Releasing Hormone Research Articles

Kisspeptin and Endometriosis—Is There a Link?

This article presents a narrative review that explores the potential link between kisspeptin—a key regulator of the hypothalamic-pituitary-gonadal axis—and the pathogenesis of endometriosis. Kisspeptin plays a significant role in regulating reproductive functions by modulating the release of gonadotropin-releasing hormone (GnRH), which in turn stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Recent studies suggest that kisspeptin may also impact peripheral reproductive tissues and influence inflammatory processes involved in the development of endometriosis. Altered kisspeptin signaling has been associated with the abnormal hormonal environment observed in endometriosis, which affects menstrual cycles and ovarian function. Research indicates that women with endometriosis exhibit altered levels of kisspeptin and its receptor, KISS1R, in both eutopic and ectopic endometrial tissues, suggesting a role in disease progression, particularly in tissue invasion and lesion formation. Kisspeptin’s role in regulating matrix metalloproteinases (MMPs), enzymes essential for tissue remodeling, further supports its potential contribution to the pathophysiology of endometriosis. Moreover, kisspeptin-based therapeutic strategies are currently under investigation, with the aim of providing targeted treatments that reduce the side effects commonly associated with existing therapies. Despite promising findings, further research is needed to fully understand the mechanisms by which kisspeptin influences endometriosis.

Analysis of cellular and molecular biomechanical correlates in emotional response monitoring via biosensors and their impact on teaching strategy modification in Japanese language instruction

Emotion states have a significant impact on language acquisition and learning outcomes. In Japanese language teaching, traditional strategies often overlook students' emotional responses, which can lead to stress and disengagement, affecting performance. To address this, the study focuses on incorporating bio-sensor-based emotional reaction monitoring. At the cellular and molecular biomechanical level, emotions can trigger a cascade of physiological changes. For example, stress can activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of stress hormones like cortisol. These hormonal changes can affect neurotransmitter systems and cellular signaling pathways in the brain, influencing cognitive functions related to language learning. During Japanese language sessions, teachers' emotional states are recorded using surveys and EEG monitoring. The EEG signals can provide insights into the neural activity and related cellular and molecular events. Participants are divided into experimental and control groups. In the experimental group, teaching strategies are adjusted based on emotional monitoring data. The Extreme Gradient Boosting (XGBoost) model classifier is used for EEG signal feature selection to create a stress level identification model. This model can help in understanding the cellular and molecular correlates of stress during teaching. Statistical analysis evaluates the relationship between EEG features and stress levels, as well as the effectiveness of adjusted teaching strategies. Tailored teaching strategies based on these insights can enhance teacher resilience and improve the classroom environment. By considering the cellular and molecular biomechanical aspects of emotions, the study aims to improve teacher well-being and student learning experiences, leading to more effective Japanese language instruction.

The therapeutic effect of different cumin essential oil fractions against gastric ulcer in rats.

Cumin, a popular spice, is widely used to treat stomach ailments in Central Asia and Xinjiang, China. Cumin essential oil has been found to effectively treat gastric ulcers, but its pharmacodynamic basis remains unclear. In this study, cumin essential oil was directly separated using column chromatography, and its components were identified through multi-dimensional gas chromatography-mass spectrometry. Finally, the cumin essential oil was fractionated into E1, E2, and E3. The effects of these fractions on gastric ulcers were studied using an anhydrous ethanol-induced rat model. The results indicated that the three fractions decreased ulcer index, gastric fluid pH, and pepsin activity to different extents. They lowered the levels of prostaglandin E2, gastrin, and epidermal growth factor in rat serum. According to an analysis of the above indices, E3 fraction had the best anti-ulcer effect. The detection results of the oxidative stress and inflammatory factors showed that all three fractions relieved the ethanol-induced oxidative stress and reduced the release of inflammatory factors to varying degrees. The E3 fraction played the most significant role. The E3 fraction was selected to explore the relevant mechanism, and the results showed that E3 fraction significantly prevented the cleaved caspase-3 and Bax protein levels that were ethanol-induced and resisted apoptosis induced by ethanol injury. The western blot results for detecting the NF-κB-related pathway protein showed that E3 fraction significantly inhibited the activation of p-p65, p-IKKβ, and p-IκBα. The study found that the E3 fraction of cumin essential oil had the most effective anti-ulcer effect by inhibiting NF-κB activation and apoptosis, thus reducing inflammation.

Change on the Brain? The Neuroscience of Organizational Transformation

True transformations aim to change the core identity of an organization, are often disruptive, and rarely result in their intended outcomes. The objective of this paper is to propose a theoretical approach for more effective transformations via the syntheses of emerging findings in managerial science, organizational psychology, and social cognitive neuroscience. The authored conducted a literature review of traditional methods and the application of neuroscience to organizational transformation, proposing that consideration to leader and employee neuroanatomy can significantly impact transformation success. The emergent five-phase approach - Exploration & Discovery, Surfacing & Co-Creation, Enablement & Prioritization, Implementation, and Empowerment - integrates practices informed by neuroscience to enhance leadership alignment, employee engagement, and change sustainability. By focusing on activities such as vision alignment, co-creation, and leadership development, the approach seeks to optimize brain functions related to trust, motivation, and adaptability. Neuroscientific concepts like neural synchrony, hormone and neurotransmitter release, and specific neural circuit activations are utilized to improve team dynamics, decision-making, and learning. This neuro-informed approach challenges conventional practices by emphasizing co-creative solutioning with employees, piloting programs, and empowering middle managers to lead transformation efforts. Data from case studies demonstrate significant improvements in employee experience and sustainable shifts in organizational behavior. The paper concludes with a call for further research to solidify the emerging intersection of neuroscience and organizational transformation.

Potential shared mechanisms in atopic dermatitis and type 2 diabetes identified via transcriptomic and machine learning approaches

Although atopic dermatitis (AD) and type 2 diabetes mellitus (T2DM) may appear clinically and pathophysiologically unrelated, AD is a common skin disease characterized by chronic inflammation and skin barrier dysfunction, whereas T2DM is a metabolic disorder marked by hyperglycemia and chronic inflammation, which further exacerbates insulin resistance (IR) through the release of systemic inflammatory factors. Despite their apparent differences, the molecular mechanisms shared between AD and T2DM remain relatively unexplored. In this study, we integrated transcriptomic data from both AD and T2DM using differential gene expression analyses (DEGs), gene set variation analysis (GSVA), and machine learning algorithms to uncover common features of these diseases. We identified several characteristic genes, including LTF, LTB4R, and CCR1, which are significantly upregulated in both conditions and may serve as potential biomarkers. Furthermore, virtual screening revealed that Dioscin, Camptothecin, and Albamycin exhibit strong affinity for the CCR1 binding site, indicating their potential as therapeutic candidates. In summary, this study elucidates the shared molecular mechanisms of AD and T2DM and introduces new potential targets and drugs for the diagnosis and treatment of these diseases.

The Effects of Leptin and Ghrelin Hormones on Metabolism

Leptin was first identified in 1994 by Zhang and colleagues as a signaling factor originating from adipose tissue. Its name is derived from the Greek word “leptos,” meaning “thin” or “slender”. While its primary site of secretion is white adipose tissue, leptin is also secreted in smaller amounts by brown adipose tissue, as well as by the placenta, skeletal muscle, stomach, mammary epithelium, and brain tissue. By acting at the hypothalamic level, leptin reduces appetite. Leptin is a 16-kilodalton, single-chain polypeptide hormone. Initially recognized for its role in satiety and energy balance, leptin was later identified as an anti-obesity factor that exerts feedback effects from adipocytes to the hypothalamus. It has been reported as a key physiological factor in mammals for preventing fat accumulation.Ghrelin, discovered in 1999 by Kojima and colleagues in the stomachs of mice, is a 28-amino acid oligopeptide hormone that stimulates the release of growth hormone. Although primarily secreted by stomach tissue, ghrelin is also produced by the brain, intestines, placenta, kidneys, pituitary gland, and pancreas. The name “ghrelin” is derived from the root “ghre,” meaning “grow,” in Indo-European languages, combined with “relin,” which implies secretion. Ghrelin is also referred to as the "appetite hormone. Isolated from mouse stomach tissue, this 28-amino acid peptide plays crucial physiological roles. Ghrelin has been reported to increase food intake, promote positive energy balance, and influence gastrointestinal motility, cell proliferation, bone metabolism, and reproduction.

MiR-146a-5p downregulated TRAF6/NF-κB p65 pathway to attenuate the injury of HT-22 cells induced by oxygen-glucose deprivation/reoxygenation.

MicroRNA-146a-5p (miR-146a-5p) actively participates in the process of cerebral ischemia-reperfusion (CI/R) injury. Dysregulation of the tumor necrosis factor receptor-associated factor 6 (TRAF6)/nuclear factor kappa-B (NF-κB) p65 axis is closely associated with inflammatory response. This study aimed to investigate the potential involvement of miR-146a-5p and TRAF6/NF-κB p65 in mediating CI/R progression in vitro. HT-22 cells were challenged with oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate CI/R in vitro. HT-22 cells were transfected with miR-146a-5p mimics or TRAF6 overexpression constructs. The impact of miR-146a-5p on apoptosis, inflammation, and TRAF6/NF-κB p65 activation were investigated. OGD/R inhibited HT-22 cell viability, induced apoptosis, reduced miR-146a-5p levels and activated the TRAF6/NF-κB p65 pathway. MiR-146a-5p mimics reduced pro-inflammatory factor release, limited apoptosis-related protein expression, and inactivated the TRAF6/NF-κB p65 pathway in OGD/R-challenged HT-22 cells. Mechanistically, miR-146a-5p was verified to bind to TRAF6 3'UTR. TRAF6 overexpression reversed the beneficial effects of miR-146a-5p mimics on apoptosis, inflammation, and TRAF6/NF-κB p65 activation. This work revealed that miR-146a-5p targeted TRAF6 and suppressed the TRAF6/NF-κB p65 pathway, thereby reducing OGD/R-induced inflammation and apoptosis in HT-22 cells. These findings suggest the potential of the miR-146a-5p/TRAF6/NF-κB p65 axis in the treatment of CI/R.

Injectable, cryopreservable, preconditioned mesenchymal stromal cell-loaded microbeads for pro-angiogenic therapy: in vitro proof-of-concept.

Despite their recognized potential for ischemic tissue repair, the clinical use of human mesenchymal stromal cells (hMSC) is limited by the poor viability of cells after injection and the variability of their paracrine function. In this study, we show how the choice of biomaterial scaffolds and the addition of cell preconditioning treatment can address these limitations and establish a proof-of-concept for cryopreservable hMSC-loaded microbeads. Injectable microbeads in chitosan, chitosan-gelatin, and alginate were produced using stirred emulsification to obtain a similar volume moment mean diameter (D[4,3]500 µm). Cell viability was determined through live/dead assays, and vascular endothelial growth factor (VEGF) release was measured by ELISA. Proangiogenic function was studied by measuring the wound closure velocity of endothelial cells (HUVEC) co-cultured with MSC-loaded microbeads. The effect of freeze-thawing on microbeads morphology, porosity, injectability and encapsulated MSC was also studied. hMSC-loaded chitosan-based microbeads were found to release 11-fold more VEGF than alginate microbeads (p˂0.0001) and chitosan-gelatin was chosen for further studies because it presented the best cell viability. Preconditioning with celastrol significantly enhanced the viability (1.12-fold) and VEGF release (1.40-fold) of MSC-loaded in chitosan-gelatin microbeads, as well as their proangiogenic paracrine function (1.2-fold; p˂0.05). In addition, preconditioning significantly enhanced the viability of hMSC after 1 and 3 days in low-serum medium after cryopreservation (p˂0.05). Cryopreserved hMSC-loaded microbeads maintained their mechanical properties, were easily injectable through a 23G needle, and maintained their paracrine function, enhancing the proliferation and migration of scratched HUVEC. This study shows the advantage of chitosan as a scaffold material and concludes that chitosan-gelatin microbeads with celastrol-preconditioned cells form a promising off-the-shelf, cryopreservable allogenic MSC product. In vivo testing is required to confirm their potential in treating ischemic diseases or other clinical applications.

Nanocarriers Made of Natural Fatty Acids: Modulation of Their Release Profiles through Photo‐Crosslinking

AbstractNatural fatty acids are attractive carrier materials for drug delivery, but their rapid dissolution and degradation in vivo calls for new strategies to enhance their stability. Here we report a simple and versatile method capable of photo‐crosslinking carriers made of natural fatty acids for drug delivery under controlled release. By optimizing the crosslinking density, the nanoscale carriers show a high drug loading efficiency, together with a stable network structure for minimal degradation in a body fluid mimic. Fluorescence microscopy analysis also reveals the exceptional intracellular stability of the crosslinked network, resulting in negligible cytotoxicity toward A549 cells up to 24 h when loaded with a potent anticancer drug. We further extend this strategy to microscale carriers fabricated using electrospray. Upon photo‐crosslinking, the carriers show a retarded release of nerve growth factor, resulting in slower neurite outgrowth from dorsal root ganglion. This work holds promise for addressing the efficacy and safety issues critical to nanomedicine and related applications.

Evaluation of the effect of phellodendrin application on rats creating an experimental model of non-compression lumbar disc herniation on the NF-κB-related inflammatory signaling pathway

ObjectiveTo explore the therapeutic effects of phellodendrine on non-compression lumbar disc herniation (NCLDH).MethodsThe Sprague Dawley rat model of NCLDH was established via autologous caudal nucleus pulposus transplantation. Behavioral observations and neurological function scoring were conducted in Sprague Dawley rats, and the serum levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured via enzyme-linked immunosorbent assay (ELISA). Real-time quantitative polymerase chain reaction (RT‒qPCR) was used to detect the expression of nuclear factor kappa-B (NF-κB) p65 mRNA in L5 nerve roots and surrounding tissues. Western blotting was used to assess the protein expression of NF-κB p65 and TNF-α. Immunofluorescence and immunohistochemical analyses were performed to investigate the distribution and expression of the NF-κB p65 protein in the L5 nerve and its surrounding tissues.ResultsIn this animal study, phellodendrine was found to downregulate the expression of p65 mRNA, decrease the release of inflammatory factors, and alleviate motor dysfunction caused by lumbar disc herniation(LDH). Therefore, the phellodendrine technique has potential value for the treatment of NCLDH.ConclusionIn this animal experiment, phellodendrine was found to significantly reduce the expression level of p65 mRNA, decrease the release of inflammatory cytokines, and alleviate lumbar disc pain.Clinical trial numberNot applicable.

Network Pharmacology and In Vivo Experimental Verification of the Mechanism of the Qing'e Pill for Treating Intervertebral Disc Degeneration.

The Qing'e Pill (QEP) is widely used to alleviate low back pain and sciatica caused by Intervertebral Disc Degeneration (IDD). However, its active components, key targets, and molecular mechanisms are not fully understood. The aim of this study is to elucidate the molecular mechanisms through which the QEP improves IDD using database mining techniques. Active components and candidate targets of the QEP were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and the Bioinformatics Analysis Tool for Molecular Mechanisms of Traditional Chinese Medicine. IDD-related targets were obtained from the GeneCards database, and liver- and kidney-specific genes were retrieved from the BioGPS database. The intersection of these candidate targets was analyzed to identify potential targets for the QEP in IDD. A protein-protein interaction network analysis was performed using STRING and Cytoscape 3.7.2 software. Core targets were further analyzed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking was used to assess the binding affinity of active components to candidate targets, and animal experiments were conducted for validation. We identified 65 potentially active components of the QEP that corresponded to 1,093 candidate targets, 2,108 IDD-related targets, and 1,113 liver- and kidney-specific genes. Key components included quercetin, berberine, isorhamnetin, and emodin. The primary candidate targets were Wnt5A, CTNNB1, IL-1β, MAPK14, MMP9, and MMP3. The GO and KEGG analyses revealed the involvement of these targets in Wnt signaling, TNF signaling, Wnt receptor activation, Frizzled binding, and Wnt-protein interactions. Molecular docking showed strong binding between these components and their targets. Animal experiments demonstrated that the QEP treatment significantly reduced the expression of Wnt5A, CTNNB1, IL-1β, MAPK14, MMP9, and MMP3 at high, medium, and low doses compared with the model group. The QEP alleviated IDD by modulating the Wnt/MAPK/MMP signaling pathways and reducing the release and activation of key factors.

Regulation of sleep amount by CRTC1 via transcription ofCrhin mice

The cAMP-response element binding protein (CREB) is required for regulation of daily sleep amount, whereas gain-of-function of CREB-regulated transcription coactivator 1 (CRTC1) causes severe insomnia in mice. However, the physiological functions of CRTCs and their downstream target genes in the regulation of sleep amount remain unclear. Here, we use adult brain chimeric (ABC)-expression/knockout platform for somatic genetics analysis of sleep in adult male mice. ABC-expression of constitutively active mutant CRTC1/2CAin the mouse brain neurons significantly reduces the amount of non-rapid eye movement sleep (NREMS) and/or REMS. Consistent with that SIK3 phosphorylates and inhibits CRTCs, ABC-expression of CRTC1/2/3CArescues the hypersomnia phenotype ofSleepy(Sik3Slp) mice. While ABC-Crtc2KOorCrtc3KOcauses no sleep phenotype, ABC-Crtc1KOor ABC-expression of dominant-negative CRTC (dnCRTC) results in modest reduction of NREMS amount accompanied with elevated NREMS delta power. Moreover, ABC-expression of CRTC1CAor dnCRTC in the excitatory neurons causes bidirectional changes of NREMS/REMS amount and/or NREMS delta power, whereas expression of CRTC1CAin the inhibitory neurons decreases REMS amount and increases NREMS delta power. The ability of CRTC1CAto regulate sleep requires its transactivation domain and CREB-binding domain and is dependent on CREB. Furthermore, we showed that inducible ABC-expression of corticotropin releasing hormone (Crh) and brain-derived neurotrophic factor (Bdnf)–two target genes of CRTCs–significantly reduces daily sleep amount. Notably, ABC-CrhKO, but notBdnfKO, rescues the insomnia phenotype of ABC-CRTC1CAmice. Taken together, these results indicate that CREB-CRTC1 complex regulates daily sleep amount by modulating the transcription ofCrhin the mouse brain neurons.Significance StatementCRTCs function as coactivators for CREB, a transcription factor required for the regulation of daily sleep amount in mice. Here, we found that CRTC1/2/3 function similarly to suppress NREMS and REMS in a CREB-dependent manner. Consistent with that CRTCs are substrates of SIK3 kinase, expression of constitutive active mutant CRTCsCArescue the hypersomnia phenotype ofSleepy(Sik3Slp) mice. Furthermore, we showed that CRTC1 reduces NREMS amount by upregulating the expression of neuropeptide CRH. These results elucidate the mechanism by which CRTCs regulates sleep amount and suggest a potential transcriptional mechanism in the stress-induced sleep/wake regulation.

The background sodium leak channel NALCN is a major controlling factor in pituitary cell excitability

AbstractThe pituitary gland produces and secretes a variety of hormones that are essential to life, such as for the regulation of growth and development, metabolism, reproduction, and the stress response. This is achieved through an intricate signalling interplay between the brain and peripheral feedback signals that shape pituitary cell excitability by regulating the ion channel properties of these cells. In addition, endocrine anterior pituitary cells spontaneously fire action potentials to regulate the intracellular calcium ([Ca2+]i) level, an essential signalling conduit for hormonal secretion. To this end, pituitary cells must regulate their resting membrane potential (RMP) close to the firing threshold, but the molecular identity of the ionic mechanisms responsible for this remains largely unknown. Here, we revealed that the sodium leak channel NALCN, known to modulate neuronal excitability elsewhere in the brain, regulates excitability in the mouse anterior endocrine pituitary cells. Using viral transduction combined with powerful electrophysiology methods and calcium imaging, we show that NALCN forms the major Na+ leak conductance in these cells, appropriately tuning cellular RMP for sustaining spontaneous firing activity. Genetic depletion of NALCN channel activity drastically hyperpolarised these cells, suppressing their firing and [Ca2+]i oscillations. Remarkably, despite this profound function of NALCN conductance in controlling pituitary cell excitability, it represents a very small fraction of the total cell conductance. Because NALCN responds to hypothalamic hormones, our results also provide a plausible mechanism through which hormonal feedback signals from the brain and body could powerfully affect pituitary activity to influence hormonal function. imageKey points Pituitary hormones are essential to life as they regulate important physiological processes, such as growth and development, metabolism, reproduction and the stress response. Pituitary hormonal secretion relies on the spontaneous electrical activity of pituitary cells and co‐ordinated inputs from the brain and periphery. This appropriately regulates intracellular calcium signals in pituitary cells to trigger hormonal release. Using viral transduction in combination with electrophysiology and calcium imaging, we show that the activity of the background leak channel NALCN is a major controlling factor in eliciting spontaneous electrical activity and intracellular calcium signalling in pituitary cells. Remarkably, our results revealed that a minute change in NALCN activity could have a major influence on pituitary cell excitability. Our study provides a plausible mechanism through which the brain and body could intricately control pituitary activity to influence hormonal function.

Beaveria bassiana (Balsamo) Vuillemin combined with cinnamaldehyde enhances anti-hepatocellular carcinoma effects of T cells by the PGC-1α/DRP1-regulated mitochondrial biogenesis and fission

Beaveria bassiana (Balsamo) Vuillemin (BEA) and cinnamaldehyde (CA), primarily derived from traditional Chinese medicine (TCM) named Bombyx batryticatus and Cinnamomum cassia, play an immunomodulatory role in different disease. Hepatocellular carcinoma (HCC) is a prevalent malignant tumor characterized by immune dysfunction. In this study, we investigated BEA and CA's regulate ability on T cell mitochondrial metabolism and anti-HCC effect. We used RT-qPCR, Western blot, Enzyme-linked immune sorbent assay (ELISA), Flow CytoMetry (FCM) methods to examine BEA and CA's regulation of T cell mitochondrial function and anti-HCC ability. Furthermore, the mechanism of PGC-1α/DRP1 pathway on the morphology and function of T cell mitochondria was investigated. Our data demonstrated that the administration of BEA and CA, either alone or in combination, effectively suppressed HCC growth and mitigated T cell apoptosis and mitochondrial dysfunction, assessed by mitochondrial reactive oxygen species (mitoROS), mitochondrial membrane potential (MMP) and ATP level. Moreover, BEA and CA could enhance the release of tumor-killing factors (Perforin (PF) and Granzyme B (Gzm B)) from T cells, inducing H22 cell apoptosis. Additionally, BEA and CA-treated T cell reinfusion into BALB/c nude HCC mice could significantly inhibited HCC growth by promoting T cell infiltration into tumor tissue. T cell mitochondrial biogenesis/fission balance and apoptosis in tumor mice were regulated by PGC-1α/DRP1 pathway. Our findings reveal that BEA and CA enhance anti-HCC effects of T cells by regulating mitochondrial biogenesis and fission through the PGC-1α/DRP1 pathway.

Mechanism of Saikosaponin D on Lipopolysaccharide-Induced Acute Lung Injury in Neonatal Rats

This study investigates the mechanism of saikosaponin D on lipopolysaccharide (LPS) aspiration pneumonia in neonatal rats. Inhalation lung injury model was constructed and rats were assigned into control group, model group, saikosaponin D (5, 10 or 20 mg/kg) group and dexamethasone 2 mg/kg group (positive control group). The dry and wet mass ratio of lung tissue was measured by wet and dry method. Superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), IL-6, IL-1β and TNF-α were measured by ELISA. HMGB1, TLR4 and p-NF-κB p65 protein expressions were detected by Western blot. Compared with control group, model group had significantly higher wet and dry mass ratio of lung tissue, lower SOD and GSH contents, higher MDA content, higher IL-6/IL-1β/TNF-α levels, higher HMGB1 and TLR4 levels and higher p-NF-κB p65 to NF-κB p65 ratio (P <0.05). Compared with model group, dry and wet mass ratios of lungs in saikosaponin D groups and dexamethasone group were reduced, SOD and GSH contents were increased, and MDA contents were reduced. Meanwhile, IL-6/IL-1β/TNF-α levels were reduced and HMGB1 and TLR4 levels and p-NF-κB p65 ratio were reduced (P < 0.05). In conclusion, saikosaponin D inhibited release of inflammatory factors, improved oxidative stress and HMGB1/TLR4/NF-κB signaling in LPS-induced inhalational lung injury.

Construction of a charge-reversal polyelectrolyte nanocarrier for targeted intestinal releasing of kidney tea saponin based on sodium alginate/ε-polylysine/alliin.

Herein, a pH-responsive delivery system based on sodium alginate (ALG), ε-polylysine (PLL) and alliin (ALL) has been designed. The innovative use of the charged nature of alliin to prepare carriers loaded with kidney tea saponins has rarely been reported in the literature before. The size and morphology of the complex was quantified by dynamic light scattering (DLS) analysis and scanning electron microscopy (SEM), exhibiting a size of 141 ± 1 nm. The carrier shows effective pH-responsiveness, stability in the gastric environment and dissociation in the intestinal environment. Kidney tea saponins can easily pass through the stomach directly into the intestine after encapsulation at pH = 1. Furthermore, in vitro simulated digestion was used to validate the efficacy of the delivery system. When kidney tea saponin was administered orally, it could reach the intestinal tract barely. However, when it was encapsulated in the carrier, approximately 60 % of the kidney tea saponin could be delivered to the intestinal tract. The strategy increases bioavailability of kidney tea saponins within the intestine successfully. The findings indicate that ALG-PLL-ALL may serve as a suitable delivery system for the intestinal targeted releasing of health factors that are susceptible to hydrolysis and unstable in the stomach.

Molecular response of canine testis to GnRH agonist: Insights into AR, HIF-1α, and HSPs expression during arrest and recovery of spermatogenesis.

Slow release gonadotropin releasing hormone (GnRH) agonist implants are frequently used for contraception in male dogs. Although the effects are fully reversible, there is still concern about the safety of the implant's mode of action. Addressing this, we investigated cellular stress and androgen receptor signaling during downregulation and recovery. Testicular tissues were sampled from dogs castrated at different time points after GnRH implant removal and compared with untreated controls. Androgen receptor (AR), hypoxia-inducible factor 1 (HIF1A) and heat shock proteins HSP72, HSP73, HSPA2, HSP90AA1 and HSP90AB1 were investigated by qPCR, and AR, HSP72, HSP73 and HSP90 immunohistochemically. While AR, HIF1A and HSP70 were upregulated at mRNA level, HSPA8, HSPA2 and HSP90AA1 expression were downregulated during spermatogenic arrest; HSP90AB1 expression did not change. Immunohistochemistry verified AR-expression in Sertoli, peritubular and Leydig cells, occasionally also in spermatogonia. Stress-inducible HSP72 was occasionally detected, while constitutive HSP73 and HSP90 were abundantly expressed by germ cells. Our results were similar with studies on seasonal breeders such as pine voles, geese, fish and soft-shelled turtles. Accordingly, GnRH implants did not impose additional cellular stress on testicular cells when compared with natural recrudescence. Since comparative data on HIF1α is scarce, we cannot draw conclusions about hypoxic conditions.

Teneurin C-Terminal Associated Peptide (TCAP)-1 Attenuates Restraint Stress-Induced Corticosterone Increases in Male Mice and Rats.

Hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis response can result in anxiety and other neuropsychiatric disorders and effective therapeutics are needed to mitigate this maladaptive response. Here we examined the effects of Teneurin C-terminal Associated Peptide (TCAP)-1, a peptide known to inhibit corticotropin releasing factor (CRF)-mediated stress, on the physiological expression of stress, and whether the effects of TCAP-1 were dependent on the route of administration. We first examined whether subcutaneous administration of TCAP-1 influenced tube restraint stress-induced corticosterone (CORT) increases in both male mice and rats. Using a similar model, we further examined the efficacy and time course of intranasal TCAP-1. Results showed that subcutaneous TCAP-1 administration attenuated the expression of the physiological manifestation of stress in male mice and rats, and that intranasal TCAP-1 delivered prophylactically is effective at attenuating stress-induced CORT increases in male rats. These data indicate that TCAP-1 delivered though non-invasive routes of administration could have potential as a clinically relevant anxiolytic.

Self-assembled Arginine-Glycine-Aspartic Acid Mimic Peptide Hydrogels as Multifunctional Biomaterials for Wound Healing.

Clinical management of nonhealing ulcers requires advanced materials that can enhance wound closure rates without relying on the release of drugs or other growth factors to obviate systemic deleterious side effects. In our previous work, we synthesized an integrin-binding cell adhesive MNH2 {Fmoc-FFβAR(K)βA-NH2 consisting of an RGD mimic, [R(K)], with an amide terminus}, MOH {Fmoc-FFβAR(K)βA-OH consisting of an RGD mimic, [R(K)], with acid terminus}, and MR (Fmoc-FFβARGDβA-NH2 consisting of an RGD peptide, reference) with multifunctional activity. Here, we reported the synthesis, characterization, and performance of a reversed derivative, R-MNH2 (Fmoc-FFβA(K)RβA-NH2 consisting of an RGD mimic, [K(R)], with an amide terminus) of an antimicrobial cell adhesive peptide, MNH2. Both peptides (MNH2 and R-MNH2) were found to interact with αvβ3 integrin, as shown by docking studies; however, they differed in cell adhesive properties, hydrogel formation, and antimicrobial efficacy. Later, the wound healing ability of a series of RGD/RGD peptide mimics (MR, R-MNH2, MNH2, and MOH) was studied in a methicillin-resistant Staphylococcus aureus (MRSA)-infected Balb/c mouse model. All studied peptides showed cell adhesion and wound healing properties; however, only the amide-terminal RGD peptide mimic, MNH2, and its reversed derivative, R-MNH2, showed antimicrobial activity in both in vitro and in vivo studies. Of these, MNH2 showed the highest integrin-mediated spreading, migration, and proliferation of dermal cells in vitro as well as in vivo. Therefore, the MNH2 peptide mimic represents a paradigm shift in the development of dermoconductive strategies to treat chronic wounds.

The evaluation of the mechanism of interleukin-6 in immune inactivation of oral cancer

This study demonstrates the potential of sulindac to enhance resistance to tumor proliferation by both blocking tumor-induced immune suppression and stopping the growth of oral tumors. In contrast to adriamycin, sulindac significantly reduces the release of vascular endothelial growth factor (VEGF) and IL-6 from tumor cells by downregulating the NFκB and JNK signaling pathways. Additionally, it reduces the simultaneously induced production of VEGF and IL-6 during contacts between immune cells and tumors. Furthermore, sulindac dramatically reduces VEGF levels in the presence of IL-2-stimulated NK cells, indicating an improved immune response against tumor cells. Even the immunological suppression caused by tumor cells stimulated with TNF-α is reversed by sulindac. Consequently, the combination of sulindac with chemotherapy can effectively inhibit tumor growth and increase resistance to oral malignancies.