Biased agonism at free-fatty acid receptor-4 (FFA4/GPR120).

Free-fatty acid receptor-4 (FFA4), previously known as GPR120, is a G protein-coupled receptor (GPCR) activated by medium-to-long chain free fatty acids (FFAs), including saturated, monounsaturated, and polyunsaturated fats, many of which (e.g., omega-3 fatty acids) are critical contributors to human health and disease.

ROS-mediated regulation of β2AR function: Does oxidation play a meaningful role towards β2-agonist tachyphylaxis in airway obstructive diseases?

β2-adrenergic receptor (β2AR) agonists are the clinical gold standard for treatment and prophylaxis of airway constriction in pulmonary obstructive diseases such as asthma and COPD. Inhaled β2-agonists elicit rapid bronchorelaxation of the airway smooth muscle, yet, clinical tachyphylaxis to this response can occur over repeated and chronic use, which reduces the bronchodilatory effectiveness. Several mechanisms have been proposed to impart β2-agonist tachyphylaxis, most notably β2AR desensitization.

Cognitive factors impacting patient understanding of laboratory test information.

Laboratory testing can provide information useful to promote patient health literacy and ultimately patient well-being. The human state of mind involves not only cognition but also emotion and motivation factors when receiving, processing, and acting upon information. The cognitive load for patients acquiring and processing new information is high.

Agonists and hydrogen peroxide mediate hyperoxidation of β2-adrenergic receptor in airway epithelial cells: Implications for tachyphylaxis to β2-agonists in constrictive airway disorders.

Asthma and other airway obstructive disorders are characterized by heightened inflammation and excessive airway epithelial cell reactive oxygen species (ROS), which give rise to a highly oxidative environment. After decades of use, β2-adrenergic receptor (β2AR) agonists remain at the forefront of treatment options for asthma, however, chronic use of β2-agonists leads to tachyphylaxis to the bronchorelaxant effects, a phenomenon that remains mechanistically unexplained. We have previously demonstrated that β2AR agonism increases ROS generation in airway epithelial cells, which upholds proper receptor function via feedback oxidation of β2AR cysteine thiolates to Cys-S-sulfenic acids (Cys-SOH).

Gut feelings in the islets: The role of the gut microbiome and the FFA2 and FFA3 receptors for short chain fatty acids on β-cell function and metabolic regulation.

Short-chain fatty acids (SCFAs) are biosynthesized via fermentation of polysaccharides by gastrointestinal microbiota and have been shown to have wide-reaching effects on almost all tissues, including the pancreatic islets. Historically, the effects of SCFAs have been attributed to their intracellular metabolism and function as energy sources, but the discovery of free fatty acid G protein-coupled receptors (GPCRs) in the 2000s suggested that many functional outcomes of SCFAs are receptor-mediated. The SCFA receptors FFA2/GPR43 and FFA3/GPR41 are expressed on β-cells, where they regulate glucose-dependent insulin secretion, making them attractive targets for treatment of diabetes and other metabolic disorders.

Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT.

Background: Papillary renal cell carcinoma (pRCC) is a highly metastatic genitourinary cancer and is generally irresponsive to common treatments used for the more prevalent clear-cell (ccRCC) subtype. The goal of this study was to examine the novel role of the free fatty-acid receptor-1 (FFA1/GPR40), a cell-surface expressed G protein-coupled receptor that is activated by medium-to-long chained dietary fats, in modulation of pRCC cell migration invasion, proliferation and tumor growth.

Methods: We assessed the expression of FFA1 in human pRCC and ccRCC tumor tissues compared to patient-matched non-cancerous controls, as well as in RCC cell lines.

Free-Fatty Acid Receptor-4 (FFA4/GPR120) differentially regulates migration, invasion, proliferation and tumor growth of papillary renal cell carcinoma cells.

Kidney cancer is among the 10 most common cancers, and renal cell carcinoma (RCC), which represent 90% of all kidney cancers, has the highest mortality rate of all genitourinary cancers. Papillary RCC (pRCC) is the second most frequent subtype of RCC and demonstrates distinct characteristics compared to other subtypes, including a high degree of metastasis and resistance to treatments against the more common clear cell RCC (ccRCC) subtype. Here, we demonstrate that the Free-Fatty Acid Receptor-4 (FFA4), a G protein-coupled receptor that is endogenously activated by medium-to-long chain free-fatty acids, is upregulated in pRCC compared to patient-matched normal kidney tissue, and that the expression of FFA4 increases with the degree of pathological grading of pRCC.

Omadacycline for management of Mycobacterium abscessus infections: a review of its effectiveness, place in therapy, and considerations for use.

The Mycobacterium abscessus complex (MABC) is a group of acid-fast, rapidly dividing non-tuberculous mycobacteria (NTM) that include a number of clinically important subspecies, including M. abscessus, M. bolletii, and M.

Oncogenic signaling of the free-fatty acid receptors FFA1 and FFA4 in human breast carcinoma cells.

Globally, breast cancer is the most frequent type of cancer in women, and most breast cancer-associated deaths are due to metastasis and recurrence of the disease. Dietary habits, specifically dietary fat intake is a crucial risk factor involved in breast cancer development and progression. Decades of research has revealed that free-fatty acids (FFA) modulate carcinogenic processes through fatty acid metabolism and lipid peroxidation.

A review of web-based application of online learning in pathology and laboratory medicine.

Web-based learning applications can support health sciences education, including knowledge acquisition in pathology and laboratory medicine. Websites can be developed to provide learning content, assessments, and products supporting pathology education. In this paper, we review informatics principles, practices, and procedures involved with educational website development in the context of existing websites and published studies of educational website usage outcomes, including that of the authors.

"Selective" serotonin 5-HT receptor antagonists.

Blockade of the serotonin 5-HT G protein-coupled receptor (5-HTR) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are FDA-approved to treat schizophrenia, bipolar disorder, and as adjunctive therapies in major depressive disorder. Meanwhile, activation of the 5-HTR by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HTR agonists, however, often bind other receptors, and standard 5-HTR antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HTR-dependent effects of these compounds and the general neurobiological function of 5-HTRs.

The Skeletal Muscle Relaxer Cyclobenzaprine Is a Potent Non-Competitive Antagonist of Histamine H1 Receptors.

Cyclobenzaprine is a tricyclic dimethylpropanamine skeletal muscle relaxant, which is used clinically to decrease muscle spasm and hypercontractility, as well as acute musculoskeletal pain. Although the absolute mechanism of action of cyclobenzaprine remains elusive, it is known to mediate its effects centrally via inhibition of tonic somatic motor function, likely through modulation of noradrenergic and serotonergic systems. While cyclobenzaprine is effective as a muscle relaxant, greater than 30% of patients experience drowsiness and sedative-hypnotic effects, yet the mechanisms that cause this adverse effect are also undescribed.

The effect of albinism on avian predator attack rates in eastern garter snakes.

Albinism is a conspicuous and distinctive phenotype arising from the absence of melanin in the integument that has been documented in all major vertebrate groups. With few exceptions, albinism is rare in natural populations, suggesting that it incurs significant fitness costs as compared to wild-type phenotypes. One possible explanation for this rarity is that albinos experience higher predation risk as compared to wild-type individuals.

A dual-delivery platform for vaccination using antigen-loaded nanoparticles in dissolving microneedles.

Effective vaccines delivered via painless methods would revolutionize the way people approach vaccinations. This study focused on the development of fast-dissolving microneedles (MNs) to deliver antigen-loaded sustained release polymeric nanoparticles (NPs), achieving a dual-delivery platform for vaccination through the skin. The platform utilizes dissolving MNs (dMNs), which penetrate to the epidermal layer of the skin and rapidly dissolve, releasing the antigen-loaded NPs.

α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and high and low affinity monoamine transporters.

While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent.

Short-chain free-fatty acid G protein-coupled receptors in colon cancer.

The dietary role of macronutrients and their metabolites in cancer has been evident for many decades. Dietary ingestion of fat, carbohydrates, protein, and fiber, as well as probiotics that influence gut microbiota, have all been linked to gastrointestinal (GI) tract health and disease, particularly in the colon, where it has long been known that fat and fiber can regulate inflammation and carcinogenesis. Short-chained fatty acids (SCFA), including acetate, propionate, and butyrate, which are biosynthesized by microbiota-mediated metabolism of dietary fiber, have previously been shown to play important roles in colorectal health, including decreasing inflammation and oxidative stress.

The Endocannabinoid System and Alcohol Dependence: Will Cannabinoid Receptor 2 Agonism be More Fruitful than Cannabinoid Receptor 1 Antagonism?

Alcohol-use disorder (AUD) remains a major public health concern. In recent years, there has been a heightened interest in components of the endocannabinoid system for the treatment of AUD. Cannabinoid type 1 (CB1) receptors have been shown to modulate the rewarding effects of alcohol, reduce the abuse-related effects of alcohol, improve cognition, exhibit anti-inflammatory, and neuroprotective effects, which are all favorable properties of potential therapeutic candidates for the treatment of AUD.

Alcohol induces TGFβ1 via downregulation of miR-1946a in murine lung fibroblast.

Exaggerated transforming growth factor-beta 1 (TGFβ1) expression worsens fibroproliferation following bleomycin-induced lung injury in alcohol-fed mice. MicroRNA (miR)-1946a is predicted to bind to the TGFβ1 3' untranslated region (UTR), thereby inhibiting its transcription. We hypothesize that alcohol suppresses miR-1946a and induces TGFβ1.

Canagliflozin ameliorates renal oxidative stress and inflammation by stimulating AMPK-Akt-eNOS pathway in the isoprenaline-induced oxidative stress model.

Diabetes is a leading cause of chronic kidney disease, and the high prevalence of sympathetic nervous system (SNS) hyperactivity in diabetic patients makes them further susceptible to SNS-mediated oxidative stress and accelerated kidney damage. Here, we investigated if canagliflozin can reverse isoprenaline (ISO)-induced renal oxidative damage in rats, a model that mimics SNS overstimulation-induced organ injuries in humans. We found that ISO administration elevates renal oxidative stress markers including malondialdehyde (MDA), advanced protein oxidation product (APOP), myeloperoxidase (MPO) and nitric oxide (NO), while depleting levels of endogenous antioxidants such as catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH).

()-5-(2'-Fluorophenyl)-,-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder.

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disabilities and a plethora of neuropsychiatric symptoms. FXS is the leading monogenic cause of autism spectrum disorder (ASD), which is defined clinically by repetitive and/or restrictive patterns of behavior and social communication deficits. Epilepsy and anxiety are also common in FXS and ASD.

Carboxy-Terminal Phosphoregulation of the Long Splice Isoform of Free-Fatty Acid Receptor-4 Mediates -Arrestin Recruitment and Signaling to ERK1/2.

Free-fatty acid receptor-4 (FFA4), previously termed GPR120, is a G protein-coupled receptor (GPCR) for medium and long-chained fatty acids, agonism of which can regulate a myriad of metabolic, sensory, inflammatory, and proliferatory signals. Two alternative splice isoforms of FFA4 exist that differ by the presence of an additional 16 amino acids in the longer (FFA4-L) transcript, which has been suggested to be an intrinsically -arrestin-biased GPCR. Although the shorter isoform (FFA4-S) has been studied more extensively, very little is known about mechanisms of regulation or signaling of the longer isoform.

Cysteine redox state regulates human β2-adrenergic receptor binding and function.

Bronchoconstrictive airway disorders such as asthma are characterized by inflammation and increases in reactive oxygen species (ROS), which produce a highly oxidative environment. β2-adrenergic receptor (β2AR) agonists are a mainstay of clinical therapy for asthma and provide bronchorelaxation upon inhalation. We have previously shown that β2AR agonism generates intracellular ROS, an effect that is required for receptor function, and which post-translationally oxidizes β2AR cysteine thiols to Cys-S-sulfenic acids (Cys-S-OH).

Docosahexaenoic acid protects motor function and increases dopamine synthesis in a rat model of Parkinson's disease via mechanisms associated with increased protein kinase activity in the striatum.

Parkinson's disease (PD) is a devastating neurodegenerative disease that leads to motor deficits and selective destruction of nigrostriatal dopaminergic neurons. PD is typically treated by dopamine replacement agents; however, dopamine replacement loses effectiveness in the later stages of the disease. Here, we describe the neuroprotective effects of the omega-3 fatty acid docosahexaenoic acid (DHA) in the medial forebrain bundle 6-hydroxydopamine (6-OHDA) model of advanced-stage PD in rats.

A Classroom Activity to Increase Student Pharmacists Confidence in Dealing with the Opioid Epidemic.

To implement and assess the impact of a hybrid flipped-classroom activity designed to increase the motivation and confidence of Doctor of Pharmacy (PharmD) students in addressing the opioid crisis. Third-professional year student pharmacists were provided with reading material developed by federal agencies and professional pharmacy organizations, as well as Georgia-specific information covering medical amnesty and local resources for opioid-overdose prevention prior to class. They then attended a four-hour classroom session that included hearing a lecture on opioid pharmacology and opioid overdose, viewing training videos, and engaging in extensive discussion.

The acute toxic and neurotoxic effects of 3,4-methylenedioxymethamphetamine are more pronounced in adolescent than adult mice.

3,4-methylenedioxymethamphetamine (MDMA) recently achieved breakthrough status from the Food and Drug Administration (FDA) for post-traumatic stress disorder (PTSD). However, evidence indicates that exposure to toxic doses of MDMA can lead to long-lasting dysregulation of brain monoaminergic neurotransmitters, primarily from studies conducted in young adult rodents. To date, there is a paucity of data on whether toxic doses of MDMA can differentially affect neurotransmitter systems in adolescents and mature adults, which is an important question as adolescents and adults may be differentially vulnerable to MDMA abuse.