Administration Of Vehicle Research Articles

Development and Implementation of “E-Commerce Restaurant Management Web Application”

Online Food Conveyance Framework is a frame which will help café with enhanced and controlling over their beaneries The web- grounded food vehicle frame set up menu on the web and the guests effectively puts in the request with a straightforward mouse click.. For the waiters, it's making life simpler on the grounds that they do not need to effectively go kitchen and give the orders to cook. For the administration perspective, the chief will ready to control the café by having every one of the reports to hand and ready to see the records of every workers and orders. This point assists the beaneries with doing all functionalities all the more precisely and improves the spend of the multitude of errands. Online Food Conveyance Framework decreases homemade workshop and farther develops productivity of café. Likewise with a food menu online you can really follow the orders, keep up with customer's data set and further develop your food vehicle administration. This frame permits the customer to choose the ideal food effects from the showed menu. The customer arranges the food effects. The investiture can be made on the web or pay- on- vehicle frame. The customer's craft are kept up with private since it keeps a different record for every customer. An id and secret expression is accommodated every customer. In this manner, it gives a more gotten requesting. The Café The directors point give convert to the customer. The café the directors frame is there to help correspondence between all groups inside an café by limiting the liability of mortal boob and getting a more complete and feasible data. This Framework set up menu on the web and the guests effectively submits the request with a straightforward mouse click. By exercising the food menu online anybody can without important of a stretch track the orders, keep up with customer's information base and further develop food vehicle administration.

Effect of soy protein isolate supplementation on the estradiol biosynthesis pathway in a female rat model

Background Soy protein isolate (SPI) has gained popularity as an alternative to animal proteins. Soy consumption may have a link to rising serum estrogen in humans. This concern is attributed to phytoestrogens, specifically isoflavones present in soy protein, acting as estrogen substitutes and modulators. Objective The objective of this research was to assess the influence of SPI supplementation on estradiol hormone levels and the expression of genes associated with estrogen synthesis in female rats. Materials and methods Female Wistar rats (n=18) were evenly divided into three groups: group 1 (normal control) received oral administration of a saline vehicle. Group 2 (low dose) received 450 mg/kg body weight of SPI for 30 days. Group 3 (high dose) received 900 mg/kg body weight of SPI for 30 days. All administrations were conducted intragastrically. Results and conclusion The results of our study indicate that there was a significant increase in the levels of estradiol hormone in groups receiving low and high doses of SPI when compared with the control group. There was an upregulation in the messenger ribonucleic acid expression of the Cyp19 gene in low-dose and high-dose groups. Moreover, the low-dose group showed upregulation in the expression of the HSD3B gene. These genes are involved in the biosynthesis pathway of estrogen hormone in females. Therefore, the use of SPI should be cautious because it contains phytoestrogens (isoflavones), which have structural similarities to endogenous female estrogen and may cause hormonal disturbance in females.

Cicer arietinum phytosome ameliorates hepatosteatosis via downregulation of fatty acid synthase and stearoyl-CoA desaturase 1 in rats

BackgroundHepatosteatosis is considered a universal problematic health due to bad lifestyle. Thereby, the current study evaluates the influence of the Cicer arietinum polyunsaturated fatty acids (CAP) and newly synthesized C. arietinum polyunsaturated fatty acids phytosome (CAPP) against non-alcoholic fatty liver disease (NAFLD) persuaded through a high-fat diet (HFD) in addition to tamoxifen (TAM) in male albino rats. Forty-eight rats were separated into eight groups (6 rats/group). Rats of the control group were administered distilled water for 45 consecutive days, while phosphatidyl choline (PC), CAP, and CAPP groups administered distilled water (15 days), afterward administered PC, CAP, and CAPP, respectively (500 mg/kg b.wt), orally for 30 days. All the previous groups fed normal diet for the 45 days, while NAFLD rats feed HFD for 45 days and receive TAM (200 mg/kg b.wt, i.p) daily for 15 days, followed by administration of vehicle, PC, CAP, and CAPP orally for another 30 days.ResultsHepatosteatosis was appraised biochemically by significant increase in the concentrations of serum AST, ALT, γGT, LDH, ALP, total bilirubin, total lipid, triglycerides, fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD-1), and LDL-cholesterol, as well as hepatic total lipids and triglycerides. In addition, a significant decline in serum total protein, albumin, and HDL-cholesterol concentrations was observed in comparison with the control group. NAFLD induces oxidative stress by noteworthy increase in hepatic MDA, H2O2, and meaningful reduction in hepatic GSH, SOD, GST, GRD, and CAT levels as compared with the corresponding control group. Liver histological changes were noted in the NAFLD group as compared to the control. Interestingly, CAP and CAPP treatments modulate the abnormal effects of NAFLD in all the previous parameters. For the histological changes caused by NAFLD, the liver tissue appeared nearly normal after the treatment with CAP and CAPP.ConclusionCAP and CAPP administration may have a potential role in alleviating hepatosteatosis. This may relate to its downregulation against FAS, SCD-1, and oxidative stress.

The Effect of Pexidartinib on Neuropathic Pain via Influences on Microglia and Neuroinflammation in Mice.

Chronic pain is a debilitating medical condition that lacks effective treatments. Increasing evidence suggests that microglia and neuroinflammation underlie pain pathophysiology, which therefore supports a potential strategy for developing pain therapeutics. Here, our study is testing the hypothesis that the promise of pain amelioration can be achieved using the small-molecule pexidartinib (PLX-3397), a previously food and drug administration (FDA)-approved cancer medicine and a colony-stimulating factor-1 receptor (CSF-1R) inhibitor that display microglia-depleting properties. We used the previously reported chronic constriction injury (CCI) mouse model, in which PLX-3397 or vehicle was orally administrated to mice daily for 21 days, then applied to the CCI model, followed by PLX-3397 or vehicle administration for an additional 28 days. Additionally, we examined microglia-related neuroinflammation markers using positron emission tomography (PET) neuroimaging and immunofluorescence (IF). We showed that PLX-3397 significantly ameliorated pain-related behavioral changes throughout the entire experimental period after CCI (vehicle versus PLX-3397 at day 14, effect size: 2.57, P = .002). Microglia changes were first analyzed by live-animal PET neuroimaging, revealing PLX-3397-associated reduction of microglia by probing receptor-interacting serine/threonine-protein kinase 1 (RIPK1), a protein primarily expressed in microglia, which were further corroborated by postmortem immunohistochemistry (IHC) analysis using antibodies for microglia, including ionized Ca2+ binding adaptor molecule 1 (Iba-1) (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size 3.6, P = .011) and RIPK1 (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size 2.9, P = .023. The expression of both markers decreased in the PLX-3397 group. Furthermore, we found that PLX-3397 led to significant reductions in various proteins, including inducible nitric oxide synthase (iNOS) (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size: 2.3, P = .048), involved in neuroinflammation through IHC. Collectively, our study showed PLX-3397-related efficacy in ameliorating pain linked to the reduction of microglia and neuroinflammation in mice. Furthermore, our research provided new proof-of-concept data supporting the promise of testing PLX-3397 as an analgesic.

Long-term administration of atorvastatin had no effect on the occurrence and progression of spontaneous hypertensive intracerebral hemorrhage in mice

Abstract Background Intracerebral hemorrhage (ICH) is a catastrophic disease with limited treatment options. Statins and low low-density lipoprotein cholesterol (LDL-C) levels have been reported to be associated with increased risk of ICH. Safety concerns of statins were raised as statins become the cornerstone of anti-atherosclerosis therapy. To date, the effect of statins on the incidence of ICH still remains a controversial topic. Purpose The aim of this study was to investigate the effect of atorvastatin on the occurrence and progression of hypertensive ICH in mice. Methods Male wild-type C57BL/6J mice, 13 months old, were randomly divided into atorvastatin (Ato, n=20) group and vehicle (Veh, n=20) group. The atorvastatin group and vehicle group were given atorvastatin (20 mg/kg) and same volume of 0.5% sodium carboxymethylcellulose by oral gavage for 8 weeks, separately. Angiotensin II (Ang II) and L-NAME were then used to induce hypertensive ICH. The time of stroke symptom onset was documented. Hemorrhage volumes were measured by spectrophotometric hemoglobin assay. Results After 8 weeks of atorvastatin or vehicle administration, serum LDL-C levels were significantly lower in the mice treated with atorvastatin than vehicle controls (0.705 vs. 1.008 mmol/L, P<0.001). The administration of atorvastatin did not show significant effects on the systolic blood pressure (SBP) levels when compared with the vehicle group (164 vs. 166 mmHg, P=0.497) after the induction of Ang II and L-NAME. Hemorrhage was observed in brain morphology, and was further verified by hematoxylin and eosin staining or MRI scans in mice that showed signs of stroke. During the 28-day experimental period, 75% (15/20) of mice in the atorvastatin group developed signs of ICH, and 70% (14/20) of mice in the vehicle group developed in the similar time window. The incidence of hypertensive ICH had no significant difference between atorvastatin and vehicle groups (Log-rank P=0.761). Hemorrhage volumes were also comparable between the two groups (1.462 vs. 1.392 uL, P=0.788). Conclusion Reducing serum LDL-C levels by long-term administration of atorvastatin had no effect on the occurrence and progression of spontaneous hypertensive ICH in middle-aged mice.

Milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 (MOP3) attenuates inflammation and improves survival in hepatic ischemia/reperfusion injury

IntroductionHepatic ischemia/reperfusion injury is a severe clinical condition leading to high mortality as the result of excessive inflammation, partially triggered by released damage-associated molecular patterns. Extracellular cold-inducible RNA-binding protein is a new damage-associated molecular pattern. Current clinical management of hepatic ischemia/reperfusion injury is limited to supportive therapy, necessitating the development of novel and effective treatment strategies. Milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 is a newly invented oligopeptide originating from milk fat globule-epidermal growth factor-VIII. This peptide acts as an opsonic compound that specifically binds to extracellular cold-inducible RNA-binding protein to facilitate its clearance by phagocytes, thereby attenuating inflammation. In this study, we hypothesized that milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 attenuated hepatic ischemia/reperfusion injury by inhibiting extracellular cold-inducible RNA-binding protein–induced inflammation in Kupffer cells. MethodsWe treated Kupffer cells isolated from male C57BL/6 mice with extracellular cold-inducible RNA-binding protein and various doses of milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 for 4 hours, then measured cytokines in the culture supernatants. In addition, mice underwent 70% hepatic ischemia for 60 minutes immediately followed by the intravenous administration of either vehicle or milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3. Blood and ischemic liver tissues were collected 24 hours later, and inflammatory markers including cytokines, liver enzymes, chemokines, myeloperoxidase activity, and Z-DNA-binding protein 1 were measured. Hepatic tissue damage and cell death were evaluated histologically. Survival rates were monitored for 10 days posthepatic ischemia/reperfusion. ResultsThe release of interleukin-6 and tumor necrosis factor-α from extracellular cold-inducible RNA-binding protein–challenged Kupffer cells was significantly reduced by milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 in a dose-dependent manner. In hepatic ischemia/reperfusion mice, milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 treatment significantly decreased serum levels of extracellular cold-inducible RNA-binding protein, interleukin-6, tumor necrosis factor-α, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase. Milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 treatment also significantly reduced mRNA levels of interleukin-6, tumor necrosis factor-α, interleukin-1β, Z-DNA-binding protein 1, and chemokine macrophage inflammatory protein-2, as well as myeloperoxidase activity in hepatic tissues. Histologic evaluation demonstrated that treatment with milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 significantly attenuated tissue damage and cell death in the liver of hepatic ischemia/reperfusion mice. Milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 treatment significantly improved the survival rate of hepatic ischemia/reperfusion mice. ConclusionMilk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 significantly attenuated inflammation and liver tissue damage and improved survival after hepatic ischemia/reperfusion. Thus, milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 holds promise as a potential future therapeutic strategy for hepatic ischemia/reperfusion injury.

Healing sequelae following tooth extraction and dental implant placement in an aged, ovariectomy model.

At present, a lack of consensus exists regarding the clinical impact of osteoporosis on alveolar bone metabolism during implant osseointegration. While limited preclinical and clinical evidence demonstrates a negative influence of osteoporosis on dental extraction socket healing, no preclinical studies offer data on the results of implant placement in 6-mo-old, ovariectomized (OVX) Sprague-Dawley rats. This study aimed to investigate the outcomes of dental tooth extraction socket healing and implant placement in a rodent model of osteoporosis following daily vehicle (VEH) or abaloparatide (ABL) administration. Micro-CT and histologic analysis demonstrated signs of delayed wound healing, consistent with alveolar osteitis in extraction sockets following 42d of healing in both the VEH and ABL groups. In a semiquantitative histological analysis, the OVX-ABL group demonstrated a tendency for improved socket regeneration with a 3-fold greater rate for moderate socket healing when compared to the OVX-VEH group (43% vs 14%), however, this finding was not statistically significant (p=.11). No significant differences were observed between vehicle and test groups in terms of implant outcomes (BMD and bone volume/total volume) at 14- and 21-d post-implant placement. Abaloparatide (ABL) significantly increased BMD of the femoral shaft and intact maxillary alveolar bone sites in OVX animals, demonstrating the therapeutic potential for oral hard tissue regeneration. The present model involving estrogen-deficiency-induced bone loss demonstrated an impaired healing response to dental extraction and implant installation.

High fat, high sucrose diet promotes increased expression of ACE2 receptor in the SIV-infected host: implications for SARS-CoV-2 infection.

People with pre-existing conditions, including metabolic comorbidities, are at greater risk for complications of SARS-CoV-2 infection and expression of machinery required for viral entry into host cells may be a contributing factor. This study tested the hypothesis that high fat, high sucrose diet (HFSD) and alcohol use increase expression of angiotensin converting enzyme 2 (ACE2) receptor and transmembrane serine protease 2 (TMPRSS2) in tissues isolated from simian immunodeficiency virus (SIV) infected macaques, the most clinically relevant model for the study of HIV. Biospecimens obtained from a longitudinal study of SIV-infected, antiretroviral therapy (ART)-treated female rhesus macaques (Macaca mulatta) were used to determine whether HFSD and chronic binge alcohol (CBA) increased ACE2 and TMPRSS2 protein and gene expression. Macaques (n = 10) were assigned to HFSD or standard diet (SD) for 3 months before CBA or vehicle administration. Three months later, macaques were infected with SIV; ART was initiated 2.5 months thereafter. Tissue samples including lung, pancreas, and kidney were collected at study endpoint (12 months post-SIV infection). Protein expression of ACE2 in the lung, whole pancreas, and pancreatic islets was significantly greater in HFSD- than SD-fed macaques with no significant differences in protein expression of TMPRSS2 or mRNA expression of ACE2 or TMPRSS2. CBA did not significantly alter any measures. The increased ACE2 receptor expression observed in lung and pancreas of SIV-infected HFSD-fed female rhesus macaques aligns with reports that diet may increase susceptibility to COVID-19. These data provide direct evidence for a link between dietary quality and cellular adaptations that may increase the risk for SARS-CoV-2 infection.

Acute nicotine exposure attenuates neurological deficits, ischemic injury and brain inflammatory responses and restores hippocampal long-term potentiation in ischemic stroke followed by lipopolysaccharide-induced sepsis-like state

Ischemic stroke is followed by an increased susceptibility to bacterial infections, which exacerbate histological stroke outcome, neurological deficits and memory impairment due to increased neuroinflammation and neurotransmitter dysfunction. Pharmacological activation of nicotinic acetylcholine receptors was suggested to mitigate brain inflammatory responses in ischemic stroke. The functional responses associated with nicotinic acetylcholine receptor activation were unknown. In this study, male NMRI mice subjected to transient intraluminal middle cerebral artery occlusion (MCAO) were intraperitoneally exposed to vehicle treatment or Escherichia coli lipopolysaccharide (LPS; 4 mg/kg)-induced sepsis-like state 24 h post-MCAO, followed by intraperitoneal administration of vehicle or nicotine (0.5 mg/kg) 30 min later. Over 96 h, rectal temperature, neurological deficits, spontaneous locomotor activity, working memory, ischemic injury, synaptic plasticity, and brain inflammatory responses were evaluated by temperature measurement, behavioral analysis, infarct volumetry, electrophysiological recordings, and polymerase-chain reaction analysis. LPS-induced sepsis induced hypothermia, increased general and focal neurological deficits, reduced spontaneous exploration behavior, reduced working memory, and increased infarct volume post-MCAO. Additional treatment with nicotine attenuated LPS-induced hypothermia, reduced neurological deficits, restored exploration behavior, restored working memory, and reduced infarct volume. Local field potential recordings revealed that LPS-induced sepsis decreased long-term potentiation (LTP) in the dentate gyrus post-MCAO, whereas concomitant nicotine exposure restored LTP in the contralateral dentate gyrus. LPS-induced sepsis increased microglial/ macrophage Iba-1 mRNA and astrocytic GFAP mRNA levels post-MCAO, whereas add-on nicotine treatment reduced astrocytic GFAP mRNA. Taken together, these findings indicate that acute nicotine exposure enhances functional stroke recovery. Future studies will have to evaluate the effects of (1) chronic nicotine exposure, a clinically relevant vascular risk factor, and (2) the cessation of nicotine exposure, which is widely recommended post-stroke, but might have detrimental effects in the early stroke recovery phase.

In Utero and Lactational Exposure to an Environmentally Relevant Mixture of Phthalates Alters Hypothalamic Gene Expression and Sexual Preference in Rats.

Several phthalates, mainly used as plasticizers, are known for their adverse effects on the male genital system. Previously, we demonstrated that an environmentally relevant mixture of six antiandrogenic phthalates (PMix), derived from a biomonitoring study in pregnant Brazilian women, was able to disrupt the reproductive development in male rats. Experimental groups (control, 0.1, 0.5, and 500 mg PMix/kg/day) were established starting from the extrapolated human dose (0.1 mg/kg/day), followed by doses 5 times and 5000 times higher. Pregnant rats received daily oral gavage administration of either vehicle (control) or PMix from gestational day 13 to postnatal day 10. Here, we examined male and female offspring regarding changes in gene expression of key reproductive factors in the hypothalamus and pituitary gland at adulthood and conducted a battery of behavioral tests in males, including partner preference, sexual behavior, and male attractiveness tests. PMix induced some changes in mating-related behavior in males, as demonstrated by the absence of preference for females against males and a higher number of penetrations up to ejaculation in the 0.5 dose group. PMix decreased Esr2 expression in the male hypothalamus across all three doses, and in females at mid and high doses in both the hypothalamus and pituitary. In male hypothalamus, we also observed decreased Kiss1 transcripts in these groups and a reduction in AR at the 0.5 dose group. In summary, our results provide further evidence that phthalates in a mixture, even at low doses, may exert cumulative effects on the structures underlying sexual behavior, which seems to be more sensitive than reproductive endpoints for the same experimental design.

Abstract 18: Persistent beneficial effects of angiotensinogen small interfering RNA (siRNA) and valsartan in spontaneously hypertensive rats after drug removal

Objective: Dual blockade of the renin-angiotensin system (RAS) with siRNA targeting hepatic angiotensinogen (AGT) plus the angiotensin receptor blocker valsartan synergistically lowers blood pressure and diminishes cardiac hypertrophy in spontaneously hypertensive rats (SHR). Since the effects of one siRNA injection may last for up to six months, here we evaluated whether the REVERSIR (reverse siRNA silencing, RVR) technology and/or stopping valsartan might acutely reverse the effects of dual RAS blockade in SHR. Methods: Ten-week old SHR were subjected to a 3-week treatment with vehicle or AGT-siRNA (10 mg/kg) + valsartan (4 mg/kg per day), followed by administration of vehicle or AGT-RVR at doses of 1, 10 and 20 mg/kg, both with and without continuation of valsartan, for 1 week. Mean arterial blood pressure (MAP) was monitored using radiotelemetry, and circulating AGT and renin were measured by enzyme-kinetic assay. Results: Baseline MAP was 143±2 mm Hg. Dual treatment lowered MAP by ≈70 mm Hg, cardiac hypertrophy (heart weight/tibia length) by ≈30%, and circulating AGT by >99%, while renin increased >100-fold versus vehicle. Discontinuing valsartan or applying AGT-RVR (1, 10 or 20 mg/kg) increased MAP similarly (by ≈20 mm Hg), while discontinuing valsartan + AGT-RVR (10 mg/kg) increased MAP by ≈40 mm Hg. Changes in cardiac hypertrophy mimicked those in MAP. Only valsartan discontinuation + AGT-RVR fully restored circulating AGT and renin to normal. When discontinuing valsartan only, AGT remained suppressed by >95%, and renin was up 10-fold, while with AGT-RVR 1, 10 and 20 mg/kg only, AGT suppression was 25, 50 and 50%, while renin was up 25-, 15- and 15-fold, respectively. Conclusions: Discontinuing valsartan or applying AGT-RVR in SHR treated with valsartan + AGT siRNA partially restored MAP, AGT, and renin, likely reflecting the fact that this approach replaces dual RAS blockade by single RAS blockade. However, although discontinuing valsartan plus AGT-RVR fully restored RAS activity, MAP and cardiac hypertrophy remained suppressed under this condition. This agrees with observations that early RAS inhibition resets genetic pathways and networks, allowing persistent blood pressure normalization even when treatment has stopped.

Abstract Tu008: Efficient Intramyocardial Delivery of EV-Encapsulated AAVs to Target Cardiomyocytes in a Pre-Clinical Swine Model

Background: Adeno-associated viruses (AAV) have been widely used to deliver therapeutic genes to the heart due to their safety and efficacy. However, a major obstacle to their successful gene delivery is the presence of neutralizing antibody (NAb) which form during natural exposure to AAV or following AAV administration. Our recent publication has shown that EV-encapsulated AAVs (EV-AAVs) shields AAVs from NAb neutralization, and overcoming this key roadblock associated with AAV-mediated gene therapy. Hypothesis: In this study, we addressed whether EV-AAVs can target cardiomyocytes in vivo . Aims: To test whether cardiomyocytes effectively uptake EV-AAVs in vivo , in a pre-clinical swine model. Methods and Results: Adult pigs prescreened for a lower NAb titer were randomly assigned to receive intramyocardial administration of either vehicle, AAV6-Luciferase or EV-AAV6-Luciferase. A total of six injections across three injection sites within the left ventricle (LV) were administered per animal. All animals were sacrificed at four weeks and liver and the LV tissues were collected. Luciferase activity assay, flow cytometry analysis of isolated cardiomyocytes (CM) and non-myocytes (NM), and immunofluorescence microscopy were performed to evaluate transgene expression and cellular tropism. Echocardiography was performed at baseline and at 4W to monitor cardiac function. At 4W, EV-AAV6s resulted in a higher luciferase expression in LV compared to nude AAV6 particles. Expression in the LV was higher compared to the liver. Flow cytometry analysis revealed a higher luciferase expression in CM compared to NM, which was corroborated by Immunofluorescence. No differences were detected in the global heart function across groups. Biodistribution of EV-AAV uptake and transgene expression are being studied with intramyocardial and intracoronary delivery mechanisms. Conclusion: EV-AAVs deliver higher amounts of genes than nude AAV6 via intramyocardial administration in a pre-clinical swine model. CMs preferentially uptake EV-AAVs compared to NMs. Our studies suggest that EV-AAVs are a superior cardiac gene delivery vector for future clinical studies.

Impact of excessive sucrose intake on mouse behavior across different developmental stages.

This study aimed to elucidate the effects of sucrose (SUC) consumption on neurodevelopmental processes through behavioral changes in rodents and determine whether these effects could be because of sweet taste, energy supply, or both. Mice were divided into five groups based on the time of SUC or sucralose (SUR, a noncaloric sweetener) administration: for 6 days from gestation day (GTD) 7, to birth from GTD13 and for 15 days from postnatal day (PND) 21, PND38, and PND56. SUC and SUR administration did not impact body weight. However, food intake in the PND56 group and water intake in the GTD13 and PND56 groups were increased by SUC and SUR administration. Amphetamine (0.5, 1, 2, and 3 mg/kg), a dopamine reuptake inhibitor, administration to assess alterations in the dopaminergic system induced increases in distance traveled after SUC administration in the GTD13 and PND21 groups compared with that in the control (vehicle administration) group. In contrast, the SUR group showed a decrease in the distance traveled in the PND56 group. Although there were no differences in locomotor activity and foraging behavior, SUC preference increased in the SUC group regarding the GTD13 and PND38 groups. The correlations between SUC preference and foraging behavior and between SUC preference and amphetamine response varied in both groups according to the developmental stage. Excessive SUC consumption might affect neural function at different developmental stages, as it could affect brain function through complex mechanisms involving sweet taste and energy supply and influence the dopaminergic system.

“Blocking-like” effects in attentional set-shifting: Redundant cues facilitate shifting in male rats with medial prefrontal cortex inactivation

Without a functioning prefrontal cortex, humans and other animals are impaired in measures of cognitive control and behavioral flexibility, including attentional set-shifting. However, the reason for this is unclear with evidence suggesting both impaired and enhanced attentional shifting. We inhibited the medial prefrontal cortex (mPFC) of rats while they performed a modified version of an attentional set-shifting task to explore the nature of this apparent contradiction.Twelve adult male Lister hooded rats received AAV5-CaMKIIa-hM4D(Gi)-mCherry viral vector bilaterally into mPFC to express inhibitory ‘Designer Receptors Exclusively Activated by Designer Drugs’ (iDREADDs). The receptors were activated by systemic clozapine N-oxide (CNO) to inhibit mPFC function. The rats were tested in the standard attentional set-shifting task four times: twice after i.p. administration and twice after oral administration of vehicle or CNO (10 mg/kg). They were then tested twice in a modified task, with or without oral CNO. The modified task had an extra stage before the extradimensional shift, in which the relevant exemplars remained relevant and new exemplars that were fully predictive but redundant replaced the previous irrelevant exemplars. These exemplars then became relevant at the subsequent ED stage.In the standard task, mPFC inactivation impaired attentional set-shifting, consistent with previous findings. However, in the modified task, mPFC inactivation abolished ED shift-costs. The results support the suggestion that the mPFC is needed for the downregulation of attention that prevents learning about redundant and irrelevant stimuli. With mPFC inactivated, the rat learns more rapidly when previously redundant exemplars become the only relevant information.

Canadian Expert Consensus on the Use of Halobetasol Propionate/Tazarotene Lotion for Plaque Psoriasis.

An expert panel of Canadian dermatologists was assembled to develop consensus statements regarding the current landscape of topical therapies for plaque psoriasis and the place in therapy of the recently approved fixed-dose combination halobetasol propionate (HP)/tazarotene (TAZ) lotion (HP/TAZ) in the treatment algorithm for plaque psoriasis. A modified nominal group technique, which combined both independent and group input from the expert panel, was used to develop the consensus statements. The expert panel completed surveys to elicit their independent views on the current landscape of topical therapies for plaque psoriasis in Canada. The first expert panel session was held to discuss the existing body of literature and develop draft consensus statements about topical therapies and the place in therapy of HP/TAZ. Independent feedback on the draft consensus statements was solicited from expert panel members prior to another expert panel session where the amended consensus statements were further discussed, edited and, finally, voted on. The expert panel reached consensus on 20 statements. Expert panel members agreed, based on the existing body of literature, that there is a place in therapy for HP/TAZ to address several current unmet treatment needs of patients with plaque psoriasis. Studies have shown that HP/TAZ is an effective and safe first-line treatment for moderate-to-severe plaque psoriasis. Due to its cosmetically pleasing vehicle and once-daily administration, HP/TAZ may improve patient acceptance and treatment adherence.

Gasdermin D Inhibitor Necrosulfonamide Alleviates Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice.

Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4+ T cells, CD8+ T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1β and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1β and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease.

Levilactobacillus brevis SG031 modulates mood-related behaviors and attenuates stress-related sleep disturbance and autonomic dysfunction via gut microbiota modulation in Wistar–Kyoto rats

AimsThe probiotic bacterium Levilactobacillus brevis (L. brevis) has been proposed as a potential solution to manage mood disorders and alleviate stress-related sleep disturbances. However, the underlying mechanisms of its effects have not been fully elucidated. The aim of this study was to explore the impact and potential mechanisms of L. brevis SG031 supplementation on anxiety/depression-like behaviors and stress-induced changes in sleep patterns and sleep-related autonomic function. Main methodsMale Wistar–Kyoto rats were administered low, medium, or high doses of L. brevis SG031 or a vehicle for 4 weeks, followed by behavioral tests to evaluate anxiety and depression. After an additional 2 weeks of SG031 or vehicle administration, a cage-exchange paradigm was performed with 24-hour physiological signal measurements under different stress conditions. Fecal samples were collected to construct a 16S rRNA library and assess fecal short-chain fatty acids (SCFAs). Key findingsHigh-dose SG031 administration yielded reduced depression-like responses and enhanced social interaction in behavioral tests. It also exhibited a protective effect against stress-induced sleep disturbance characterized by decreased sleep time, increased awake time, and autonomic dysfunction during sleep. Fecal examination indicated that high-dose SG031 administration exerted beneficial effects on gut health by maintaining the gut microbial abundance, preserving stability of the microbial composition, and enriching the gut with SCFAs, which were associated with improvements in sleep and autonomic function. SignificanceThese findings collectively underscore the multifaceted potential of SG031 in addressing mental health and stress-related sleep challenges through the modulation of the gut microbiota.

Single high-dose intravenous injection of Wharton’s jelly-derived mesenchymal stem cell exerts protective effects in a rat model of metabolic syndrome

BackgroundMetabolic syndrome (MetS) is a significant epidemiological problem worldwide. It is a pre-morbid, chronic and low-grade inflammatory disorder that precedes many chronic diseases. Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) could be used to treat MetS because they express high regenerative capacity, strong immunomodulatory properties and allogeneic biocompatibility. This study aims to investigate WJ-MSCs as a therapy against MetS in a rat model.MethodsTwenty-four animals were fed with high-fat high-fructose (HFHF) diet ad libitum. After 16 weeks, the animals were randomised into treatment groups (n = 8/group) and received a single intravenous administration of vehicle, that is, 3 × 106 cells/kg or 10 × 106 cells/kg of WJ-MSCs. A healthy animal group (n = 6) fed with a normal diet received the same vehicle as the control (CTRL). All animals were periodically assessed (every 4 weeks) for physical measurements, serum biochemistry, glucose tolerance test, cardiovascular function test and whole-body composition. Post-euthanasia, organs were weighed and processed for histopathology. Serum was collected for C-reactive protein and inflammatory cytokine assay.ResultsThe results between HFHF-treated groups and healthy or HFHF-CTRL did not achieve statistical significance (α = 0.05). The effects of WJ-MSCs were masked by the manifestation of different disease subclusters and continuous supplementation of HFHF diet. Based on secondary analysis, WJ-MSCs had major implications in improving cardiopulmonary morbidities. The lungs, liver and heart show significantly better histopathology in the WJ-MSC-treated groups than in the untreated CTRL group. The cells produced a dose-dependent effect (high dose lasted until week 8) in preventing further metabolic decay in MetS animals.ConclusionsThe establishment of safety and therapeutic proof-of-concept encourages further studies by improving the current therapeutic model.

Aromadendrin alleviates LPS-induced kidney apoptosis and inflammation by inhibiting phosphorylation of MAPK and NF-κB signaling pathways.

Excessive inflammation and apoptosis in kidneys are critical players in the pathogenesis of acute kidney injury (AKI). Aromadendrin is a natural flavonoid characterized by anti-inflammatory, anti-apoptotic, and antioxidant actions. Thus, we investigated the roles and mechanisms of aromadendrin in the development of AKI. Lipopolysaccharide (LPS) was used to induce AKI mice, and one hour after LPS challenge, the mice received oral administration of aromadendrin or vehicle. Renal functions were assessed by measuring blood urea nitrogen and creatinine in serum. Histological changes were determined by hematoxylin and eosin staining. Apoptotic cells of renal tissues were detected by TUNEL staining. Gene expression was measured by western blotting and RT-qPCR. Aromadendrin alleviated LPS-induced renal dysfunctions and histological defects in mice. Additionally, aromadendrin suppressed excessive inflammation and tissue apoptosis in the kidneys of LPS-induced AKI mice. Mechanistically, aromadendrin blocked the activation of NF-κB and MAPK pathways in LPS-induced AKI mice. Aromadendrin alleviates LPS-stimulated inflammation and tissue cell apoptosis in kidneys by inactivating the NF-κB and MAPK pathways.

Effects of oral administration of nonselective Trk inhibitor on bladder overactivity in rodent models of prostatic inflammation.

Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI). Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin. The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity. The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity.