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Organic Letters Jun 2024Herein, we describe a novel approach to the synthesis of benzocycloheptene derivatives via base-promoted (5 + 2) annulation between 2-(alkynylaryl)acetonitriles and...
Herein, we describe a novel approach to the synthesis of benzocycloheptene derivatives via base-promoted (5 + 2) annulation between 2-(alkynylaryl)acetonitriles and arylalkynes. In this chemistry, 2-(alkynylaryl)acetonitriles are employed as a new C5 synthon to construct various benzocycloheptene(s) derivatives by building two C-C bonds in one single step. This method features excellent regioselectivity, the use of readily available starting materials, and good functional group tolerance. The practicality of the strategy was further demonstrated by gram-scale synthesis, late-stage functionalizations, and the post-modification of natural products such as probenecid and tetrahydrofurfuryl alcohol.
PubMed: 38912965
DOI: 10.1021/acs.orglett.4c00940 -
Life Sciences Jun 2024Pannexin-1 (PANX1) is a hemichannel that releases ATP upon opening, initiating inflammation, cell proliferation, and migration. However, the role of PANX1 channels in...
AIMS
Pannexin-1 (PANX1) is a hemichannel that releases ATP upon opening, initiating inflammation, cell proliferation, and migration. However, the role of PANX1 channels in colon cancer remains poorly understood, thus constituting the focus of this study.
MAIN METHODS
PANX1 mRNA expression was analyzed using multiple cancer databases. PANX1 protein expression and distribution were evaluated by immunohistochemistry on primary tumor tissue and non-tumor colonic mucosa from colon cancer patients. PANX1 inhibitors (probenecid or Panx) were used to assess colon cancer cell lines viability. To study the role of PANX1 in vivo, a subcutaneous xenograft model using HCT116 cells was performed in BALB/c NOD/SCID immunodeficient mice to evaluate tumor growth under PANX1 inhibition using probenecid.
KEY FINDINGS
PANX1 mRNA was upregulated in colon cancer tissue compared to non-tumor colonic mucosa. Elevated PANX1 mRNA expression in tumors correlated with worse disease-free survival. PANX1 protein abundance was increased on tumor cells compared to epithelial cells in paired samples, in a cancer stage-dependent manner. In vitro and in vivo experiments indicated that blocking PANX1 reduced cell viability and tumor growth.
SIGNIFICANCE
PANX1 can be used as a biomarker of colon cancer progression and blocking PANX1 channel opening could be used as a potential therapeutic strategy against this disease.
PubMed: 38897345
DOI: 10.1016/j.lfs.2024.122851 -
Chemical Communications (Cambridge,... Jun 2024A method for the radiosynthesis of F-labelled aryl trifluoromethyl ketones starting from widely available Weinreb amides using [F]fluoroform is presented. The method...
A method for the radiosynthesis of F-labelled aryl trifluoromethyl ketones starting from widely available Weinreb amides using [F]fluoroform is presented. The method uses potassium hexamethyldisilazane as base and delivers products in high molar activity (up to 24 GBq μmol) and excellent radiochemical conversions. The applicability for PET tracer synthesis is demonstrated by the radiosynthesis of ten (hetero)aryl trifluoromethylketones, bearing electron-withdrawing and -donating substituents including a derivative of bioactive probenecid.
PubMed: 38869169
DOI: 10.1039/d4cc01776e -
Expert Opinion on Pharmacotherapy May 2024The neuroimmune system has emerged as a novel target for the treatment of substance use disorders (SUDs), with immunomodulation producing encouraging therapeutic... (Review)
Review
INTRODUCTION
The neuroimmune system has emerged as a novel target for the treatment of substance use disorders (SUDs), with immunomodulation producing encouraging therapeutic benefits in both preclinical and clinical settings.
AREAS COVERED
In this review, we describe the mechanism of action and immune response to methamphetamine, opioids, cocaine, and alcohol. We then discuss off-label use of immunomodulators as adjunctive therapeutics in the treatment of neuropsychiatric disorders, demonstrating their potential efficacy in affective and behavioral disorders. We then discuss in detail the mechanism of action and recent findings regarding the use of ibudilast, minocycline, probenecid, dexmedetomidine, pioglitazone, and cannabidiol to treat (SUDs). These immunomodulators are currently being investigated in clinical trials described herein, specifically for their potential to decrease substance use, withdrawal severity, central and peripheral inflammation, comorbid neuropsychiatric disorder symptomology, as well as their ability to improve cognitive outcomes.
EXPERT OPINION
We argue that although mixed, findings from recent preclinical and clinical studies underscore the potential benefit of immunomodulation in the treatment of the behavioral, cognitive, and inflammatory processes that underlie compulsive substance use.
Topics: Humans; Substance-Related Disorders; Animals; Immunologic Factors; Immunomodulating Agents; Off-Label Use; Alcoholism; Immunomodulation
PubMed: 38803314
DOI: 10.1080/14656566.2024.2360653 -
Biochemical and Biophysical Research... Aug 2024Chronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor...
PURPOSE
Chronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels are implicated in hypothalamic-pituitary-adrenal axis disorders. Previous proteomic analysis indicated a reduction in TRPV2 levels in the chronic unpredictable mild stress (CUMS) rat model, yet its role in synaptic plasticity during depression remains to be elucidated. This study aims to investigate TRPV2's role in depression and its underlying mechanisms.
METHODS
In vivo and in vitro experiments were conducted using the TRPV2-specific agonist probenecid and ERK1/2 inhibitors SCH772984. In vivo, rats underwent six weeks of CUMS before probenecid administration. Depressive-like behaviors were assessed through behavioral tests. ELISA kits measured 5-HT, DA, NE levels in rat hippocampal tissues. Hippocampal morphology was examined via Nissl staining. In vitro, rat hippocampal neuron cell lines were treated with ERK1/2 inhibitors SCH772984 and probenecid. Western blot, immunofluorescence, immunohistochemical staining, and RT-qPCR assessed TRPV2 expression, neurogenesis-related proteins, synaptic markers, and ERK1/2-CREB-BDNF signaling proteins.
RESULTS
Decreased hippocampal TRPV2 levels were observed in CUMS rats. Probenecid treatment mitigated depressive-like behavior and enhanced hippocampal 5-HT, NE, and DA levels in CUMS rats. TRPV2 activation countered CUMS-induced synaptic plasticity inhibition. Probenecid activated the ERK1/2-CREB-BDNF pathway, suggesting TRPV2's involvement in this pathway via ERK1/2.
CONCLUSION
These findings indicate that TRPV2 activation offers protective effects against depressive-like behaviors and enhances hippocampal synaptic plasticity in CUMS rats via the ERK1/2-CREB-BDNF pathway. TRPV2 emerges as a potential therapeutic target for depression.
Topics: Animals; TRPV Cation Channels; Neuronal Plasticity; Male; Brain-Derived Neurotrophic Factor; Stress, Psychological; Hippocampus; Rats; Rats, Sprague-Dawley; MAP Kinase Signaling System; Cyclic AMP Response Element-Binding Protein; Depression; Chronic Disease; Probenecid
PubMed: 38776831
DOI: 10.1016/j.bbrc.2024.150128 -
Cellular and Molecular Biology... Apr 2024This study aimed to experimentally compare the uric acid-lowering effect and renal protection of Yiqing Fang in a rat model of hyperuricemia. Additionally, we used...
This study aimed to experimentally compare the uric acid-lowering effect and renal protection of Yiqing Fang in a rat model of hyperuricemia. Additionally, we used network pharmacology to predict the potential active components, targets, and pathways of Yiqing Fang. Male SD rats were randomly divided into control, model, Yiqing Fang, allopurinol, and probenecid groups. Serum creatinine (Scr), blood urea nitrogen (BUN), serum uric acid (UA), alanine transaminase (ALT), complete blood count, and urinary NAG enzyme levels were measured. Standard pathology and electron microscopy samples were prepared from the left kidney to observe renal pathological changes, renal fibrosis, and collagen III expression levels. In addition, we employed network pharmacology to investigate the molecular mechanisms and pathways of Yiqing Fang. The Yiqing Fang group showed significantly lower levels of Scr, BUN, UA, ALT, urinary NAG enzyme, complete blood count, and liver function tests compared to the model group (P < 0.05). Furthermore, both the Yiqing Fang and allopurinol groups exhibited significant reductions in renal pathological changes compared to the model group, along with decreased expression of collagen III. Network pharmacology analysis identified a total of 27 specific sites related to hyperuricemia. The main active components were predicted to include quercetin, berberine, beta-sitosterol, epimedin C, and dioscin. The primary target sites were predicted to include TNF, IL-6, IL-17, IL-1B, and VEGFA. Yiqing Fang may exert its effects through regulation of drug response, urate metabolism, purine compound absorption, inflammation response, lipopolysaccharide response, cytokine activity, and antioxidant activity. These effects may be mediated through signaling pathways such as IL-17, HIF-1, and AGE-RAGE. Yiqing Fang offers potential as a treatment for hyperuricemia due to its multiple active components, targeting of various sites, and engagement of multiple pathways.
Topics: Animals; Hyperuricemia; Male; Rats, Sprague-Dawley; Kidney; Drugs, Chinese Herbal; Uric Acid; Rats; Disease Models, Animal; Network Pharmacology; Creatinine; Blood Urea Nitrogen
PubMed: 38678602
DOI: 10.14715/cmb/2024.70.4.34 -
Pharmaceutics Apr 2024Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently...
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently associated with adverse effects due to their inhibitory effect on the constitutively expressed cyclooxygenase enzyme 1 (COX-1) in, for instance, the gastrointestinal tract. A systemic delivery, such as a buccal delivery, of NSAIDs would be beneficial and additionally has the advantage of a non-invasive administration route, especially favourable for children or the elderly. To investigate the transport of NSAIDs across the buccal mucosa and determine their potential for buccal therapeutic usage, celecoxib, diclofenac, ibuprofen and piroxicam were tested using an established oral mucosa Transwell model based on human cell line TR146. Carboxyfluorescein and diazepam were applied as internal paracellular and transcellular marker molecule, respectively. Calculated permeability coefficients revealed a transport ranking of ibuprofen > piroxicam > diclofenac > celecoxib. Transporter protein inhibitor verapamil increased the permeability for ibuprofen, piroxicam and celecoxib, whereas probenecid increased the permeability for all tested NSAIDs. Furthermore, influence of local inflammation of the buccal mucosa on the transport of NSAIDs was mimicked by treating cells with a cytokine mixture of TNF-α, IL-1ß and IFN-γ followed by transport studies with ibuprofen (+ probenecid). Cellular response to pro-inflammatory stimuli was confirmed by upregulation of cytokine targets at the mRNA level, increased secreted cytokine levels and a significant decrease in the paracellular barrier. Permeability of ibuprofen was increased across cell layers treated with cytokines, while addition of probenecid increased permeability of ibuprofen in controls, but not across cell layers treated with cytokines. In summary, the suitability of the in vitro oral mucosa model to measure NSAID transport rankings was demonstrated, and the involvement of transporter proteins was confirmed; an inflammation model was established, and increased NSAID transport upon inflammation was measured.
PubMed: 38675204
DOI: 10.3390/pharmaceutics16040543 -
International Journal of Molecular... Apr 2024Reactive astrocytes are key players in HIV-associated neurocognitive disorders (HAND), and different types of reactive astrocytes play opposing roles in the...
Reactive astrocytes are key players in HIV-associated neurocognitive disorders (HAND), and different types of reactive astrocytes play opposing roles in the neuropathologic progression of HAND. A recent study by our group found that gp120 mediates A1 astrocytes (neurotoxicity), which secrete proinflammatory factors and promote HAND disease progression. Here, by comparing the expression of A2 astrocyte (neuroprotective) markers in the brains of gp120 tgm mice and gp120/α7nAChR mice, we found that inhibition of alpha 7 nicotinic acetylcholine receptor (α7nAChR) promotes A2 astrocyte generation. Notably, kynurenine acid (KYNA) is an antagonist of α7nAChR, and is able to promote the formation of A2 astrocytes, the secretion of neurotrophic factors, and the enhancement of glutamate uptake through blocking the activation of α7nAChR/NF-κB signaling. In addition, learning, memory and mood disorders were significantly improved in gp120 tgm mice by intraperitoneal injection of kynurenine (KYN) and probenecid (PROB). Meanwhile, the number of A2 astrocytes in the mouse brain was significantly increased and glutamate toxicity was reduced. Taken together, KYNA was able to promote A2 astrocyte production and neurotrophic factor secretion, reduce glutamate toxicity, and ameliorate gp120-induced neuropathological deficits. These findings contribute to our understanding of the role that reactive astrocytes play in the development of HAND pathology and provide new evidence for the treatment of HAND via the tryptophan pathway.
Topics: Animals; Astrocytes; Glutamic Acid; Mice; Kynurenine; Kynurenic Acid; alpha7 Nicotinic Acetylcholine Receptor; HIV Envelope Protein gp120; Signal Transduction; Mice, Knockout; Probenecid; Mice, Inbred C57BL; Male; Brain; NF-kappa B
PubMed: 38673879
DOI: 10.3390/ijms25084286 -
Toxicology in Vitro : An International... Jun 2024Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome,...
Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 μM for benzbromarone towards CES1 and CES2, respectively, and 2.94 μM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice.
Topics: Humans; Molecular Docking Simulation; Microsomes, Liver; Carboxylic Ester Hydrolases; Gout Suppressants; Enzyme Inhibitors; Carboxylesterase
PubMed: 38670244
DOI: 10.1016/j.tiv.2024.105833 -
JCI Insight Apr 2024Chronic kidney disease (CKD) causes accumulation of uremic metabolites that negatively affect skeletal muscle. Tryptophan-derived uremic metabolites are agonists of the...
Chronic kidney disease (CKD) causes accumulation of uremic metabolites that negatively affect skeletal muscle. Tryptophan-derived uremic metabolites are agonists of the aryl hydrocarbon receptor (AHR), which has been shown to be activated in CKD. This study investigated the role of the AHR in skeletal muscle pathology of CKD. Compared with controls with normal kidney function, AHR-dependent gene expression (CYP1A1 and CYP1B1) was significantly upregulated in skeletal muscle of patients with CKD, and the magnitude of AHR activation was inversely correlated with mitochondrial respiration. In mice with CKD, muscle mitochondrial oxidative phosphorylation (OXPHOS) was markedly impaired and strongly correlated with the serum level of tryptophan-derived uremic metabolites and AHR activation. Muscle-specific deletion of the AHR substantially improved mitochondrial OXPHOS in male mice with the greatest uremic toxicity (CKD + probenecid) and abolished the relationship between uremic metabolites and OXPHOS. The uremic metabolite/AHR/mitochondrial axis in skeletal muscle was verified using muscle-specific AHR knockdown in C57BL/6J mice harboring a high-affinity AHR allele, as well as ectopic viral expression of constitutively active mutant AHR in mice with normal renal function. Notably, OXPHOS changes in AHRmKO mice were present only when mitochondria were fueled by carbohydrates. Further analyses revealed that AHR activation in mice led to significantly increased pyruvate dehydrogenase kinase 4 (Pdk4) expression and phosphorylation of pyruvate dehydrogenase enzyme. These findings establish a uremic metabolite/AHR/Pdk4 axis in skeletal muscle that governs mitochondrial deficits in carbohydrate oxidation during CKD.
Topics: Animals; Receptors, Aryl Hydrocarbon; Mice; Male; Renal Insufficiency, Chronic; Tryptophan; Muscle, Skeletal; Humans; Oxidative Phosphorylation; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Mice, Inbred C57BL; Uremia; Mitochondria, Muscle; Basic Helix-Loop-Helix Transcription Factors; Female; Mice, Knockout; Cytochrome P-450 CYP1B1; Cytochrome P-450 CYP1A1; Middle Aged; Energy Metabolism; Disease Models, Animal
PubMed: 38652558
DOI: 10.1172/jci.insight.178372