Sham Control Research Articles

Effects of Apelin-13 on auditory system in STZ-induced diabetic rats

AimDamage to the auditory pathways is one of the complications of diabetes. The aim of this study was to investigate the potential therapeutic effects of apelin-13 in the auditory pathways of rats with experimentally induced diabetes by examining its effect on auditory brainstem responses, cochlear oxidative stress and inflammatory cytokines. MethodsThirty-two male Wistar albino rats were divided into four groups: sham control, diabetes, apelin and diabetes + apelin. A single dose of 45 mg/kg streptozotocin (STZ) was administered to induce diabetes. The apelin group received 50 µg/kg apelin-13 for seven days intraperitoneally (ip). At the end of the apelin and STZ applications auditory brainstem responses (ABR) was recorded. At the end of the experiment, cochlea was removed and biochemical analyzes were performed. ResultsIn ABR recordings, the latencies of wave V in diabetic group were observed to be longer than those of the control, with the apelin treatment exhibiting a partial reversal of this situation, particularly at specific frequencies and intensity levels. Apelin treatment leads to a significant increase in total antioxidant status (TAS) and a reduction in total oxidant status (TOS) and oxidative stress index (OSI) in cochlea compared to diabetic groups. The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 1-beta (IL-1 beta) in cochlear tissue were found to be significantly reduced in the apelin-treated group compared to the diabetic group. ConclusionApelin-13 may have a protective effect on the auditory system and may be proposed as a potential new therapeutic strategy for the management diabetic auditory impairment.

Endovascular Ablation of the Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction

Greater splanchnic nerve ablation may improve hemodynamics in patients with heart failure and preserved ejection fraction (HFpEF). To explore the feasibility and safety of endovascular right-sided splanchnic nerve ablation for volume management (SAVM). This was a phase 2, double-blind, 1:1, sham-controlled, multicenter, randomized clinical trial conducted at 14 centers in the US and 1 center in the Republic of Georgia. Patients with HFpEF, left ventricular ejection fraction of 40% or greater, and invasively measured peak exercise pulmonary capillary wedge pressure (PCWP) of 25 mm Hg or greater were included. Study data were analyzed from May 2023 to June 2024. SAVM vs sham control procedure. The primary efficacy end point was a reduction in legs-up and exercise PCWP at 1 month. The primary safety end point was serious device- or procedure-related adverse events at 1 month. Secondary efficacy end points included HF hospitalizations, changes in exercise function and health status through 12 months, and baseline to 1-month change in resting, legs-up, and 20-W exercise PCWP. A total of 90 patients (median [range] age, 71 [47-90] years; 58 female [64.4%]) were randomized at 15 centers (44 SAVM vs 46 sham). There were no differences in adverse events between groups. The primary efficacy end point did not differ between SAVM or sham (mean between-group difference in PCWP, -0.03 mm Hg; 95% CI, -2.5 to 2.5 mm Hg; P = .95). There were also no differences in the secondary efficacy end points. There was no difference in the primary safety end point between the treatment (6.8% [3 of 44]) and sham (2.2% [1 of 46]) groups (difference, 4.6%; 95% CI, -6.1% to 15.4%; P = .36). There was no difference in the incidence of orthostatic hypotension between the treatment (11.4% [5 of 44]) and sham (6.5% [3 of 46]) groups (difference, 4.9%; 95% CI, -9.2% to 18.8%; P = .48). Results show that SAVM was safe and technically feasible, but it did not reduce exercise PCWP at 1 month or improve clinical outcomes at 12 months in a broad population of patients with HFpEF. ClinicalTrials.gov Identifier: NCT04592445.

Discriminating fingerprints of chronic neuropathic pain following spinal cord injury using artificial neural networks and mass spectrometry analysis of female mice serum

Spinal cord injury (SCI) often leads to central neuropathic pain, a condition associated with significant morbidity and is challenging in terms of the clinical management. Despite extensive efforts, identifying effective biomarkers for neuropathic pain remains elusive. Here we propose a novel approach combining matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with artificial neural networks (ANNs) to discriminate between mass spectral profiles associated with chronic neuropathic pain induced by SCI in female mice. Functional evaluations revealed persistent chronic neuropathic pain following mild SCI as well as minor locomotor disruptions, confirming the value of collecting serum samples. Mass spectra analysis revealed distinct profiles between chronic SCI and sham controls. On applying ANNs, 100% success was achieved in distinguishing between the two groups through the intensities of m/z peaks. Additionally, the ANNs also successfully discriminated between chronic and acute SCI phases. When reflexive pain response data was integrated with mass spectra, there was no improvement in the classification. These findings offer insights into neuropathic pain pathophysiology and underscore the potential of MALDI-TOF MS coupled with ANNs as a diagnostic tool for chronic neuropathic pain, potentially guiding attempts to discover biomarkers and develop treatments.

Effect of manual acupressure (points SP6, SP10, ST36, and LI11) on the uremic pruritus and quality of life in hemodialysis patients: A parallel, randomized controlled trial

The present study was conducted to determine the effect of manual acupressure on uremic pruritus and quality of life (QoL) in patients undergoing hemodialysis. This randomized controlled trial was conducted with a pre-post design on 90 patients with hemodialysis in southern Iran. The patients were divided into three groups using block randomization: intervention, sham control, and passive control. The intervention group received acupressure on SP6, SP10, ST36, and LI11 points. In the sham group, pressure was exerted on sham points two Cuns away from the actual points, and the passive control group solely received routine treatment. The intervention was carried out three times a week for four weeks. The patient's QoL was evaluated before and after the intervention using the Itchy QoL scale, and the dimensions of itching were assessed before the intervention and two and five weeks after commencing the intervention using the 5-D Pruritus scale. The groups' QoL and itching parameters were the same before the intervention. The analysis of variance (ANOVA) showed significant differences among the groups in terms of QoL following intervention. This index improved significantly in the intervention group compared to the other groups (P<0.001, G1=107.20 (standard deviation [SD]=5.45)). Repeated measures ANOVA showed that acupressure significantly reduced the severity and duration of itching and the number of itching points in the intervention group. Acupressure can improve hemodialysis patients' QoL and itching sensations. Being a non-pharmaceutical, risk-free, and inexpensive method, this intervention could be recommended to be used for relieving uremic pruritus.

Effectiveness of Transcranial-Direct Current Stimulation in Individuals with Methamphetamine Use Disorder: A Systematic Review and Meta-Analysis

Context: Non-alcoholic substance abuse is a major public health concern worldwide, with methamphetamine being the second most widely used non-alcoholic substance globally, and Iran ranks fifth in methamphetamine addiction. To date, no approved pharmacological or non-pharmacological treatment by the Food and Drug Administration has been introduced for methamphetamine use disorder (MUD). Therefore, various treatment methods are currently utilized. One non-pharmacological approach that has gained attention is transcranial-direct current stimulation (tDCS), with various clinical evaluations focused on it. Objectives: The aim of this review is to assess the effectiveness of this method in improving symptoms in individuals with MUD. Methods: Databases were reviewed up to October 10, 2023, in both Persian and English languages, using PubMed, Scopus, Web of Science, Google Scholar, Science Direct, Scientific Information Database (SID), and Noormags. Keywords were MUD, tDCS, Addiction, Craving, and Cognitive Function. Studies were included based on Population, Intervention, Comparison (sham or active control), Outcomes (craving or cognition), and Study Design (randomized controlled trial). Studies were excluded if they involved brain mapping or neuroimaging. Meta-analysis was conducted based on Standardized Mean Difference (SMD) to compare tDCS to sham intervention (P ≤ 0.05, two-tailed). Random effects models were used for individual MUD data from studies that reported end-of-treatment craving data. The risk of bias was calculated using the Cochrane Risk-of-Bias Tool (RoB-2), and meta-analysis was conducted using Comprehensive Meta-Analysis Software. Results: A total of 870 studies were initially identified; twenty-three studies (mean age 30.13 ± 6.67) were identified that examined the effects of tDCS on MUD outcomes (e.g., craving, cognition). After removing heterogeneous studies, meta-analyses were performed for tDCS vs. sham control studies in the craving domain. We found that tDCS reduced craving, indicated by medium to large effect sizes (Hedges' g: -0.64; SMD -0.58, 95% CI -0.85 to -0.30; I² = 10.71%, Q value: 8.96). Results showed that complementary treatment with tDCS can be useful. The DLPFC (F3, F4) was the most commonly targeted brain region for stimulation or inhibition. However, the number of sessions and their duration varied significantly across studies. Conclusions: This systematic review and meta-analysis found that tDCS can reduce momentary and cue-induced cravings. However, the studies varied in quality and sample size and used different scales for assessing cravings and cognitive functions, leading to inconsistencies. The review highlighted the importance of targeting the DLPFC due to its role in executive functions and self-control, with right-sided stimulation showing greater effectiveness. Emotional dysregulation in MUD, such as anxiety and depression, was also noted, with tDCS showing limited support for emotion regulation. The review identified the need for larger RCTs, standardized measurement tools, and detailed participant information to improve the understanding and effectiveness of tDCS in treating MUD.

Nigella sativa oil on chronic constrictive injury (CCI) induced neuropathic pain of sciatic nerve in Wistar rats

Background: Various adverse effects have been reported with conventional treatments of neuropathic pain. Nigella sativa (N. sativa), a medicinal herb, has been shown to possess several beneficiary effects. Objective: To assess the effects of N. sativa oil on neuropathic pain and ATP sensitive potassium channel (KATP) in Wistar rats. Methods: This experimental study was conducted on 120 Wistar rats (200±50gm). On the basis of treatments, all rats were grouped into Group I [normal control (NC) normal saline (NS) 5 ml/kg]; Group II [sham control (SC) {sham surgery + NS}], Group III [CCI control (CCIC) {Chronic constriction injury to sciatic nerve (CCI) + NS}]; Group IV [N. sativa oil experimental (NSOexp) {CCI + N.sativa (400 mg/kg)}], Group V [Glibenclamide experimental (Gliexp) {CCI + N. sativa (400 mg/kg) + glibenclamide (15 mg/kg)}] groups. Both the NSO and NS were administered orally once daily for consecutive 21 days and single dose of glibenclamide was given intraperitoneally on the day of experiment, to the respective rats. Then on the basis of neuropathic pain evaluation tests, all the groups were subdivided into ‘a’ [for sciatic functional index (SFI) in walking track analysis], ‘b’ [for tail flick latency (TFL) in cold tail immersion test], ‘c’ [for paw withdrawal threshold (PWT) in von Frey test], and ‘d’ (for rection time in hot plate test). The statistical analysis was done by one way ANOVA followed by Bonferroni post hoc test. Results: In this study, significantly (pd”0.001) higher SFI, TFL, PWT and reaction time were found in NSO exp rats when compared to those of CCIC rats. In addition, there were significant (pd”0.001) differences in the above-mentioned variables between rats of NSO exp group and Gliexp group. Conclusion: From the present study it might be concluded that, N. sativa prevents worsening of neuropathic pain in Wistar rats by blocking KATP channel. J Bangladesh Soc Physiol 2023;18(1): 35-45

The Potential Renoprotective Effect of Fedratinib in Renal Ischemia Reperfusion Injury in Male Rat Model

Renal Ischemia Reperfusion Injury (RIRI) is a serious condition that arises following kidney transplantation or other circumstances that result in decreased blood supply to the kidneys, these conditions cause a harm to the renal tissue. Gaining insight into the fundamental mechanisms of RIRI, including inflammation, cell death pathways, is essential for the development of successful therapeutic approaches. Objective: This study aimed to assess the effects of Fedratinib, a JAK2 inhibitor, in reducing RIRI in a rat model. The study involved rats divided into four groups: Sham group, control group, vehicle group, and Fedratinib group. Rats underwent anaesthesia and midline incision to expose renal pedicles, with blood flow halted using microvascular clamps. The wound was stitched, and the animals were left for 90 minutes to allow reperfusion. Blood samples were collected from the heart apex to assess serum urea and creatinine, and renal slices were used for PCR to detect the jak2/stat3 pathway. The Elisa was used to evaluate TNF, IL-6, NF-κB, Bax, Bcl2, and HMGB levels. Results: IL-6 and TNF-α, and HMGB1 were identified to have a role in the development of RIRI, inhibition of JAK2/STAT3 pathway by Fedratinib significantly decrease their concentration and minimizing RIRI. Suppression of JAK2/STAT3 pathway led to a significant inhibition in NF-κB and apoptosis. Conclusion: Fedratinib has a potential preventive effect against RIRI through their activity as JAK2 inhibitor and inhibition of the following downstream inflammatory pathways.

Gut microbiota and their relationship with circulating adipokines in an acute hepatic encephalopathy mouse model induced by surgical bile duct ligation

Background and aimsVarious studies have shown the importance of the gut microbiota in human health. However, little is known about gut microbiome patterns and their effect on circulating adipo-myokine levels in hepatic encephalopathy (HE). We investigated the relationship between the gut microbiota and adipo-myokine levels using a mouse model of HE induced by surgical bile duct ligation (BDL). Methods and resultsWild-type C57BL/6J mice were subjected to sham surgery or BDL. Severe body weight loss, suppressed feed intake, and liver failure were observed in BDL mice compared with sham control mice. Additionally, changes in gut microbial communities and serum adipo-myokine levels were noted in BDL mice. In the BDL mouse gut, we identified 15 differentially abundant taxa including the phylum Verrucomicrobiota, the classes Actinomycetes and Verrucomicrobiae, the order Verrucomicrobiales, the families Akkermansiaceae, Bacteroidaceae, Rikenellaceae, and Oscillospiraceae, the genera Alistipes, Akkermansia, Muribaculum, and Phocaeicola, and the species Akkermansia muciniphila, Alistipes okayasuensis, and Muribaculum gordoncarteri by LEfSe analysis (LDA score≥4.0). Higher levels of certain adipo-myokines such as BDNF were detected in the serum of BDL mice. Spearman correlation analysis revealed that certain adipo-myokines (e.g., FSTL1) were positively correlated with the class Actinomycetes, the family Rikenellaceae, the genus Alistipes, and the species Alistipes okayasuensis. Interestingly, A. okayasuensis and M. gordoncarteri, recently isolated microbes, showed richness in the gut of BDL mice and demonstrated positive correlations with adipo-myokines such as FGF21. ConclusionsOverall, our results suggest that alteration of the gut microbiota in patients with HE may be closely correlated to the levels of adipo-myokines in the blood.

Molecular profiling of a rat model of vascular dementia: Evidences from proteomics, metabolomics and experimental validations

Decrease of cerebral blood flow is the primary cause of vascular dementia (VD), but its pathophysiological mechanisms are still not known. This study aims to profile the molecular changes of a rat model of VD induced by bilateral common carotid artery ligation. The Morris water maze and new object recognition tasks were used to test the cognitive function of rats. Hematoxylin and Eosin (HE) staining was used to detect pathological changes in the hippocampus. After confirming the model, proteomics was used to detect differentially expressed proteins in the hippocampus, and metabolomics was used to detect differential metabolites in rat serum. Thereafter, bioinformatics were used to integrate and analyze the potential molecular profile. The results showed that compared with the sham control group, the spatial and recognition memory of the rats were significantly reduced, and pathological changes were observed in the hippocampal CA1 region of the model group. Proteomic analysis suggested 206 differentially expressed proteins in the hippocampus of VD rats, with 117 proteins upregulated and 89 downregulated. Protein-protein interaction network analysis suggested that those differentially expressed proteins might play crucial roles in lipid metabolism, cell adhesion, intracellular transport, and signal transduction. Metabolomics analysis identified 103 differential metabolites, and comparison with the human metabolome database revealed 22 common metabolites, which predicted 265 potential targets. Afterwards, by intersecting the predicted results from metabolomics with the differentially expressed proteins from proteomics, we identified five potential targets, namely ACE, GABBR1, Rock1, Abcc1 and Mapk10. Furthermore, western blotting confirmed that compared with control group, hippocampal GABBR1 and Rock1 were enhanced in the model group. Together, this study showed the molecular profile of VD rats through a combination of proteomics, metabolomics, and experimental confirmation methods, offering crucial molecular targets for the diagnosis and treatment of VD.

Nandrolone Abuse Prior to Head Trauma Mitigates Endoplasmic Reticulum Stress, Mitochondrial Bioenergetic Deficits, and Markers of Neurodegeneration.

The abuse of synthetic steroids, such as nandrolone decanoate (ND), is often associated with violent behavior, increasing the risk of traumatic brain injury (TBI). After a TBI, proteins like APP, β-amyloid peptide-42 (Aβ42), and phosphorylated tau (pTau) accumulate and trigger endoplasmic reticulum (ER) stress associated with an unfolded protein response (UPR). The involvement of mitochondrial bioenergetics in this context remains unexplored. We interrogate whether the abuse of ND before TBI alters the responses of ER stress and mitochondrial bioenergetics in connection with neurodegeneration and memory processing in mice. Male CF1 adult mice were administered ND (15mg/kg) or vehicle (VEH) s.c. for 19days, coinciding with the peak day of aggressive behavior, and then underwent cortical controlled impact (CCI) or sham surgery. Spatial memory was assessed through the Morris water maze task (MWM) post-TBI. In synaptosome preparations, i) we challenged mitochondrial complexes (I, II, and V) in a respirometry assay, employing metabolic substrates, an uncoupler, and inhibitors; and ii) assessed molecular biomarkers through Western blot. TBI significantly increased APP, Aβ42, and pTauSer396 levels, along with ER-stress proteins, GRP78, ATF6, and CHOP, implying it primed apoptotic signaling. Concurrently, TBI reduced mitochondrial Ca2+ efflux in exchange with Na+, disturbed the formation/dissipation of membrane potential, increased H2O2 production, decreased biogenesis (PGC-1⍺ and TOM20), and ATP biosynthesis coupled with oxygen consumption. Unexpectedly, ND abuse before TBI attenuated the elevations in APP, Aβ42, and pTauSer396, accompanied by a decrease in GRP78, ATF6, and CHOP levels, and partial normalization of mitochondrial-related endpoints. A principal component analysis revealed a key hierarchical signature featuring mitochondrial Ca2+ efflux, CHOP, GRP78, TOM20, H2O2, and bioenergetic efficiency as a unique variable (PC1) able to explain the memory deficits caused by TBI, as well as the preservation of memory fitness induced by prior ND abuse.

A meta-analysis of the effects of transcranial direct current stimulation combined with cognitive training on working memory in healthy older adults.

Working memory (WM) loss, which can lead to a loss of independence, and declines in the quality of life of older adults, is becoming an increasingly prominent issue affecting the ageing population. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, is emerging as a potential alternative to pharmacological treatments that shows promise for enhancing WM capacity and May enhance the effects of cognitive training (CT) interventions. The purpose of this meta-analysis was to explore how different tDCS protocols in combination with CT enhanced WM in healthy older adults. Randomized controlled trials (RCTs) exploring the effects of tDCS combined with CT on WM in healthy older adults were retrieved from the Web of Science, PubMed, Embase, Scopus and the Cochrane Library databases. The search time period ranged from database inception to January 15, 2024. Methodological quality of the trials was assessed using the risk-of-bias criteria for RCTs from the Cochrane Collaboration Network, and RevMan 5.3 (Cochrane, London, United Kingdom) was used for the meta-analysis of the final literature outcomes. Six RCTs with a total of 323 participants were ultimately included. The results of the meta-analysis show that tDCS combined with CT statistically significantly improves WM performance compared to the control sham stimulation group in healthy older adults [standard mean difference (SMD) = 0.35, 95% CI: 0.11-0.59, I 2 = 0%, Z = 2.86, p = 0.004]. The first subgroup analysis indicated that, when the stimulus intensity was 2 mA, a statistically significant improvement in WM performance in healthy older adults was achieved (SMD = 0.39, 95% CI: 0.08-0.70, I 2 = 6%, Z = 2.46, p = 0.01). The second subgroup analysis showed that long-term intervention (≥ 10 sessions) with tDCS combined with CT statistically significantly improved WM compared to the control group in healthy older adults (SMD = 0.72, 95% CI: 0.22-1.21, I 2 = 0%, Z = 2.85, p = 0.004). tDCS combined with CT statistically significantly improves WM in healthy older adults. For the stimulus parameters, long-term interventions (≥ 10 sessions) with a stimulation intensity of 2 mA are the most effective.

Chronic stress and functional health in older adults with concerns about falling: a study protocol of a randomized controlled trial with multicomponent exercise intervention (FEARFALL)

BackgroundMaintenance of physical function, mobility, and independent living are important goals for older adults. However, concerns about falling (CaF) play a central role in the vicious cycle of CaF, inflammation, loss of muscle mass, and decreasing physical function ultimately resulting in negative health outcomes. CaF, like other states of chronic stress and anxiety, can be considered as enduring adverse stimuli affecting the stress systems and the inflammatory system. Therefore, the aim of this study is to investigate whether a reduction of CaF leads to a reduction of stress and therefore possibly reduces chronic low-grade inflammation. Understanding the role and directionality of the effects of inflammation on CaF increases our understanding of age-related loss of mobility and physical function.MethodsIn this study, community-dwelling older adults, aged 70 years and older, will be randomly assigned to either a 4-month, multi-component intervention with exercise training and cognitive-behavioral components or to a sham control group with light stretching exercises, cognitive training, and educational health lectures. For the operationalization of specific CaF, the Falls Efficacy Scale—International will be used. Stress and related psychological symptoms will be monitored using established self-reports and by measuring salivary cortisol. Concentrations of C-reactive protein, interleukin 6, interleukin 10, and tumor-necrosis-factor-alpha, as well as gene expression of selected inflammatory transcripts, will be used as surrogate parameters of the inflammatory status at baseline, after the 4-month intervention and 8-month follow-up.DiscussionThis study will be the first to test whether CaF are related with stress system activity or reactivity or with markers of inflammation in the context of a multi-component intervention with exercise training and cognitive-behavioral components addressing CaF. The reduction of specific CaF or general psychological symptoms should reverse alterations in stress systems, and / or slow down low-grade inflammation. Changes in activity, as well as psychological and biological pathways leading from CaF to muscle loss will be measured, to disentangle the individual contribution to sarcopenia, and to provide an additional pathway to break or slow-down the vicious cycle of CaF and sarcopenia.Trial registrationGerman Clinical Trials Register (DRKS): DRKS00029171. Registered 22 July 2022.

Protective effect of propolis in protecting against radiation-induced oxidative stress in the liver as a distant organ

Stresses caused by ionizing radiation can also damage tissues and organs through the circulatory system. In this study, we aimed to determine the radioprotective effect of propolis, a natural and powerful antioxidant product, against oxidative liver damage caused by cranial irradiation. Thirty-two male albino Sprague–Dawley rats, divided into four groups, were designed as sham group, irradiation (IR) group, propolis plus IR, control group of propolis. Biochemical parameters were measured in liver tissue of rats. While Total enzymatic superoxide scavenging activity (TSSA) and non-enzymatic superoxide scavenging activity (NSSA), glutathione peroxidase (GSH-Px) activities of all groups were statistically significantly higher than rats receiving only-irradiation, Glutathione-S-transferase (GST) activity in the IR group was significantly lower than in the sham control group and IR + propolis group. Superoxide dismutase (SOD) activity in the IR group was found to be significantly higher than both the sham control group and the propolis control group, but lower than the IR + propolis group. Malondialdehyde level and xanthine oxidase activity were higher in the IR group than in the other groups. Compared to the sham control group, in the group treated with propolis, a significant elevation in antioxidant parameters, specifically TSSA, NSSA, SOD, and GST activities, was noted, with corresponding increases of 32.3%, 23.2%, 47.6%, and 22.6%, respectively. Our findings show that propolis can be a radioprotective agent against ionized radiation damage by increasing antioxidant activity and reducing oxidant stress in liver tissue.

Oxytocin shortens spreading depolarization-induced periorbital allodynia

BackgroundMigraine is among the most prevalent and burdensome neurological disorders in the United States based on disability-adjusted life years. Cortical spreading depolarization (SD) is the most likely electrophysiological cause of migraine aura and may be linked to trigeminal nociception. We previously demonstrated, using a minimally invasive optogenetic approach of SD induction (opto-SD), that opto-SD triggers acute periorbital mechanical allodynia that is reversed by 5HT1B/1D receptor agonists, supporting SD-induced activation of migraine-relevant trigeminal pain pathways in mice. Recent data highlight hypothalamic neural circuits in migraine, and SD may activate hypothalamic neurons. Furthermore, neuroanatomical, electrophysiological, and behavioral data suggest a homeostatic analgesic function of hypothalamic neuropeptide hormone, oxytocin. We, therefore, examined the role of hypothalamic paraventricular nucleus (PVN) and oxytocinergic (OXT) signaling in opto-SD-induced trigeminal pain behavior.MethodsWe induced a single opto-SD in adult male and female Thy1-ChR2-YFP transgenic mice and quantified fos immunolabeling in the PVN and supraoptic nucleus (SON) compared with sham controls. Oxytocin expression was also measured in fos-positive neurons in the PVN. Periorbital mechanical allodynia was tested after treatment with selective OXT receptor antagonist L-368,899 (5 to 25 mg/kg i.p.) or vehicle at 1, 2, and 4 h after opto-SD or sham stimulation using von Frey monofilaments.ResultsOpto-SD significantly increased the number of fos immunoreactive cells in the PVN and SON as compared to sham stimulation (p < 0.001, p = 0.018, respectively). A subpopulation of fos-positive neurons also stained positive for oxytocin. Opto-SD evoked periorbital mechanical allodynia 1 h after SD (p = 0.001 vs. sham), which recovered quickly within 2 h (p = 0.638). OXT receptor antagonist L-368,899 dose-dependently prolonged SD-induced periorbital allodynia (p < 0.001). L-368,899 did not affect mechanical thresholds in the absence of opto-SD.ConclusionsThese data support an SD-induced activation of PVN neurons and a role for endogenous OXT in alleviating acute SD-induced trigeminal allodynia by shortening its duration.

Therapeutic Potential of Crocin and Nobiletin in a Mouse Model of Dry Eye Disease: Modulation of the Inflammatory Response and Protection of the Ocular Surface

Background: Dry eye disease (DED) is a multifactorial condition characterized by ocular surface inflammation, tear film instability, and corneal epithelial damage. Current treatments often provide temporary relief without addressing the underlying inflammatory mechanisms. Objectives: This study examined the therapeutic potential of crocin and nobiletin, two naturally derived compounds with well-known antioxidant and anti-inflammatory properties, in a mouse model of DED induced by lacrimal gland excision (ELG). Methods: Thirty female Balb/c mice were divided into five groups (n = 6 each): Control (sham surgery), untreated DED, nobiletin-treated DED (32.75 µM), crocin-treated DED (34 µM), and 1% betamethasone-treated DED. Treatments were administered three times daily for 28 days. Ocular tissues were evaluated using Hematoxylin and Eosin (H&amp;E) staining and fluorescein staining. Conjunctival inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α), were measured by enzyme-linked immunosorbent assay (ELISA). Results: Histological analysis showed that the crocin and nobiletin treatment groups exhibited reduced epithelial disruption, keratinization, and inflammatory cell infiltration compared to the untreated DED group. The ELISA assay revealed that both compounds efficiently inhibited the production of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β, which are key mediators of DED pathogenesis. Fluorescein staining further confirmed the protective impact of crocin and nobiletin on corneal epithelial integrity. Moreover, the anti-inflammatory and epithelial-preserving effects of these compounds were comparable to those of the corticosteroid betamethasone. Conclusions: Overall, these findings suggest that crocin and nobiletin have therapeutic potential for DED management by modulating inflammatory responses and enhancing ocular surface healing. These naturally derived compounds offer promising avenues for the development of safer and more effective treatments for this challenging condition. However, further investigations, including clinical trials, are essential to elucidate the underlying mechanisms of action and optimize therapeutic approaches.

PSIV-6 Blood biomarkers of oxidative stress in offspring from dams infected with bovine viral diarrhea virus during late-term gestation

Abstract The objective of this experiment was to examine the impact of dams infected with bovine viral diarrhea virus (BVDV) during late gestation on inflammatory blood biomarkers in their offspring. Fetal infection with BVDV before d 125 to 150 of gestation results in the birth of immunotolerant, persistently infected (PI) calves. Infection of BVDV during late gestation results in transient fetal infections (TI). It was hypothesized that offspring of dams transiently infected with BVDV on d 175 of gestation would have greater inflammatory blood biomarkers than control offspring. Unvaccinated, yearling Hereford heifers (n = 24), seronegative for antibodies to BVDV1 and BVDV2 were bred by artificial insemination with X chromosome-bearing sperm from an Angus sire. On d 175 of pregnancy, heifers were intranasally inoculated with either Dulbecco’s Modified Eagle Medium + 2% horse serum (sham control) or 4.0 log TCID50 noncytopathic type 2 BVDV to generate control and transient infected calves, respectively. All BVDV-inoculated dams seroconverted by d 14 post-inoculation and all sham-inoculated control dams remained seronegative. Twelve, seronegative control heifer calves were born to the control dams, and 11 seropositive (to type 2 BVDV) TI heifer calves were born to BVDV-inoculated dams. All offspring were raised on pasture until weaning. At weaning, all calves were transported to our feedlot research facility, housed in one group feedlot pen, and transitioned to a high-energy concentrate-based diet until reaching an approximate body weight (BW) of 600 kg. Upon arrival, all animals received a standard heifer growth implant containing 200 mg of testosterone propionate and 20 mg of estradiol benzoate, a modified live viral vaccine containing IBR-BRSV-PI3, and were dewormed. Jugular blood samples were obtained every 28 d until harvest (280 d on feed) and analyzed for biomarkers of inflammation. Data were analyzed as a randomized block design with the MIXED procedures of SAS. There was a treatment x time interaction (P &amp;lt; 0.05) for plasma ceruloplasmin and the oxidized form of glutathione. On d 0 and 28 of the feeding period, all biomarkers were similar across treatments. By d 56 of the feeding period, ceruloplasmin (P &amp;lt; 0.03) and the oxidized form of glutathione (P &amp;lt; 0.01), indicators of chronic inflammation, were increased in plasma samples from TI heifers compared with controls. These parameters remained greater in TI heifers compared with controls throughout the feeding period. There were no treatment or treatment x time interactions for plasma interferon (INF)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and haptoglobin. These data suggest that TI heifers may be experiencing a greater level of oxidative stress later in the finishing period. This research was supported by USDA-NIFA Grant #2019-67015-29866.

PSIV-15 Effect of transient fetal bovine viral diarrhea virus infection on postnatal growth, estimated dry matter digestibility, glucose concentrations, and carcass characteristics

Abstract Fetal infection of bovine viral diarrhea virus (BVDV) before d 125 to 150 of gestation results in the birth of immunotolerant, persistently infected (PI) calves. Infection of BVDV during late gestation results in transient fetal infections (TI). Unvaccinated, yearling Hereford heifers (n = 25), seronegative for antibodies to BVDV1 and BVDV2, were bred by artificial insemination with X chromosome-bearing sperm from an Angus sire to examine the impact of TI on postnatal growth, estimated dry matter digestibility, blood glucose concentrations, and carcass characteristics. On d 175 of pregnancy, heifers were intranasally inoculated with either DMEM + 2% horse serum (sham control) to generate control calves or 4.0 log TCID50 noncytopathic type2 BVDV to generate TI calves. All sham-inoculated control dams remained seronegative, and all BVDV-inoculated dams seroconverted by d 14 post-inoculation. Sham-inoculated control dams (n = 12) and BVDV-inoculated dams (n = 12) gave birth to live calves. All control offspring were seronegative, and all TI offspring were seropositive for antibodies to type 2 BVDV at birth. All offspring were raised on pasture until weaning. At weaning, all calves were transported to our feedlot research facility, housed in one group feedlot pen, and transitioned to a high-energy concentrate-based diet until reaching an approximate BW of 600 kg. Upon arrival at the feedlot, all animals received a standard heifer growth implant, a modified live viral vaccine containing IBR-BRSV-PI3 and were dewormed. Heifer BW and jugular blood samples were collected every 28 d. On d 84 of the feeding period, titanium dioxide was added to the diet of 12, age-paired, individually fed, heifers (3 control and 3 TI heifers; approximately 1 yr of age) for 28 d and used to estimate dry matter digestibility. After approximately 280 d on feed heifers were transported to a USDA-inspected abattoir and harvested. The TI heifers had lighter birth weights (P &amp;lt; 0.03) and final BW (P &amp;lt; 0.04) when compared with control heifers. Average daily gain was greater (P &amp;lt; 0.01) in control compared with TI heifers. Blood glucose concentrations were similar between control and TI heifers at all sampling time points. Dry matter intake of individually fed heifers was similar across treatments. TI heifers had a 2.2% lesser (P &amp;lt; 0.05) dry matter digestibility and lighter (P &amp;lt; 0.01) hot carcass weights compared with controls. These data suggest that TI fetal BVDV infection negatively impacts growth throughout the feeding period, possibly by impacting gastrointestinal tract function. This research was supported by USDA-NIFA Grant # 2019-67015-29866.

Assessment of cognitive-motor functions in adults with perceived neuropsychological problems using NIH toolbox after remote biofield energy treatment as non-pharmacological intervention: A randomized double-blind placebo controlled trial.

Non-pharmacological interventions include physical activity, biofield energy therapy, reiki, Tai chi, and therapeutic touch. However, no reports analyzed the effectiveness of biofield therapy on cognition and motor function performance in adult subjects. The study aimed to investigate the impact of remote biofield energy healing therapy on cognition and motor functioning in adults with self-perceived neuropsychological impairments. This was a randomized double-blind clinical trial that involved 114 participants with self-perceived neuropsychological impairments. The participants were divided into three groups (control, sham control, and biofield intervention). Cognitive and motor function scores were assessed using the NIH Toolbox at baseline (day 0), day 90, and day 180. The biofield treatment group showed significant improvements in language function (p < 0.0001), working memory (p < 0.0001), and episodic memory (p < 0.0001) scores. Other cognitive functions also improved, although not statistically significant. The biofield intervention group also demonstrated significant enhancements (p < 0.05 to p < 0.0001) in locomotion, standing balance, dexterity, grip strength, and muscle endurance. No adverse effects were reported. The results suggest that remote biofield energy therapy is a safe, noninvasive intervention that improves cognitive and motor functions in adults. Further research is needed to understand its clinical benefits.

Investigation of effect peripheral kisspeptin treatment on hypothalamo-pituitary-gonadal axis and hypothalamo-pituitary-adrenal axis in male rats.

Kisspeptin is an endogenous peptide hormone that is the most potent stimulator of the hypothalamo-pituitary-gonadal (HPG) axis. The HPG axis can be suppressed by the activation of the hypothalamo-pituitary-adrenal (HPA) axis. The physiological role of kisspeptin in the interaction of the HPG axis and the HPA axis is not fully understood yet. The purpose of the current study was to investigate the possible effects of peripheral injection (intraperitoneally) of kisspeptin on HPG axis and HPA axis activity as well. Adult male Wistar rats were randomly divided into seven groups as sham (control), kisspeptin(10nmol), p234 (10nmol), kisspeptin + p234, kisspeptin + antalarmin (10mg/kg), kisspeptin + astressin2b (100μg/kg), and kisspeptin + atosiban (0.250mg/kg) (n = 10 each group). At the end of the experiment, the hypothalamus, pituitary gland, and serum samples of the rats were collected. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin and kisspeptin + astressin2b groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin, kisspeptin + antalarmin, kisspeptin + astressin2b, and kisspeptin + atosiban groups that compared to the control group. There was no a significant difference in corticotropic releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone and corticosterone concentrations among all groups. Moreover, no significant difference was found in the concentration of pituitary oxytocin. Our results suggest that peripheral kisspeptin injection induces an activation in the HPG axis, but not in the HPA axis in male rats.

Muscle Atrophy and mRNA-miRNA Network Analysis of Vascular Endothelial Growth Factor (VEGF) in a Mouse Model of Denervation-Induced Disuse.

Skeletal muscle atrophy is frequently caused by the disuse of muscles.It impacts quality of life, especially in aging populations and those with chronic diseases. Understanding the molecular mechanisms underlying muscle atrophy is crucial for developing effective therapies. To investigate the roles of vascular endothelial growth factor (VEGF) and various microRNAs (miRNAs) in muscle atrophy using a mouse model of denervation (DEN)-induced disuse, and to elucidate their interactions and regulatory functions through comprehensive network analysis. The right sciatic nerve of C57BL/6J mice (n=6) was excised to simulate DEN, with the left serving as a sham surgery control (Sham). Following a two-week period, wet muscle weight was measured. Total RNA was extracted from the tibialis anterior muscle for microarray analysis. Significant expression changes were analyzed via Kyoto Encyclopedia of Genes and Genomes (KEGG)pathway analysis and miRNet for miRNAs. Denervated limbs showed a significant reduction in muscle weight. Over 1,000 genes displayed increased expression, while 527 showed reductions to less than half of control levels. VEGF, along with specific miRNAs such as miR-106a-5p, miR-mir20a-5p, mir93-5p and mir17-5p, occupied central regulatory nodes within the gene network. Functional analysis revealed that these molecules are involved in key biological processes including regulation of cell migration, vasculature development, and regulation of endothelial cell proliferation. The increased miRNAswere subjected to further network analysis that revealed significant regulatory interactions with target mRNAs. VEGF and miRNAs play crucial roles in the progression of skeletal muscle atrophy, offering potential targets for therapeutic interventions aimed at reducing atrophy and enhancing muscle regeneration.