bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Gene Signature Classification Model for Predicting Severity of Skin Fibrosis
Authors: Yates Cecelia C. , Jones Jacqueline D , Feghali‐Bostwick Carol , Conley Yvette
Published: November 2023

Scleroderma or systematic sclerosis (SSc) is a clinically heterogeneous disease with a complex phenotype. The disease is characterized by vascular dysfunction, tissue fibrosis, internal organ dysfunction, and immune dysfunction. Because it has no validated biomarkers or effective disease‐modifying therapies, scleroderma represents a major unmet medical need. Although a rare disease those afflicted with the systemic form of the disease suffer from severe vascular and other organ manifestations including pulmonary fibrosis. The leading cause of death is end‐organ dysfunction caused by fibrosis. An improved understanding of the molecular mechanisms involved in the initiation and perpetuation of fibrosis is mandatory to facilitate the rational design of new diagnostic and therapeutic strategies to detect earlier, arrest, and perhaps even reverse disease. We have also determined that chemokines, cytokines that help recruit immune cells to sites of infection and function in the migration of cells to aid in tissue repair, are key to ECM regulation. Diverse expressions of chemokine receptors on multiple dermal cellular populations are likely driven by inflammatory stimuli from excessive fibrosis. The contribution of chemokines to the human immune response is known, but its direct role on fibroblast‐induced ECM synthesis resulting in SSc disease severity is less clear.

We three constructed classification models for making predictions on the severity of SSc, based on (1) gene expression profiles and (2) identifying marker gene sets that correlate with the classification. We utilized two existing genome‐wide microarray gene expression data from the Gene Expression Omnibus (GEO) database of SSc patients. Patients were divided into two groups based on skin score: low 0–17 (low‐mild) and high 18–51 (moderate‐sever modified Rodnan skin thickness score (mRSS), a predictor of disease outcome. In both the Group 1 and Group 2 dataset, random forest (RF) classifier combined with correlation‐based feature selection method (CFS) and naive bayes (NB) combined with CFS or support vector machine based recursive feature elimination method (SVM‐RFE) performed better than all other classification and feature selection methods. We then perform DAVID‐based GO enrichment analysis to evaluate if the chemokine pathways are enriched among differentially expressed genes. First, these data support the feasibility of accurately aligning the phenotype of each subset of patients and individual patient mRSS to generate gene signatures. Second, we uncovered differential expression of chemokine and ECM genes profiles that could potentially predict diseases severity
Individual Differences in the Relative Reinforcing Effects of 3,4‐Methylenedioxypyrovalerone (MDPV) Under Fixed and Progressive Ratio Schedules of Reinforcement in Rats
Authors: Gannon Brenda M. , Galindo Kayla I. , Rice Kenner C. , Collins Gregory T.
Published: November 2023

The abuse of “designer drugs” such as “bath salts” over the past 10 years has reached epidemic proportions. 3,4‐Methylenedioxypyrovalerone (MDPV), a synthetic cathinone and common “bath salt” constituent, is classified by the US Drug Enforcement Agency as Schedule I. MDPV has a cocaine‐like mechanism of action and the present study aimed to directly compare the reinforcing effects of MDPV and cocaine in male Sprague‐Dawley rats. When available under a fixed ratio (FR) 1 schedule, a rapid acquisition of responding was observed for both MDPV (0.032 mg/kg/inf; n=28 of 32) and cocaine (0.32 mg/kg/inf; n=13 of 16). Upon increasing the response requirement to an FR5, two distinct patterns of responding for MDPV emerged, with 0.032 mg/kg/inf MDPV maintaining relatively low rates (~35 infusions/90 min) in approximately half of the rats and significantly higher rates of responding (~85 infusions/90 min) in the other rats. These differential patterns of responding were observed across a range of doses of MDPV (0.0032–0.1 mg/kg/inf), as well as when cocaine (0.032–1 mg/kg/inf) was substituted for MDPV. Unlike in rats trained to self‐administer MDPV, the pattern of responding in cocaine‐trained rats was much more homogenous, regardless of whether they responded for cocaine, or MDPV. In order to determine if these differences in FR responding for MDPV were due to individual differences in the reinforcing effectiveness of MDPV, dose‐response curves (n=16) for MDPV (0.001–0.32 mg/kg/inf) were generated under a progressive ratio (PR) schedule, and compared to those obtained for cocaine (0.032–1.78 mg/kg/inf), methamphetamine (0.01–0.178 mg/kg/inf), and caffeine (0.032–1.78 mg/kg/inf). MPDV was the most potent (MDPV > methamphetamine > cocaine >> caffeine) and effective (MDPV > methamphetamine = cocaine >> caffeine) reinforcer. Although the potency of these drugs to maintain PR responding did not differ between the two sub‐sets of rats, those that self‐administered more MDPV under the FR5 schedule also earned significantly more infusions when MDPV was available under a PR schedule. Moreover, these differences were also apparent when methamphetamine, cocaine, and to a lesser degree, caffeine were available for responding under the PR schedule. Although the factors that contributed to unusually high rates of MDPV‐maintained responding, observed in a sub‐set of rats, are unclear, they might be related to individual differences in human drug‐taking behavior.

Support or Funding Information

This study was supported by an NIH research grant (R01 DA039146) from NIDA, as well as the NIH Intramural Research Programs of NIDA and NIAAA.
Revisiting the Tamoxifen Scaffold for Therapeutics Against Amphetamine Abuse
Authors: Carpenter Colleen , Altshuler Rachel , Zestos Alexander , Sorenson Roderick , Kennedy Robert , Jutkiewicz Emily , Showalter Hollis , Gnegy Margaret
Published: November 2023

The abuse liability of amphetamine (AMPH) is largely due to its ability to act as a substrate at the dopamine transporter and significantly increase extracellular dopamine in the brain. Protein kinase C (PKC) activation contributes to this process and blocking PKC reduces AMPH activities. Tamoxifen remains the only available brain‐permeant PKC inhibitor and data from our lab show that tamoxifen reduces AMPH‐stimulated dopamine release from synaptosomal preparations. However, tamoxifen is also a selective estrogen receptor modulator and though effective against the recurrence of breast cancer, it also causes side effects such as hotflashes that affect patient compliance. Therefore, revisiting the tamoxifen scaffold may be an essential first step towards filling the current need for a therapeutic against AMPH abuse.

Our goal is to use information from previous structure‐activity relationship studies to create a new generation of tamoxifen analogs with increased selectivity for PKC inhibition and reduced affinity at the estrogen receptor. Here we evaluated the extent to which our lead compound, C091, reduced AMPH‐stimulated dopamine release and AMPH‐reinforcing effects in rats. We also investigated more thoroughly the effects of C091 at the dopamine transporter.

C091 inhibits PKC activity with an IC50 of 0.2 μM in our cellular assay and does not bind to estrogen receptor α at concentrations up to 1 μM. Suprafusion of rat striatal synaptosomes with concentrations from 0.3 μM to 3 μM C091 robustly and significantly reduces dopamine efflux stimulated by 10 μM AMPH. Similarly, direct administration of 1 μM C091 into the nucleus accumbens reduces both dopamine release and locomotion induced by 2 mg/kg i.p. AMPH by ~40% as measured during microdialysis in freely‐moving rats. Initial data show that administering 6 mg/kg s.c. C091 reduces i.v. AMPH self‐administration (0.032 mg/kg AMPH per infusion) by ~40% but does not affect food self‐administration in rats. 3 μM C091 significantly inhibits [3H]dopamine uptake in rat striatal synaptosomes. Yet, unlike classical dopamine transporter inhibitors, such as cocaine, C091 does not increase basal dopamine or locomotion in vivo, suggesting C091 will not have an abuse potential. Interestingly, C091 does not displace [3H]WIN 35428 binding at the dopamine transporter showing that it does not bind near the active site. This suggests that C091's effects on AMPH action could be due to allosteric modulation of the transporter and/or its interaction with a mediator of dopamine transporter functioning, such as PKC.

Support or Funding Information

NIH grant 1R01 DA11697, HHMI International Student Research Fellowship, Rackham Graduate Student Research Grant
Cocaine‐like Discriminative Stimulus Effects of Amphetamine, Cathinone, and Alpha‐Pyrrolidinovalerophenone Analogs in Male Rhesus Monkeys
Authors: Smith Douglas , Negus Steve , Blough Bruce , Banks Matthew
Published: November 2023

Synthetic cathinones, popularized as “bath salts,” are beta‐ketone amphetamine analogs and have emerged worldwide as a diverse class of abused compounds that are classified as either monoamine transporter inhibitors or monoamine transporter substrates. Chemical structure modifications have been shown to dramatically impact a drug's abuse liability. Preclinical drug discrimination procedures are useful for determining structure activity relationships (SAR) and the behavioral pharmacology of an abused drug's subjective‐like effects. However, the SAR of synthetic cathinones using a drug discrimination procedure in nonhuman primates is unknown. The first aim of the present study was to determine whether amphetamine vs. cathinone analogs were differentially sensitive to a 3,4‐methylenedioxy moiety. The second aim was to determine whether the monoamine transporter inhibitor alpha‐pyrrolidinovalerophenone (alpha‐PVP) and the monoamine transporter substrate methcathinone were differentially sensitive to 4‐methyl and 3,4‐methylenedioxy moieties. Male rhesus monkeys (n=4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two‐key food‐reinforced discrimination procedure. Potency and time course of cocaine‐like discriminative stimulus effects were determined for (±)‐amphetamine, (±)‐cathinone, (±)‐methamphetamine, (±)‐methcathinone, (±)‐alpha‐PVP, and their 3,4‐methylenedioxy analogs. Additionally, the behavioral effects of (±)‐4‐methylPVP and (±)‐4‐methylmethcathinone were determined to examine SAR differences between monoamine transporter inhibitors and substrates. Amphetamine, cathinone, methamphetamine, and methcathinone all produced dose‐dependent cocaine‐like effects. Despite similar potencies to produce cocaine‐like effects, cathinone and methcathinone displayed a shorter time course compared to their respective amphetamine derivatives. The addition of a 3,4‐methylenedioxy moiety attenuated the cocaine‐like discriminative stimulus effects of the monoamine transporter substrate cathinone to a greater extent than amphetamine and methamphetamine but not for methcathinone; however, the effects of methcathinone were reduced by the 4‐methyl moiety. The monoamine transporter inhibitor alpha‐PVP also substituted completely for cocaine, and neither the 3,4‐methylenedioxy nor the 4‐methyl moiety altered the potency or efficacy of alpha‐PVP to produce cocaine‐like effects. Overall, these results suggest that phenyl ring substitutions can differentially affect the pharmacology of amphetamine‐ and cathinone‐based monoamine releasers while exhibiting lesser effects on the pharmacology of structurally related monoamine uptake inhibitors.

Support or Funding Information

Funding for this study was supported by National Institutes of Health grants R01‐DA026946, R01‐DA012970, R01‐DA033930, and institutional professional funds.
Discriminative Stimulus Effects of Mephedrone, A Constituent of “Bath salts”
Authors: Fournett Alyssa Christine , Winsauer Peter
Published: November 2023

Mephedrone (4‐methylmethcathinone) is one of the major constituents of the recreational substances known as “bath salts”. It is a synthetic cathinone and psychostimulant that has been reported to cause auditory and visual hallucinations, as well as problematic cardiovascular effects. The purpose of this study was to compare the discriminative stimulus effects of mephedrone (0.32–10 mg/kg) alone with other prototypical drugs of abuse, such as cocaine (0.56–32 mg/kg), delta‐9‐tetrahydrocannabinol (THC, 0.56–10 mg/kg), ketamine (1.8–18 mg/kg), phencyclidine (PCP, 1–5.6 mg/kg), 2,5‐dimethoxy‐4‐iodoamphetamine (R‐DOI, 0.1‐1 mg/kg), heroin (1–10 mg/kg) and d‐amphetamine (0.18–3.2 mg/kg). The discriminative stimulus effects of mephedrone were also examined after the administration of rimcazole (0.32–10 mg/kg), a sigma receptor antagonist, and desipramine (1.8–18 mg/kg), a tricyclic antidepressant with relatively selective affinity for norepinephrine transporters (NET). Rats were trained to discriminate an intraperitoneal injection of mephedrone from saline under a fixed‐ratio 20 schedule of food presentation. The training dose of mephedrone (3.2 mg/kg) was reliably discriminated from saline by all subjects. Following training, substitution of varying doses of mephedrone produced dose‐dependent increases in mephedrone‐lever responding, with full substitution considered to be greater than 80% responding on this lever. Of the drugs tested, only cocaine and THC fully substituted for mephedrone. However, full substitution of THC occurred in only 2 of 9 animals and at a dose that substantially decreased response rate. Both THC and R‐DOI produced dose‐dependent rate‐decreasing effects (≥ 20% decrease in response rate compared to vehicle). In addition, although rimcazole and desipramine did not substitute for mephedrone, both drugs potentiated mephedrone's discriminative stimulus effects by producing leftward shifts of the dose‐effect curve for mephedrone‐lever responding. In summary, the discriminative stimulus effects of mephedrone most closely approximate those for the stimulant, cocaine, and these effects may be mediated, in part, by the sigma receptor and NET.
Blockade of striatal mu opioid receptors attenuates methamphetamine‐induced conditioned place preference
Authors: Logan Mary Caroline , Fisher Trevor J. , Logue Jordan B. , Horner Kristen Ashley
Published: November 2023

The behavioral effects of METH are mediated by the striatum, which is involved in habit learning and reward association. The striatum can be divided into the patch compartment, which mediates limbic and reward functions, and the matrix compartment, which mediates sensorimotor tasks. METH treatment results in repetitive behavior that is related to enhanced activation of the patch compartment relative to the matrix compartment. The patch compartment contains a high density of mu opioid receptors, while the matrix compartment expresses very few mu opioid receptors, and localized blockade of patch‐based mu opioid receptors prior to METH treatment attenuates enhanced activity of the patch compartment and reduces repetitive behavior. However, while numerous studies have examined patch‐enhanced activity and the contribution of patch‐associated mu opioid receptors to METH‐induced repetitive behavior, it is currently not known whether patch‐enhanced activity occurs during METH‐mediated reward, nor is it known if patch‐based mu opioid receptors contribute to METH reward. The goal of this study was to determine if blockade of patch‐based mu opioid receptors alters METH‐induced conditioned place preference (CPP). A biased conditioning paradigm was used to assess CPP, and conditioning occurred over an 8‐day period. Animals were bilaterally infused in the striatum with the mu‐specific antagonist CTAP (0.8 mg/ml) or vehicle prior to conditioning with METH (2 mg/kg) or saline. Animals were tested for preference 24h after the last day of conditioning, sacrificed and the brains processed for immunohistochemistry. Blockade of patch‐based mu opioid receptors reduced METH‐induced CPP, and reduced patch‐enhanced c‐Fos expression in the striatum following METH‐mediated CPP. These data indicate that patch‐enhanced activity is associated with METH‐mediated reward and patch‐based mu opioid receptors contribute to this phenomenon.

Support or Funding Information

DA025303 (KAH)
Alternating Access to a Highly Palatable Diet Alters Amphetamine Sensitivity and Self‐Administration
Authors: Moore Catherine F , Sabino Valentina , Cottone Pietro
Published: November 2023

Eating disorders and certain forms of obesity are associated with mesolimbic dopaminergic reward dysfunction. Overeating of diets rich in sugar and fat alter dopamine neurotransmission in the nucleus accumbens, likely contributing to the persistence of excessive intake. Amphetamine‐like drugs, which act in the mesolimbic pathway to enhance the release of dopamine, also confer long‐lasting neuroadaptations. However, it is not yet known if a history of disordered eating can alter sensitivity to these drugs. In this study, we investigated the effects of palatable food diet alternation on sensitivity to amphetamine (AMPH) and AMPH self‐administration. Ad libitum diet alternation occurred for 5 weeks prior to any testing. One group was provided a chow diet 7 days a week (‘Chow/Chow’), and a second group was provided chow 5 days a week followed by 2 days of access to a highly palatable, chocolate flavored, high‐sucrose diet (‘Chow/Palatable’). While continuing diet alternation, we measured locomotor activity following an AMPH challenge (0, 0.1, 0.5, 1.0 mg/kg) to test sensitivity during the 2 days of access to the palatable diet as well as when animals were withdrawn from palatable food. Following this within‐subject AMPH challenge schedule, animals were allowed to self‐administer AMPH in water (0.05 mg/ml) in the home cage. ‘Chow/Palatable’ rats exhibited excessive food intake when fed the palatable diet, and pronounced hypophagia when fed the chow diet. ‘Chow/Palatable’ rats also dramatically escalated the intake of the palatable diet during the first hour of renewed access, and during withdrawal, showed compulsive‐like eating as assessed in the light/dark conflict test. During access to palatable food, ‘Chow/Palatable’ rats showed decreased locomotor sensitivity to AMPH at the highest dose, but showed no differences from ‘Chow/Chow’ rats during palatable food withdrawal. When allowed to orally self‐administer AMPH in the home cage, ‘Chow/Palatable’ rats showed an increase in intake during palatable food access, with no differences from ‘Chow/Chow’ rats during withdrawal. These results show that palatable food diet alternation affects AMPH sensitivity and self‐administration, specifically during access to palatable food.

Support or Funding Information

Research was supported by grant numbers DA030425, MH091945, and MH093650 from NIH and NIMH, by the Peter Paul Career Development Professorship (PC), the McManus Charitable Trust (VS), and Boston University's Undergraduate Research Opportunities Program (UROP). CM is supported by the Burroughs Wellcome Fund through the Transformative Training Program in Addiction Sciences and the NIH/NIGMS Training in Biomolecular Pharmacology (GM008541‐17).
Anorexia Increases Sensitivity to Cocaine in Adolescent Rats: Implications for the Dopamine Transporter
Authors: Owens William Anthony , Daws Lynette C
Published: November 2023

Anorexia is a major public health concern, compounded by a lack of effective treatments. Anorexia is most common in females and often manifests during adolescence. The etiology of anorexia remains unclear, however, dysregulation of dopamine (DA) neurotransmission is a consistent finding. The DA transporter (DAT) terminates DA neurotransmission by high‐affinity uptake of DA into neurons and because of this, it is a primary regulator of both the strength and duration of DA signaling. This critical function, together with strong evidence supporting dysregulation of DA neurotransmission in eating disorders, suggests that DAT function may be aberrant in individuals with anorexia. Surprisingly, however, few studies have investigated the relationship between DAT activity and anorexia.

Here we use the activity based anorexia (ABA) model to interrogate the role of DAT in anorexia in male and female Sprague‐Dawley rats aged P30 or P90. The ABA model has many advantages over other models of eating disorders, primary among them is that rats must “choose” between eating and another rewarding condition, exercise. ABA also recapitulates key characteristics of anorexia including hyperactivity, reduced food intake and increased insulin sensitivity. To assay DAT function we assessed the dose‐dependency of the locomotor response to the DAT blocker, cocaine, and measured the kinetics of DA clearance in striatum using in vivo high‐speed chronoamperometry. Quantitative autoradiography was used to assess DAT expression.

We found that ABA rats were more sensitive to the locomotor stimulant effects of cocaine, as evidenced by a marked shift to the left in the ascending limb of the dose response curve, compared with control rats. Correspondingly, the descending limb of the dose response curve was also shifted to the left. These effects were most pronounced in adolescent female rats. Preliminary analyses show that DAT expression does not differ between adolescent and adult rats, but that DAT activity is greater in adolescent rats than in adults, and that DAT activity is increased further in ABA rats, relative to control rats. As expected, ABA rats lost the most weight and exercised more than control groups.

Together with our published studies showing that hyperinsulinemia increases DAT activity, these studies suggest that anorexia, particularly in the most prone clinical population, adolescent females, serves to ramp up DAT activity and increase sensitivity to cocaine. Combined, these studies support the idea that during adolescence, DAT function is especially sensitive to the amount of food consumed and exercise to which an individual engages. In turn, self‐imposed low food intake and increased exercise, may cause “cross sensitization” of response to drugs of abuse or to food addictions in later life. Our findings suggest that DAT may be a potential therapeutic target for the treatment of anorexia.

Support or Funding Information

Supported by DA038504 (LCD)
Chronic cocaine exposure alters D1 medium spiny neuron activity to promote relapse
Authors: Calipari Erin S , Bagot Rosemary C , Purushothaman Immanuel , Pirpinias Stephen , Davidson Thomas J , Deisseroth Karl , Nestler Eric J
Published: November 2023

Learned associations between environmental cues and experience are the basis of decision‐making and allow organisms to guide behavior towards advantageous outcomes. Dysfunction in the processes that regulate these associations, especially in the nucleus accumbens, is a critical factor in the underlying pathology of addiction. The nucleus accumbens is a heterogeneous region composed of both D1 and D2 medium spiny projection neurons (MSNs), and understanding the cell‐type specific signals that mediate learning processes has far reaching implications for treatment. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in the brain that encodes drug associations. Chronic cocaine exposure dysregulates the temporally specific D1 signals that encode contextual information to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Further, manipulating the D1 signal using designer receptors exclusively activated by designer drugs (DREADD), even after associations have been formed, can eliminate these associations indefinitely. Together, these data elucidate the underlying neural processes that control associative learning and how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse following abstinence. Further, these processes have been localized to a single cell population in the nucleus accumbens that can be manipulated to attenuate the strength of these associations and prevent relapse.

Support or Funding Information

This work was supported by grants from the National Institute on Drug Abuse and Brain & Behavior Research Foundation.
Nitric oxide ameliorates muscular dystrophy
Authors: Danialou Gawiyou
Published: November 2023

Introduction

Duchenne muscular dystrophy (DMD) is a lethal, X‐linked disorder associated with dystrophin deficiency that results in chronic inflammation, sarcolemma damage, and severe skeletal muscle degeneration. Effective drug therapy for reducing or delaying the skeletal muscle weakness and necrosis could be a great hope for individuals suffering from DMD. Here we hypothesized that the early treatment of mdx neonatal mice with L‐arginine could ameliorate muscular dystrophy.

Methods

Seven days old animals were treated IP daily with 800 mg/kg of L‐arginine (L‐arg) or saline (control group) for six weeks. The hind limb skeletal muscle, the Tibialis Anterior (TA) was investigated. The following parameters were evaluated: the force generated, muscle resistance to mechanical stress, the level of centronucleation, detection of utrophine by immonostaining and western blot, creatine kinase (CK) activity and, nitric oxide (NO) production.

Results

Our results show that: 1) TA weight and the percentage of centronucleation in L‐arg treated animals were significantly lower than in control animals despite the fact that body weights were not different; 2) L‐arg improved TA ability to resist injury caused by high‐stress contractions; 3) CK level was two time higher in control animals compared to L‐arg treated mice, however, this difference was not statistically significant; 4) NO production was significantly higher in L‐arg treated animals; 5) there was no evidence that the improvements observed in L‐arg treated mice were associated with utrophin upregulation.

Conclusion

Our data strengthen the usefulness of L‐Arginine as a powerful pharmacological tool in Duchenne muscular dystrophies. However, the improvements observed were not associated with utrophin upregulation.

Support or Funding Information

Muscular Dystrophy Association (MDA)Canadian Institutes of Health Research (CIHR)
Reduced Levels of Thyroid Receptor Interacting Protein 13 Prevents Recovery of Tubular Epithelial Cells following Renal Ischemia‐Reperfusion Injury
Authors: Pressly Jeffrey D. , Hama Taketsugu , Regner Kevin R. , Park Frank
Published: November 2023

Damage to renal tubular epithelial cells by genetic, environmental, or biological insults can initiate complex signaling mechanisms that promote kidney repair and functional recovery. Recently, there is accumulating evidence that chromatin damage and the subsequent signaling repair mechanisms in the kidney can play a pivotal role in the recovery of the injured tubular epithelial cells following a biological stress. In this study, we demonstrate that thyroid receptor interacting protein 13 (TRIP13) is a critical modulator of tubular epithelial cell repair following ischemia‐reperfusion injury (IRI), a common type of renal stress. Transcript profiling demonstrated Trip13 mRNA to be robustly increased by 7.4 ± 0.3 (P<0.001; n=3) and 4.3 ± 2.0 (P<0.01; n=3) fold during the initial 24 and 72 hour period, respectively, following IRI. To further understand the role of TRIP13 in recovery to renal stress, unilateral ischemia‐reperfusion injury (IRI) was performed on Trip13Gt/Gt hypomorphic mice. After 168 hours following the IRI procedure, the wild‐type Trip13+/+ mice kidneys exhibited a significantly lower (P<0.05) number of damaged outer medullary renal tubules (38.7 ± 8.0%; n=5) compared to the hypomorph Trip13Gt/Gt mouse kidneys (95.1 ± 1.4%; n=4). This effect was associated with a higher number of outer medullary collecting ducts as determined by AQP‐2 immunostaining in the WT (174 ± 16.7; n=5) than the hypomorph kidneys (69.0 ± 12.5; n=4). Histological analyses demonstrated significantly higher percentage of TUNEL‐positive cells, a marker of apoptosis, in the outer medulla by 2.4‐fold (P<0.05; n=3) in the Trip13Gt/Gt mouse kidneys compared to the wild‐type Trip13+/+ kidneys (n=6). This was also associated with significantly exaggerated levels of p53 and cleaved caspase‐7 by 45% and 170% (P<0.05), respectively, in Trip13Gt/Gt mouse kidneys compared to Trip13+/+ mouse kidneys (n=6). To evaluate whether inhibition of the p53 pathway could restore the tubular recovery following unilateral IRI, we performed a subsequent study in the presence of a p53 selective inhibitor, α‐pifithrin. Administration of α‐pifithrin in wild‐type Trip13+/+ compared to hypomorphic Trip13Gt/Gt kidneys resulted in a markedly reduced number of damaged outer medullary tubules (8.1 ± 0.6%; n=4 and 16.8 ± 1.1%; n=4, respectively) compared to their untreated control mouse kidneys (38.7 ± 8.0%; n=5 and 95.1 ± 1.4%; n=4, respectively). In all, this study suggests that insufficient TRIP13 levels increased the susceptibility of damaged renal tubular epithelial cells to progress towards cell death following ischemia‐reperfusion injury by exacerbating the p53 response pathway.

Support or Funding Information

This study was funded by NIH RO1‐DK90123, and UTHSC seed grant program.
Therapeutic Potential of AICAR in Attenuating Obesity‐Induced Metabolic, Liver and Kidney Disease
Authors: Borgeson Emma , Borgeson Ville Wallenius , Godson Catherine , Sharma Kumar
Published: November 2023

Study Objective

Obesity is a risk factor for organ inflammation, diabetes, and kidney disease. Here we evaluated the therapeutic potential of AICAR (an AMPK activator) in obesity‐induced metabolic, kidney and liver disease with High‐Fat‐Diet (HFD) in wild type and adiponectin‐deficient mice. We also correlate our findings to human pathophysiology, by examining human tissue responses to AICAR ex vivo in a proof of concept study.

Method

Male C57BL/6 or Adiponectin−/− mice were fed a standard (10% fat) or HFD (60% fat) diet for 12 wks. HFD induced obesity and CKD, as evident by increased albuminuria. Vehicle or AICAR (500 mg/g) was given intraperitoneal as interventional therapeutics 3 times weekly, between wk 5–12. Furthermore, omental adipose tissue biopsies were isolated from obese (BMI 35–50), non‐diabetic female bariatric surgery patients (n=4). The adipose explants were incubated ex vivo with vehicle or AICAR (1 mM) for 6 hours at 37 °C, after which leukocytes were characterized by flow cytometry.

Results

Interventional AICAR treatment protected against obesity‐induced kidney disease, liver steatosis and improved insulin sensitivity in mice. Adipose inflammation is a key driver of obesity‐induced pathophysiology. AICAR attenuated adipose inflammation, by shifting MΦ phenotype from pro‐inflammatory M1 (CD11c+) to anti‐inflammatory M2 (CD206+), while reducing the percentage of CD8+ T‐cells, which correlated with reduced TNF‐α production and increasing adipose pAMPK levels. Interestingly, AICAR reduced interstitial adipose fibrosis, but enhanced omental capsular fibrosis. AICAR‐mediated protection was adiponectin independent, as protection was observed in both obese wild‐type and adiponectin−/− mice. In omental adipose tissue explants isolated from obese patients, AICAR promoted a ‘pro‐inflammatory’ to ‘anti‐inflammatory’ MΦ phenotype switch, which correlated with a reduction in TNF‐α.

Conclusion

In conclusion, these data support a novel therapeutic paradigm for using AICAR to promote metabolic health and protect against obesity‐induced systemic pathophysiology, e.g. liver and kidney disease.

Support or Funding Information

Financial support was obtained from the National Institute of Health and Science Foundation Ireland, and EB is a recipient of grants from the Marie Curie International Outgoing fellowship (IOF‐GA‐2011‐301803) and the Swedish Research Council.
Chemerin/ChemR23 system plays crucial role upon vascular insulin signaling in db/db mice
Authors: Neves Karla Bianca , Lobato N. S. , Cat A Nguyen Dinh , Lopes R.A.M. , Hood K. Y. , Oliveira A. M. , Montezano A. C. , Touyz R. M. , Tostes R. C.
Published: November 2023

The adipokine chemerin and its receptor, chemokine‐like receptor 1 (ChemR23), influence major aspects of the metabolic syndrome, including adipogenesis and insulin sensitivity in adipocytes and skeletal muscle cells. Considering that chemerin impairs vascular reactivity and that amongst its many actions, insulin also influences vascular function, we postulate that chemerin impairs vascular insulin signaling via PI3K/Akt and that ChemR23 antagonism improves insulin signaling in diabetic mice. Lean (db/m) and obese and diabetic (db/db) mice were treated for 03 weeks by oral gavage with CCX 832 (ChemR23 antagonist). Mesenteric arteries, aorta and perivascular adipose tissue (PVAT) were isolated to perform functional and molecular experiments. Plasma levels of chemerin and body weight were increased in db/db mice compared to their counterpart controls db/m. However, db/db mice treated with ChemR23 antagonist (CCX 832) exhibited a slightly decrease in body weight. ChemR23 antagonism in db/db mice partially reversed decreased insulin‐induced vasodilatation (mesenteric resistance arteries; Emax: db/m: 60.75±4.09; db/db: 40.84±2.38; db/m + CCX832: 67.87±8.93; db/db + CCX832: 50.17±3.84). CCX 832 prevented the rise in glucose and insulin levels observed in db/db mice. In aorta, there was a decrease in PI3K, Akt and IRS1 phosphorylation as well as in GLUT4 protein expression in db/db mice. Treatment of animals with ChemR23 antagonist increased GLUT4 protein expression and IRS1 phosphorylation, with a trend to augmented PI3K and Akt phosphorylation. db/db mice exhibited increased vascular ROS generation, which was decrease by CCX 832. M2 macrophages markers mRNA expression (IL‐10 and CD206) in PVAT was decreased in db/db mice and treatment with ChemR23 antagonist prevented this effect. However, no changes were observed in M1 macrophages markers mRNA levels. CCX 832 also blunted the rise in MCP‐1 and TNF‐α gene expression in PVAT from db/db mice. CCX 832 increased plasma and PVAT adiponectin levels, which were reduced in db/db mice. In conclusion, ChemR23 antagonism by CCX 832 (1) decreases body weight of db/db mice; (2) partially restores vascular function in db/db mice; (3) improves insulin signaling in aorta from diabetic mice; (4) decreases the inflammatory profile of adipocytes from db/db mice; (5) decreases vascular oxidative stress in db/db mice. These findings indicate that chemerin/ChemR23 axis may contribute to inflammation, oxidative stress and decreased vascular insulin signaling in diabetes. Our study may contribute to a better understanding of the role of chemerin in vascular dysfunction in diabetes‐ and obesity‐associated diseases.

Support or Funding Information

FAPESP 2012/13144‐8; 2015/01630‐3.
Unpleasantness and Negative Emotions Related to Dyspnea on Exertion in Obese Women
Authors: Marines‐Price Rubria , Vipa Bernhardt , Bhammar Dharini , Stickford Jonathon , Bassett J. Todd , Roman Maria C , Babb Tony G
Published: November 2023

Introduction

Dyspnea on exertion (DOE) is a common complaint in otherwise healthy obese women, which may influence and prevent them from engaging in physical activity. DOE is composed of at least two dimensions: sensory (i.e., intensity) and affective (i.e., emotional response). We examined whether subjective ratings of breathlessness (RPB) during exercise were associated with unpleasantness and negative emotions, including depression, anxiety, frustration, anger, and fear.

Methods

Otherwise healthy, obese women underwent hydrostatic weighing and a 6 minute constant‐load cycle test at 60 W. RPB was recorded during the last minute of the cycling test as a measure of the sensory dimension of dyspnea. Visual analog scales were used to assess unpleasantness and negative emotions as a measure of the affective dimension of dyspnea immediately after the exercise.

Results

Seventy‐four women (34 ± 7 years, 36 ± 4 kg/m2, 46 ± 5 % body fat) participated. The strongest correlations were between RPB and unpleasantness (r = 0.61, p <0.001) and RPB and anxiety (r = 0.50, p < 0.001).

Conclusions

Unpleasantness and anxiety were associated with RPB, indicating that some obese women not only perceive a heightened sense of breathlessness intensity, but also experience negative emotions, specifically unpleasantness and anxiety, related to the breathlessness. Thus, it is important for healthcare providers to assess not only intensity ratings, but also the associated negative emotions, that may accompany DOE (i.e., affective dimension). Future research should focus on interventions that can help alleviate both sensory and affective symptoms of related to DOE.

Support or Funding Information

National Institutes of Health Grant HL096782, King Charitable Foundation Trust, Texas Health Presbyterian Hospital Dallas
Effect of Plant Sources of Omega‐3 PUFA on Mood Status in Healthy Subjects: A Cross Over Feeding Trial
Authors: Young Wajeeha Mazhar
Published: November 2023

Study Objective

The high prevalence of mood disturbance and inadequate efficacy of current antidepressants necessitates the search for more effective treatments. Omega‐3 PUFA may provide one such option. The aim of this paper is to test if changes in the ratio of dietary n6:n3 FA, and/or use of EPA/DHA algae supplement, is associated with changes in mood disturbance in healthy adults.

Methods

This was a tightly controlled, factorial design, randomized feeding trial (n=24) evaluating the effects of dietary intake of two n‐6:n‐3 PUFA ratios on mood states. The n‐6: n‐3 ratios of 10:1 and 2:1 in experimental diets were provided from plant sources. Subjects were randomized into 8‐week, cross‐over diet sequences where each subject consumed three of four dietary treatments: the two diets, with/without algae supplements. Subjects completed the Depression Anxiety Stress Scale (DASS) and the Profile of Mood States (POMS) questionnaires at the end of each 8‐week study period.

Results

Subject distress scores were within normal range throughout the duration of the study period. There was no statistically significant difference in DASS or POMS scores between the four diets. However there was a consistent tendency towards increased distress with the addition of algae supplement with summation of mood disturbance reaching significance. Change in dietary n‐6:n‐3 FA ratio did not play a role in mood disturbance. However, intake of EPA/DHA algae supplement resulted in increased overall mood disturbance as measured by DASS and POMS.

Conclusions

These findings suggest that EPA/DHA supplements may not be advisable for healthy adults.

Support or Funding Information

Funded by the Center for Health and Nutrition Research, University of California, Davis
Food Insecurity's Association with Gestational Weight Gain Varies by Pre‐pregnancy Weight and Parity
Authors: Metallinos‐Katsaras Elizabeth , Siu Elizabeth , Colchamiro Rachel
Published: November 2023

Food insecurity and excessive gestational weight gain (GWG) have both been associated with increased risk for obesity among women. This study examined the predictive value of household food security status (FSS), assessed prenatally, for gestational weight gain among low‐income women during their first and second pregnancies. Mothers enrolled in Massachusetts WIC (2001–2009) with two consecutive (linked) pregnancies were included. Only those with singleton, full term, live, adequate‐birth‐weight infants and with complete data on covariates and HH food security assessed at the first prenatal visit of the first (n=12,215) and second pregnancies (n=10,844) were included. The sample was diverse (55% nonwhite) with a mean age of 22.3 years (SD=5.0) and a mean gestational weight gain of 36.3 lbs (SD=15.1); 30.1% reported HH food insecurity at their first prenatal visit, with 7.7% reporting very low food security. Weight status prior to the first pregnancy was as follows: 6.7% underweight, 57.1% normal weight, 21.8% overweight, and 14.4% obese. General linear model regression examined the association between household FSS in early pregnancy and GWG (pounds) for each pregnancy, controlling for race/ethnicity, age, education, household size, timing of WIC entry, and acculturation. Additionally, inter‐pregnancy interval was included as a covariate for the second pregnancy's GWG. Analyses were stratified by pre‐pregnancy weight status because of a significant interaction between weight status and FSS (p<.05). First pregnancy's prenatal FSS, was associated with GWG among those who were overweight (BMI > 25 and < 30) but not among underweight, normal weight or obese mothers; overweight mothers with very low food security had higher GWG during their first pregnancy (adjusted mean=38.2 lbs.) than those who were food secure (34.1 lbs., p<.001) or had low food security (34.9 lbs., p < .01). Second pregnancy's prenatal FSS was associated with GWG among those who were obese (BMI>30); those who reported any food insecurity had a significantly higher weight gain than those who were food secure (29.8 vs. 28.2 pounds, p<.05). No association between second pregnancy's FSS and GWG was found among women who were underweight, normal weight or overweight prior to their second pregnancy. Food insecurity in early pregnancy is related to GWG differently, depending on pre‐pregnancy weight status and parity.

Support or Funding Information

Simmons College President's Fund
Initiation of Smell in Congenital Smell Loss
Authors: Henkin Robert I , Abdelmeguid Mona , Knoppel Alexandra B
Published: November 2023

There are about 500,000 patients in the United States with congenital loss of smell, patients born without any sense of smell. The largest group of these patients have no gross brain abnormalities as determined by brain imaging, no anatomical abnormalities of the peripheral olfactory system as determined by nasal endoscopy, no other known congenital defects and no family history of smell loss. Congenital biochemical abnormalities of their olfactory system comprise several biochemical changes from normals: inhibition of secretion of nasal growth factors cAMP, cGMP and sonic hedgehog (Shh) which normally stimulate stem cells in the olfactory epithelium to initiate growth of olfactory receptors and activation of “death factors” TNFα and TRAIL which pathologically inhibit growth of olfactory receptors. We treated 19 of these patients, aged 6–61 years, with the phosphodiesterase inhibitor theophylline, 200–800mg daily for 2–36 months with smell function and nasal mucus growth and “death” factors measured at intervals of 2–10 months. Results indicated that smell function was initiated in 12 of these patients (63%) and quantified by both subjective return of smell function and by olfactometry. Significant increases in nasal mucus cAMP, cGMP and Shh and inhibition of nasal mucus TNFα and TRAIL occurred with theophylline treatment in these patients. Initiation of smell function occurred after theophylline treatment for 2–18 months and persisted as long as therapy was continued. This is the first report of initiation of smell function in patients with congenital smell loss. This initiation was associated with correction of congenital biochemical abnormalities in their nasal mucus growth and “death” factors.

Support or Funding Information

None
A Randomized, Controlled, Parallel Study to Assess the Effects of Soy Protein on Body Composition and General Health Parameters in Healthy Children
Authors: Braun Michelle , Cook Chad , Mukherjea Ratna , Liska DeAnn
Published: November 2023

It is currently unknown whether a moderate increase in daily protein intake from lean, high quality sources will affect body composition in young growing children; however, research has demonstrated a role for higher protein diets supporting healthy body composition in adults. The aim of this randomized, controlled, parallel clinical study was to assess the effects of daily consumption of soy protein foods on body composition, general health status, sleep habits, mood, and dietary intake outcomes in generally healthy children.

Subjects were male and female children, 8–11 years of age, with a body mass index (BMI)‐for‐age within the 75th–95th percentile and habitual consumers of breakfast and snacks. Subjects were randomly assigned into one of two groups: 1) a Usual Protein (UP) group counseled to follow the 2010 Dietary Guidelines for Americans, in which 14% daily energy intake was from mixed protein sources, or 2) a Supplemental Protein (SP) group counseled similarly, but also provided lean protein sources to incorporate into their daily diet to reach 20% daily energy intake from protein. Both groups followed their assigned intervention for 12 weeks. The SP group incorporated study foods that were matched so each food item delivered 15 g of protein from soy. Multiple study product choices were provided, including vegetarian snack sticks, meal patties and 2 flavors of protein bars for inclusion at breakfast and a snack, leading to additional daily soy protein intake of 30g per day, as part of the counseled diet. Dual Energy X‐ray Absorptiometry (DXA) was used to determine changes in body composition from baseline to end of intervention.

Subjects were well matched for baseline anthropometric characteristics (BMI‐for‐age 86.8 ± 0.9 percentile), age (9.5 ± 0.2 y), and sex (24 males, 23 females), with no observed significant differences between the two groups (n=24 in UP, n=21 in SP). Results from 3‐day diet records revealed no differences in energy intake between groups, but the SP group had significantly higher protein intake at the end of the 12 week intervention (UP 69.5±5.3g, SP 93.7±3.2g, p<.001). Quality of life assessments revealed similar responses between groups. Both groups increased fat free mass from baseline, with no significant differences observed between groups.

This study demonstrates lean protein such as soy can be incorporated into a diet consistent with Dietary Guidelines to increase protein intake in children. Given that many groups are recommending increased energy from protein, this approach is an option to help aid in prevention or manage obesity.

Support or Funding Information

Funding provided by DuPont Nutrition & Health