls and patients with mild/moderate (MM) and severe/critical (SC) disease.

Results: We found that type I interferon signaling (IFNA2, TLR8, IFNA1, IFNAR1, TLR9, IRF7, ISG15, APOBEC3G, and MX1) and genes encoding proinflammatory cytokines (IL12B, IL15, IL6, IL12A and IL1B) and chemokines (CXCL9, CXCL11 and CXCL10) were upregulated in patients with MM and SC disease. Moreover, we found that IFNA1, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (APOBEC3G), and Fas-associated protein with death domain (FADD) were significantly downregulated ( < 0.05) in the SC group compared to the MM group. We also observed that microRNA (miR)-155 and miR-130a levels were markedly higher in the MM group compared to the SC group.

Conclusion: COVID-19 is associated with the activation of host antiviral genes. Induction of the IFN system appears to be particularly important in controlling SARS-CoV-2 infection, as decreased expression of IFNA1, APOBEC3G and FADD genes in SC patients, relative to MM patients, may be associated with disease progression.
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http://dx.doi.org/10.18632/aging.202877DOI Listing
March 2021

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging.

Acta Pharm Sin B 2021 Feb 25;11(2):373-393. Epub 2020 Aug 25.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA.

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.
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http://dx.doi.org/10.1016/j.apsb.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893127PMC
February 2021

"Sandwich" wound dressing to reduce surgical site infections during sacrococcygeal surgery: A retrospective analysis.

J Tissue Viability 2020 Aug 4. Epub 2020 Aug 4.

Department of Spinal Surgery, First Affiliated Hospital of Harbin Medical University, No.23 Youzheng Street, 150001, Harbin, China. Electronic address:

Objective: To explore whether the "sandwich" wound dressing method with a hydrocolloid dressing can effectively reduce surgical site infection rates in sacrococcygeal aseptic operations.

Methods: A retrospective cohort of patients with sacrococcygeal aseptic operations (class I incision category) from January 2017 to March 2018 were divided into intervention (sandwich dressing) and control groups (conventional dressing). The surgical site infections (SSI) rate, wound healing course, hospitalization time, and medical costs in the two groups were determined. To exclude the influence of other factors, operation time, blood loss, age, sex ratio, the distance of the incision from the distal edge to the anus, and initial defecation times were compared between the groups.

Results: The SSI rates and medical costs in the interventional group were significantly lower than the control group (0% vs 78.57%, P < 0.0001; 3.27 ± 0.98 vs 5.83 ± 1.66 ¥10,000, p < 0.0001). Hospitalization times were also lower in the intervention compared to the control group (17.05 ± 4.77 vs 34.50 ± 15.47 day, P = 0.001).

Conclusions: The sandwich wound dressing method with a hydrocolloid dressing can effectively prevent SSI during sacrococcygeal aseptic surgery.
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http://dx.doi.org/10.1016/j.jtv.2020.07.008DOI Listing
August 2020

Cathelicidin-related antimicrobial peptide alleviates alcoholic liver disease through inhibiting inflammasome activation.

J Pathol 2020 12 26;252(4):371-383. Epub 2020 Sep 26.

Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.

Alcoholic liver disease (ALD) is associated with gut dysbiosis and hepatic inflammasome activation. While it is known that antimicrobial peptides (AMPs) play a critical role in the regulation of bacterial homeostasis in ALD, the functional role of AMPs in the alcohol-induced inflammasome activation is unclear. The aim of this study was to determine the effects of cathelicidin-related antimicrobial peptide (CRAMP) on inflammasome activation in ALD. CRAMP knockout (Camp) and wild-type (WT) mice were subjected to binge-on-chronic alcohol feeding and synthetic CRAMP peptide was administered. Serum/plasma and hepatic tissue samples from human subjects with alcohol use disorder and/or alcoholic hepatitis were analyzed. CRAMP deficiency exacerbated ALD with enhanced inflammasome activation as shown by elevated serum interleukin (IL)-1β levels. Although Camp mice had comparable serum endotoxin levels compared to WT mice after alcohol feeding, hepatic lipopolysaccharide (LPS) binding protein (LBP) and cluster of differentiation (CD) 14 were increased. Serum levels of uric acid (UA), a Signal 2 molecule in inflammasome activation, were positively correlated with serum levels of IL-1β in alcohol use disorder patients with ALD and were increased in Camp mice fed alcohol. In vitro studies showed that CRAMP peptide inhibited LPS binding to macrophages and inflammasome activation stimulated by a combination of LPS and UA. Synthetic CRAMP peptide administration decreased serum UA and IL-1β concentrations and rescued the liver from alcohol-induced damage in both WT and Camp mice. In summary, CRAMP exhibited a protective role against binge-on-chronic alcohol-induced liver damage via regulation of inflammasome activation by decreasing LPS binding and UA production. CRAMP administration may represent a novel strategy for treating ALD. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006217PMC
December 2020

Predictor of Surgical Outcomes in Ankylosing Spondylitis Cervical Spinal Fracture: An At Least 2 Years Follow-Up Retrospective Study.

Spine (Phila Pa 1976) 2021 Jan;46(1):E31-E36

First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.

Study Design: Retrospective study.

Objective: A retrospective study was conducted to clarify the prognostic factors of postoperative for cervical spine fractures patients with ankylosing spondylitis (AS).

Summary Of Background Data: Now the high probability of cervical fractures in patients with AS is unanimously recognized. Fractures mostly occur in the lower cervical spine and two-thirds of patients are accompanied by spinal cord injury. But there are few studies on treatment of AS patients with cervical fracture and it is unclear whether the surgical method, timing of surgery, basic treatment of AS, and different doses of steroids therapy have an impact on the prognosis. Thus, this study aims to evaluate the impact of perioperative factors on the prognosis of traumatic cervical fractures in surgical patients with AS.

Methods: Preoperative and postoperative spinal cord function were assessed according to the Japanese Orthopaedic Association (JOA) Scores and Improvement rate were calculated. The neck pain severity were rated using a visual analogue scale (VAS) score. The t test and v2-test were used for comparison of clinical data between the preoperative and postoperative groups. Logistic univariate and multivariate regression analysis were used to obtain adjusted odds ratios. Pearson correlation coefficients were used to evaluate the relationship between variables.

Results: The degree of fracture displacement in cervical spine fractures patients with AS was most common at the neck-chest junction (26.1%). Patients with degree of cervical fracture displacement less than 50% had significantly improved JOA scores after surgery (P = 0). The incidence of spinal cord injury (SCI) due to fracture was high (52.2%). Patients with combined anterior and posterior is helpful for neurological recovery (P = 0.01). Basic AS treating before injury would be benefit for neurological improvement (P = 0).

Conclusion: Basic AS treatment, SCI, and surgical methods are independent factors that affect the prognosis of cervical spine fractures patients with AS. It is controversial to perform surgery and preoperative steroid application as soon as possible.

Level Of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000003754DOI Listing
January 2021

Synthesis and preliminary studies of C-labeled tetrahydro-1,7-naphthyridine-2-carboxamides for PET imaging of metabotropic glutamate receptor 2.

Theranostics 2020 14;10(24):11178-11196. Epub 2020 Sep 14.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.

Selective modulation of metabotropic glutamate receptor 2 (mGlu) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson's disease (PD), Alzheimer's disease (AD), drug abuse and addiction. Imaging mGlu using positron emission tomography (PET) would allow for quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. In this paper, we aimed to develop a novel specific radioligand derived from negative allosteric modulators (NAMs) for PET imaging of mGlu. A focused small molecule library of mGlu NAMs with tetrahydro naphthyridine scaffold was synthesized for pharmacology and physicochemical evaluation. GIRK dose-response assays and CNS panel binding selectivity assays were performed to study the affinity and selectivity of mGlu NAMs, among which compounds and were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the binding specificity and selectivity of [C] and [C] towards mGlu. binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [C] as most promising PET mGlu PET ligand. mGlu NAMs were synthesized in 14%-20% yields in five steps. NAMs and were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [C] and [C] displayed similar heterogeneous distribution by autoradiography, consistent with mGlu expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [C] demonstrated superior binding specificity compared to [C]. Further radiometabolite analysis of [C] showed excellent stability in the brain. Compound exhibited high affinity and excellent subtype selectivity, which was then evaluated by autoradiography and PET imaging study after labeling with carbon-11. Ligand [C], which we named [C]MG2-1904, demonstrated high brain uptake and excellent / specific binding towards mGlu with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu derived from NAMs, which represents a promising chemotype for further development and optimization aimed for clinical translation.
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http://dx.doi.org/10.7150/thno.42587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532674PMC
September 2020

γ-Glutamyltransferase Elevations Are Frequent in Patients With COVID-19: A Clinical Epidemiologic Study.

Hepatol Commun 2020 Jul 11. Epub 2020 Jul 11.

Department of Infectious Diseases Wenzhou Central Hospital and Sixth People's Hospital of Wenzhou Wenzhou Zhejiang China.

A newly identified coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the infectious coronavirus disease 2019 (COVID-19), emerged in December 2019 in Wuhan, Hubei Province, China, and now poses a major threat to global public health. Previous studies have observed highly variable alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in patients with COVID-19. However, circulating levels of the cholangiocyte injury biomarker γ-glutamyltransferase (GGT) have yet to be reported in the existing COVID-19 case studies. Herein, we describe the relationship between GGT levels and clinical and biochemical characteristics of patients with COVID-19. Our study is a retrospective case series of 98 consecutive hospitalized patients with confirmed COVID-19 at Wenzhou Central Hospital in Wenzhou, China, from January 17 to February 5, 2020. Clinical data were collected using a standardized case report form. Diagnosis of COVID-19 was assessed by symptomatology, reverse transcriptase-polymerase chain reaction (RT-PCR), and computed tomography (CT) scan. The medical records of patients were analyzed by the research team. Of the 98 patients evaluated, elevated GGT levels were observed in 32.7%; increased C-reactive protein (CRP) and elevated ALT and AST levels were observed in 22.5%, 13.3%, and 20.4%, respectively; and elevated alkaline phosphatase (ALP) and triglycerides (TGs) were found in 2% and 21.4%, respectively. Initially, in the 82 patients without chronic liver disease and alcohol history; age older than 40 years ( = 0.027); male gender ( = 0.0145); elevated CRP ( = 0.0366), ALT ( < 0.0001), and ALP ( = 0.0003); and increased TGs ( = 0.0002) were found to be associated with elevated GGT levels. Elevated GGT ( = 0.0086) and CRP ( = 0.0162) levels have a longer length of hospital stay. A sizable number of patients with COVID-19 infection had elevated serum GGT levels. This elevation supports involvement of the liver in persons with COVID-19.
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http://dx.doi.org/10.1002/hep4.1576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404935PMC
July 2020

COVID-19 induced liver function abnormality associates with age.

Aging (Albany NY) 2020 07 28;12(14):13895-13904. Epub 2020 Jul 28.

Department of Respiratory, The Second People's Hospital of Fuyang, Fuyang 236015, Anhui Province, P.R. China.

Background: Coronavirus disease 2019 (COVID-19) is a novel infectious disease that may cause fever, dry cough, fatigue and shortness of breath. The impact of COVID-19 on liver function is not well described.

Results: We found that the overall frequency of LFT abnormality was 17.6%. Frequency of LFT abnormality was significantly greater in patients with severe/critical (SC) COVID-19 compared to those with mild/moderate (MM) COVID-19 (32.4% vs 11.6%, p=0.011). Among patients with LFT abnormality, the median age was significantly higher in the SC group compared to the MM group (52 vs 39 years, p=0.021).

Conclusion: COVID-19 is frequently associated with mild liver function abnormality, particularly in individuals with severe/critical COVID-19 who were older. Liver function should be monitored carefully during infection, with judicious use of hepatotoxic agents where possible and avoidance of prolonged hypotension to minimize liver injury in older patients.

Methods: The No. 2 People's Hospital of Fuyang City in China has admitted a total of 159 patients with confirmed COVID-19 since the outbreak from January 2020 to March 2020. We analyzed the incidence of liver function test (LFT) abnormality in these patients with confirmed COVID-19 infection.
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http://dx.doi.org/10.18632/aging.103720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425469PMC
July 2020

Synthesis and preliminary evaluation of novel C-labeled GluN2B-selective NMDA receptor negative allosteric modulators.

Acta Pharmacol Sin 2021 Mar 13;42(3):491-498. Epub 2020 Jul 13.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to etiopathology of various CNS disorders and neurodegenerative diseases, GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs. Herein, we report the synthesis and preclinical evaluation of two C-labeled GluN2B-selective negative allosteric modulators (NAMs) containing N,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography (PET) imaging. Two PET ligands, namely [C]31 and [C]37 (also called N2B-1810 and N2B-1903, respectively) were labeled with [C]CHI in good radiochemical yields (decay-corrected 28% and 32% relative to starting [C]CO, respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/μmol). In particular, PET ligand [C]31 demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies. However, because in vivo PET imaging studies showed limited brain uptake of [C]31 (up to 0.5 SUV), further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo.
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http://dx.doi.org/10.1038/s41401-020-0456-9DOI Listing
March 2021

Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[C]methoxyphenethyl)pyridazin-3(2H)-one, a C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

Bioorg Med Chem Lett 2020 08 9;30(16):127326. Epub 2020 Jun 9.

Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States. Electronic address:

Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer's patients with early phase. Herein we report the synthesis and preliminary evaluation of a C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [C]8 failed to cross the blood-brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding.
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http://dx.doi.org/10.1016/j.bmcl.2020.127326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363051PMC
August 2020

Transdural Approach to Resection of Intraspinal Extradural Ventral Cysts in the Lumbar Spine.

World Neurosurg 2020 08 17;140:347-352. Epub 2020 May 17.

The First Affiliated Hospital of Harbin Medical University, Harbin, China.

Background: Intraspinal extradural ventral cysts in the lumbar spine can cause back pain and neurological deficits of the lower extremities. For the resection of this type of space-occupying lesion, the transdural approach has not been reported in the literature.

Case Description: A 66-year-old man presented, suffering from progressive radiation pain of his bilateral lower extremities. Imaging examination revealed a cystic lesion in ventral side of lumbar spinal canal. We conducted the excision of the cyst with the transdural approach. The symptoms of the patient disappeared immediately after the operation and recurrence of the symptoms has not been observed in the 3-month follow-up.

Conclusions: This operation approach is safe and effective. Compared with the previous surgical approach reported in the literature, by this approach surgeons could achieve less injury, shorter operation time, and the same surgical outcomes in the short term. Therefore, we would like to present this approach to provide an alternative to deal with similar lesions.
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http://dx.doi.org/10.1016/j.wneu.2020.05.110DOI Listing
August 2020

Biodegradable Iodine-Labeled Microspheres: Potential Transarterial Radioembolization Biomaterial for Primary Hepatocellular Carcinoma Treatment.

Adv Healthc Mater 2020 07 19;9(13):e2000028. Epub 2020 May 19.

Laboratory of Clinical Nuclear Medicine, Department of Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China.

Transarterial radioembolization with radionuclide-labeled microspheres is successfully used in hepatocellular carcinoma (HCC) treatment, but the non-biodegradability and rapid settlement of the microsphere material are associated with unsatisfied distribution and unable for multiple administrations. In this study, a novel biodegradable chitosan-collagen composite microsphere (CCM) with ideal settlement rate is prepared. The Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) results indicate CCMs have desirable shapes with diameters around 10 µm, and considerable biodegradability within 12 weeks. These CCMs are successfully radiolabeled with I and processed efficiency of 70.4 MBq mg of microspheres as well as favorable stability in vitro. Then, I-CCMs are injected into rats with orthotopic HCC via the hepatic artery which effectively improves the median overall survival from 19 to 44 days (p < 0.05). Single photon emission computed tomography (SPECT/CT) imaging and immunohistochemical analysis indicate well-localized biodistribution and consistent stability of I-CCMs in the liver over 28 days. Magnetic resonance imaging (MRI) and gross specimens monitoring confirm the inhibited tumor growth after I-CCMs treatment. In conclusion, these biodegradable I-CCMs exhibit optimal radiolabeling efficiency, stability, and favorably radioembolization effect for orthotopic HCC in a rodent model, suggesting potential for interventional cancer therapy.
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http://dx.doi.org/10.1002/adhm.202000028DOI Listing
July 2020

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis.

Blood 2020 08;136(6):726-739

The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to developing ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either a high-iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation, compared with healthy control subjects. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.
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http://dx.doi.org/10.1182/blood.2019002907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414596PMC
August 2020

Corrigendum to 'Fibroblast growth factor 21 is required for the therapeutic effects of Lactobacillus rhamnosus GG against fructose-induced fatty liver in mice' Mol Metabol 29 (November 2019) 145-157.

Mol Metab 2020 05;35:100999

Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY 40202, USA; Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA. Electronic address:

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http://dx.doi.org/10.1016/j.molmet.2020.100999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191246PMC
May 2020

Synthesis and pharmacokinetic study of a C-labeled cholesterol 24-hydroxylase inhibitor using 'in-loop' [C]CO fixation method.

Bioorg Med Chem Lett 2020 05 6;30(9):127068. Epub 2020 Mar 6.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Cholesterol 24-hydroxylase, also known as CYP46A1 (EC 1.14.13.98), is a monooxygenase and a member of the cytochrome P450 family. CYP46A1 is specifically expressed in the brain where it controls cholesterol elimination by producing 24S-hydroxylcholesterol (24-HC) as the major metabolite. Modulation of CYP46A1 activity may affect Aβ deposition and p-tau accumulation by changing 24-HC formation, which thereafter serves as potential therapeutic pathway for Alzheimer's disease. In this work, we showcase the efficient synthesis and preliminary pharmacokinetic evaluation of a novel cholesterol 24-hydroxylase inhibitor 1 for use in positron emission tomography.
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http://dx.doi.org/10.1016/j.bmcl.2020.127068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196435PMC
May 2020

Radiosynthesis and preliminary evaluation of C-labeled 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2-benzo[] [1,2,4] thiadiazine 1,1-dioxide for PET imaging AMPA receptors.

Tetrahedron Lett 2020 Mar 17;61(12). Epub 2020 Jan 17.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA.

The α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) belong to the family of ionotropic transmembrane receptors for glutamate (iGluRs) that are implicated in the pathology of neurological disorders and neurodegenerative diseases. Inspired by a recently developed positive allosteric modulator of AMPARs, 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2-benzo[ ][1,2,4]thiadiazine 1,1-dioxide (; EC = 2.0 nM), we designed a new synthetic route for -protected phenolic precursor and efficiently radiolabeled a PET ligand [C] ([C]) using a modified one-pot two-step strategy in high radiochemical yield and high molar activity. Preliminary evaluation was carried out to investigate the suitability of [C] as a potential PET probe for AMPAR imaging.
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http://dx.doi.org/10.1016/j.tetlet.2020.151635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062035PMC
March 2020

[F]-Alfatide PET imaging of integrin αvβ3 for the non-invasive quantification of liver fibrosis.

J Hepatol 2020 07 5;73(1):161-169. Epub 2020 Mar 5.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, USA. Electronic address:

Background & Aims: The vitronectin receptor integrin αvβ3 drives fibrogenic activation of hepatic stellate cells (HSCs). Molecular imaging targeting the integrin αvβ3 could provide a non-invasive method for evaluating the expression and the function of the integrin αvβ3 on activated HSCs (aHSCs) in the injured liver. In this study, we sought to compare differences in the uptake of [F]-Alfatide between normal and injured liver to evaluate its utility for assessment of hepatic fibrogenesis.

Methods: PET with [F]-Alfatide, non-enhanced CT, histopathology, immunofluorescence staining, immunoblotting and gene analysis were performed to evaluate and quantify hepatic integrin αvβ3 levels and liver fibrosis progression in mouse models of fibrosis (carbon tetrachloride [CCl] and bile duct ligation [BDL]). The liver AUC divided by the blood AUC over 30 min was used as an integrin αvβ3-PET index to quantify fibrosis progression. Ex vivo analysis of frozen liver tissue from patients with fibrosis and cirrhosis verified the animal findings.

Results: Fibrotic mouse livers showed enhanced [F]-Alfatide uptake and retention compared to control livers. The radiotracer was demonstrated to bind specifically with integrin αvβ3, which is mainly expressed on aHSCs. Autoradiography and histopathology confirmed the PET imaging results. Further, the mRNA and protein level of integrin αvβ3 and its signaling complex were higher in CCl and BDL models than controls. The results obtained from analyses on human fibrotic liver sections supported the animal findings.

Conclusions: Imaging hepatic integrin αvβ3 with PET and [F]-Alfatide offers a potential non-invasive method for monitoring the progression of liver fibrosis.

Lay Summary: Integrin αvβ3 expression on activated hepatic stellate cells (aHSCs) is associated with HSC proliferation during hepatic fibrogenesis. Herein, we show that a radioactive tracer, [F]-Alfatide, binds to integrin αvβ3 with high affinity and specificity. [F]-Alfatide could thus be used as a non-invasive imaging biomarker to track hepatic fibrosis progression.
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http://dx.doi.org/10.1016/j.jhep.2020.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363052PMC
July 2020

Synthesis and evaluation of 6-(C-methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein by PET.

Bioorg Med Chem Lett 2020 02 17;30(4):126879. Epub 2019 Dec 17.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States. Electronic address:

Transmembrane AMPA receptor regulatory proteins (TARPs) are a recently discovered family of proteins that modulate AMPA receptors activity. Based on a potent and selective TARP subtype γ-8 antagonist, 6-(methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one (compound 9), we perform the radiosynthesis of its C-isotopologue 1 and conduct preliminary PET evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2019.126879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045276PMC
February 2020

Risk factors of postoperative low back pain for low-grade isthmic spondylolisthesis: a retrospective study.

J Int Med Res 2020 Mar 18;48(3):300060519890791. Epub 2019 Dec 18.

Department of Orthopaedic Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjaing Province, China.

Objective: To investigate the risk factors of postoperative low back pain (LBP) following posterior lumbar interbody fusion (PLIF) surgery for low-grade isthmic spondylolisthesis (IS).

Methods: This retrospective study enrolled patients with IS that underwent PLIF between January 2011 and January 2016. Demographic, clinical, surgical and radiological characteristics were analysed to determine associations between these characteristics and LBP as measured using a visual analogue scale (VAS) pain score.

Results: A total of 192 patients were enrolled in the study. The mean VAS pain score of LBP decreased significantly after surgery. The mean preoperative VAS pain score was significantly greater in patients with symptoms of ≤3 years duration compared with those with symptoms lasting >3 years. The postoperative VAS pain score was significantly lower in patients with grade 1 slippage compared with those with grade 2 slippage. There was a significant correlation between preoperative to postoperative change of VAS pain score and postoperative disc height ( = 0.99).

Conclusion: PLIF significantly improved LBP in patients with low-grade IS, although patients still reported some postoperative LBP. The grade of slippage was a risk factor for postoperative LBP. Restoring the disc height appeared to improve LBP.
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http://dx.doi.org/10.1177/0300060519890791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607220PMC
March 2020

Probiotic culture supernatant improves metabolic function through FGF21-adiponectin pathway in mice.

J Nutr Biochem 2020 01 24;75:108256. Epub 2019 Oct 24.

Department of Medicine, University of Louisville, Louisville, KY, USA; Alcohol Research Center, University of Louisville, Louisville, KY, USA; Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA. Electronic address:

High-fat/high-fructose diet plus intermittent hypoxia exposure (HFDIH) causes metabolic disorders such as insulin resistance, obesity, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. The purpose of this study is to examine the effects and understand the mechanism of action of Lactobacillus rhamnosus GG culture supernatant (LGGs) on HFDIH-induced metabolic dysfunction. Mice were fed high-fat:high-fructose diet for 15 weeks. After 3 weeks of feeding, the mice were exposed to chronic intermittent hypoxia for the next 12 weeks (HFDIH), and LGGs was supplemented over the entire experiment. HFDIH exposure significantly led to metabolic disorders. LGGs treatment showed significant improvements in indices of metabolic disorders including fat mass, energy expenditure, glucose intolerance, insulin resistance, increased hepatic steatosis and liver injury. HFDIH mice markedly increased adipose inflammation and adipocyte size, and reduced circulating adiponectin, which was restored by LGGs treatment. LGGs treatment increased hepatic FGF21 mRNA expression and circulating FGF21 protein levels, which were associated with increased hepatic PPARα expression and fecal butyrate concentration. In addition, HFDIH-induced hepatic fat accumulation and apoptosis were significantly reduced by LGGs supplementation. In summary, LGGs treatment increased energy expenditure and insulin sensitivity and prevented metabolic abnormalities in HFDIH mice, and this is associated with the FGF21-adiponectin signaling pathway. LGGs may be a potential prevention/treatment strategy in subjects with the metabolic syndrome.
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http://dx.doi.org/10.1016/j.jnutbio.2019.108256DOI Listing
January 2020

Fibroblast growth factor 21 is required for the therapeutic effects of Lactobacillus rhamnosus GG against fructose-induced fatty liver in mice.

Mol Metab 2019 11 3;29:145-157. Epub 2019 Sep 3.

Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY 40202, USA; Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA. Electronic address:

Objectives: High fructose feeding changes fibroblast growth factor 21 (FGF21) regulation. Lactobacillus rhamnosus GG (LGG) supplementation reduces fructose-induced non-alcoholic fatty liver disease (NAFLD). The aim of this study was to determine the role of FGF21 and underlying mechanisms in the protective effects of LGG.

Methods: FGF21 knockout (KO) mice and C57BL/6 wild type (WT) mice were fed 30% fructose for 12 weeks. LGG was administered to the mice in the last 4 weeks during fructose feeding. FGF21-adiponectin (ADPN)-mediated hepatic lipogenesis and inflammation were investigated.

Results: FGF21 expression was robustly increased after 5-weeks of feeding and significantly decreased after 12-weeks of feeding in fructose-induced NAFLD mice. LGG administration reversed the depressed FGF21 expression, increased adipose production of ADPN, and reduced hepatic fat accumulation and inflammation in the WT mice but not in the KO mice. Hepatic nuclear carbohydrate responsive-element binding protein (ChREBP) was increased by fructose and reduced by LGG, resulting in a reduction in the expression of lipogenic genes. The methylated form of protein phosphatase 2A (PP2A) C, which dephosphorylates and activates ChREBP, was upregulated by fructose and normalized by LGG. Leucine carboxyl methyltransferase-1, which methylates PP2AC, was also increased by fructose and decreased by LGG. However, those beneficial effects of LGG were blunted in the KO mice. Hepatic dihydrosphingosine-1-phosphate, which inhibits PP2A, was markedly increased by LGG in the WT mice but attenuated in the KO mice. LGG decreased adipose hypertrophy and increased serum levels of ADPN, which regulates sphingosine metabolism. This beneficial effect was decreased in the KO mice.

Conclusion: LGG administration increases hepatic FGF21 expression and serum ADPN concentration, resulting in a reduced ChREBP activation through dihydrosphingosine-1-phosphate-mediated PP2A deactivation, and subsequently reversed fructose-induced NAFLD. Thus, our data suggest that FGF21 is required for the beneficial effects of LGG in reversal of fructose-induced NAFLD.
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http://dx.doi.org/10.1016/j.molmet.2019.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812038PMC
November 2019

Circular RNA LARP4 correlates with decreased Enneking stage, better histological response, and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging microRNA-424 in osteosarcoma.

J Clin Lab Anal 2020 Feb 22;34(2):e23045. Epub 2019 Oct 22.

Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

Background: This study aimed to evaluate the association of circular RNA La-related RNA-binding protein 4 (circ-LARP4) with clinical features and prognosis in osteosarcoma patients, and further explore its effect on chemosensitivity in osteosarcoma cells.

Methods: Seventy-two osteosarcoma patients with Enneking stage IIA-IIB who underwent resection were consecutively enrolled, and then, tumor tissues and non-tumor tissues were obtained. Circ-LARP4 in tumor tissue/non-tumor tissue was detected by quantitative polymerase chain reaction. After circ-LARP4 overexpression and negative control overexpression plasmid transfection, relative cell viability (%) was evaluated by Cell Counting Kit-8 in MG63 cells treated by different concentrations of cisplatin, methotrexate, and doxorubicin, and IC was calculated.

Results: Circ-LARP4 was downregulated in tumor tissue compared with non-tumor tissue and had a good value in distinguishing tumor tissue from non-tumor tissue with an area under curve of 0.829 (95% CI: 0.762-0.859). Meanwhile, tumor circ-LARP4 was negatively correlated with the Enneking stage. After resection, circ-LARP4 high expression patients showed an increased tumor cell necrosis rate to adjuvant chemotherapy compared to circ-LARP4 low expression patients, and circ-LARP4 high expression correlated with prolonged disease-free survival and overall survival. In vitro experiments revealed that circ-LARP4 overexpression elevated the chemosensitivity of MG63 cells to cisplatin and doxorubicin but not methotrexate, with decreased cisplatin IC and doxorubicin IC concentrations than negative control. Besides, miR-424 overexpression attenuated the chemosensitivity in circ-LARP4 overexpression-treated MG63 cells.

Conclusion: Circ-LARP4 high expression correlates with decreased Enneking stage and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging miR-424 in osteosarcoma.
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http://dx.doi.org/10.1002/jcla.23045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031593PMC
February 2020

Probiotic Lactobacillus rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice.

Hepatology 2020 06 16;71(6):2050-2066. Epub 2020 Mar 16.

Department of Medicine, University of Louisville, Louisville, KY.

Background And Aims: Cholestatic liver disease is characterized by gut dysbiosis and excessive toxic hepatic bile acids (BAs). Modification of gut microbiota and repression of BA synthesis are potential strategies for the treatment of cholestatic liver disease. The purpose of this study was to examine the effects and to understand the mechanisms of the probiotic Lactobacillus rhamnosus GG (LGG) on hepatic BA synthesis, liver injury, and fibrosis in bile duct ligation (BDL) and multidrug resistance protein 2 knockout (Mdr2 ) mice.

Approach And Results: Global and intestine-specific farnesoid X receptor (FXR) inhibitors were used to dissect the role of FXR. LGG treatment significantly attenuated liver inflammation, injury, and fibrosis with a significant reduction of hepatic BAs in BDL mice. Hepatic concentration of taurine-β-muricholic acid (T-βMCA), an FXR antagonist, was markedly increased in BDL mice and reduced in LGG-treated mice, while chenodeoxycholic acid, an FXR agonist, was decreased in BDL mice and normalized in LGG-treated mice. LGG treatment significantly increased the expression of serum and ileum fibroblast growth factor 15 (FGF-15) and subsequently reduced hepatic cholesterol 7α-hydroxylase and BA synthesis in BDL and Mdr2 mice. At the molecular level, these changes were reversed by global and intestine-specific FXR inhibitors in BDL mice. In addition, LGG treatment altered gut microbiota, which was associated with increased BA deconjugation and increased fecal and urine BA excretion in both BDL and Mdr2 mice. In vitro studies showed that LGG suppressed the inhibitory effect of T-βMCA on FXR and FGF-19 expression in Caco-2 cells.

Conclusion: LGG supplementation decreases hepatic BA by increasing intestinal FXR-FGF-15 signaling pathway-mediated suppression of BA de novo synthesis and enhances BA excretion, which prevents excessive BA-induced liver injury and fibrosis in mice.
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http://dx.doi.org/10.1002/hep.30975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317518PMC
June 2020

Design, Synthesis, and Evaluation of F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes.

J Med Chem 2019 10 26;62(19):8866-8872. Epub 2019 Sep 26.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School , Boston , Massachusetts 02114 , United States.

Dysfunction of monoacylglycerol lipase (MAGL) is associated with several psychopathological disorders, including drug addiction and neurodegenerative diseases. Herein we design, synthesize, and evaluate several irreversible fluorine-containing MAGL inhibitors for positron emission tomography (PET) ligand development. Compound (identified from a therapeutic agent) was advanced for F-labeling via a novel spirocyclic iodonium ylide (SCIDY) strategy, which demonstrated high brain permeability and excellent specific binding. This work supports further development of novel F-labeled MAGL PET probes.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875603PMC
October 2019

PET/SPECT Molecular Probes for the Diagnosis and Staging of Nonalcoholic Fatty Liver Disease.

Mol Imaging 2019 Jan-Dec;18:1536012119871455

1 Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Nonalcoholic fatty liver disease (NAFLD) is a significant public health challenge afflicting approximately 1 billion individuals both in the Western world and in the East world. While liver biopsy is considered as gold standard in the diagnosis and staging of liver fibrosis, noninvasive imaging technologies, including ultrasonography, computed tomography, single-photon emission computed tomography (SPECT), magnetic resonance imaging, and positron emission tomography (PET) could offer more sensitive, comprehensive, and quantitative measurement for NAFLD. In this review, we focus on recent development and applications of PET/SPECT molecular probes that enable multispatial/temporal visualization and quantification of physiopathological progress at the molecular level in the NAFLD. We shall also discuss the limitations of current radioligands and future direction for PET/SPECT probe development.
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http://dx.doi.org/10.1177/1536012119871455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724487PMC
June 2020

The long noncoding RNA HOTAIR serves as a microRNA-34a-5p sponge to reduce nucleus pulposus cell apoptosis via a NOTCH1-mediated mechanism.

Gene 2019 Oct 31;715:144029. Epub 2019 Jul 31.

Department of Orthopedic Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. Electronic address:

Intervertebral disc degeneration (IDD) is a major cause of lower back pain, but the specific molecular mechanisms governing its development are poorly characterized. This study sought to assess to what extent HOTAIR, a long non-coding (Lnc) RNA is expressed in IDD and regulates the apoptotic death of nucleus pulposus (NP) cells. We therefore used real-time qPCR to measure HOTAIR and microRNA(miR)-34a-5p in degenerative NP cells, and then validated their functional relevance via overexpressing them in these NP cells. We further verified the targets of these RNA constructs in 293 T cells through the use of a dual luciferase reporter assay. We further measured NP cell apoptosis via flow cytometry and Notch1 expression via western blotting. Our results indicated that IDD was linked with decreased HOTAIR expression relative to regular NP cells, and overexpressing this lncRNA was linked to reduced apoptotic NP cell death, whereas overexpressing miR-34a-5p had the opposite effect. We found that HOTAIR served as a miR-34a-5p sponge, sequestering this miRNA and thereby down regulating genes linked to apoptosis through the Notch signaling pathway. Even in naturally degenerated NP cells, HOTAIR delayed the onset of apoptosis. Together these results reveal that a HOTAIR/miR-34a-5p/Notch1 signaling pathway may regulate the development of IDD, potentially making HOTAIR a viable target for treatment of this disease.
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http://dx.doi.org/10.1016/j.gene.2019.144029DOI Listing
October 2019

Synthesis and Preliminary Evaluation of [ C]GNE-1023 as a Potent PET Probe for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2) in Parkinson's Disease.

ChemMedChem 2019 09 22;14(17):1580-1585. Epub 2019 Aug 22.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

Leucine-rich repeat kinase 2 (LRRK2) is a large protein involved in the pathogenesis of Parkinson's disease (PD). It has been demonstrated that PD is mainly conferred by LRRK2 mutations that bring about increased kinase activity. As a consequence, selective inhibition of LRRK2 may help to recover the normal functions of LRRK2, thereby serving as a promising alternative therapeutic target for PD treatment. The mapping of LRRK2 by positron emission tomography (PET) studies allows a thorough understanding of PD and other LRRK2-related disorders; it also helps to validate and translate novel LRRK2 inhibitors. However, no LRRK2 PET probes have yet been reported in the primary literature. Herein we present a facile synthesis and preliminary evaluation of [ C]GNE-1023 as a novel potent PET probe for LRRK2 imaging in PD. [ C]GNE-1023 was synthesized in good radiochemical yield (10 % non-decay-corrected RCY), excellent radiochemical purity (>99 %), and high molar activity (>37 GBq μmol ). Excellent in vitro binding specificity of [ C]GNE-1023 toward LRRK2 was demonstrated in cross-species studies, including rat and nonhuman primate brain tissues by autoradiography experiments. Subsequent whole-body biodistribution studies indicated limited brain uptake and urinary and hepatobiliary elimination of this radioligand. This study may pave the way for further development of a new generation of LRRK2 PET probes.
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http://dx.doi.org/10.1002/cmdc.201900321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726558PMC
September 2019

Chalcone Derivative L6H21 Reduces EtOH + LPS-Induced Liver Injury Through Inhibition of NLRP3 Inflammasome Activation.

Alcohol Clin Exp Res 2019 08 30;43(8):1662-1671. Epub 2019 Jun 30.

Hepatobiology and Toxicology Program, Department of Pharmacology and Toxicology, Alcohol Research Center, University of Louisville, Louisville, Kentucky.

Background: Chronic alcohol intake increases circulating endotoxin levels causing excessive inflammation that aggravates the liver injury. (E)-2,3-dimethoxy-4'-methoxychalcone (L6H21), a derivative of chalcone, has been found to inhibit inflammation in cardiac diseases and nonalcoholic fatty liver disease. However, the use of L6H21 in alcoholic liver disease to inhibit exotoxin-associated inflammation has not been explored. In this study, we examined the effects of L6H21 on EtOH + LPS-induced hepatic inflammation, steatosis, and liver injury and investigated the underlying mechanisms.

Methods: C57BL6 mice were treated with 5% EtOH for 10 days, and LPS was given to the mice 6 hours before sacrificing. One group of mice was supplemented with L6H21 with EtOH and LPS. RAW264.7 cells were used to analyze the effects of L6H21 on macrophage activation.

Results: EtOH + LPS treatment significantly increased hepatic steatosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), which were reduced by L6H21 treatment. EtOH + LPS treatment increased hepatic inflammation, as shown by the increased hepatic protein levels of Toll-like receptor-4, p65, and p-IκB, and increased oxidative stress, as shown by protein carbonyl levels and reactive oxygen species formation, which were reduced by L6H21 treatment. In addition, L6H21 treatment markedly inhibited EtOH + LPS-elevated hepatic protein levels of NLRP3, cleaved caspase-1, cleaved IL-1β, and caspase-1-associated apoptosis.

Conclusions: Our results demonstrate that L6H21 treatment inhibits EtOH + LPS-induced liver steatosis and injury through suppression of NLRP3 inflammasome activation. L6H21 may be used as an alternative strategy for ALD prevention/treatment.
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http://dx.doi.org/10.1111/acer.14120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790986PMC
August 2019

Microrna-130a Downregulates HCV Replication through an atg5-Dependent Autophagy Pathway.

Cells 2019 04 10;8(4). Epub 2019 Apr 10.

Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

We previously identified that miR-130a downregulates HCV replication through two independent pathways: restoration of host immune responses and regulation of pyruvate metabolism. In this study, we further sought to explore host antiviral target genes regulated by miR-130a. We performed a RT² Profiler™ PCR array to identify the host antiviral genes regulated by miR-130a. The putative binding sites between miR-130a and its downregulated genes were predicted by miRanda. miR-130a and predicted target genes were over-expressed or knocked down by siRNA or CRISPR/Cas9 gRNA. Selected gene mRNAs and their proteins, together with HCV replication in JFH1 HCV-infected Huh7.5.1 cells were monitored by qRT-PCR and Western blot. We identified 32 genes that were significantly differentially expressed more than 1.5-fold following miR-130a overexpression, 28 of which were upregulated and 4 downregulated. We found that ATG5, a target gene for miR-130a, significantly upregulated HCV replication and downregulated interferon stimulated gene expression. miR-130a downregulated ATG5 expression and its conjugation complex with ATG12. ATG5 and ATG5-ATG12 complex affected interferon stimulated gene (ISG) such as MX1 and OAS3 expression and subsequently HCV replication. We concluded that miR-130a regulates host antiviral response and HCV replication through targeting ATG5 via the ATG5-dependent autophagy pathway.
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http://dx.doi.org/10.3390/cells8040338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523735PMC
April 2019

Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a "Tail Switching" Strategy on a Piperazinyl Azetidine Skeleton.

J Med Chem 2019 04 21;62(7):3336-3353. Epub 2019 Mar 21.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology , Harvard Medical School , Boston , Massachusetts 02114 , United States.

Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with C or F. [C]8 ([C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [C]17 ([C]PAD) and [F]37 ([F]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581563PMC
April 2019