Pulsatile Release Research Articles

Quercetin Boosts Pulsatile Gonadotropin-Releasing Hormone Release to Improve Luteal Function via Inhibiting NF-κB/NLRP3-Mediated Neuron Pyroptosis.

Luteal phase deficiency (LPD) is the main cause of infertility without an effective cure. Quercetin (QUE) is a bioactive flavonoid with antioxidant properties, while its role in treating LPD remains unclear. This study aims to investigate the therapeutic effects of QUE on infertility and menstrual disorders induced by LPD, thus further exploring the underlying mechanism. Mifepristone-induced rats are used to explore the protective effects of QUE against LPD. QUE stimulates the spontaneous secretion of progesterone to improve luteal function and endometrial receptivity in LPD rats by activating the kisspeptin/GPR54 system to facilitate the gonadotropin-releasing hormone (GnRH) pulsatility. Bioinformatics analysis reveals that the core mechanism of QUE in treating LPD is to attenuate the GnRH neuron pyroptosis by inhibiting the NF-κB pathway, which is further verified in LPD rats and lipopolysaccharide (LPS)-treated GT1-7, as QUE significantly reduces the expression of key factors concerning NF-κB pathway and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. This study first proposes that neuron pyroptosis-induced GnRH pulsatility disruption accounts for the pathogenesis of LPD, and QUE facilitates the pulse secretion of GnRH to boost the spontaneous progesterone secretion by inhibiting NF-κB/NLRP3-mediated neuron pyroptosis, which provides a new therapeutic target and strategy for LPD.

Development of 3D-Printed Two-Compartment Capsular Devices for Pulsatile Release of Peptide and Permeation Enhancer.

The oral absorption of a peptide is driven by a high local concentration of a permeation enhancer (PE) in the gastrointestinal tract. We hypothesized that a controlled release of both PE and peptide from a solid formulation, capable of maintaining an effective co-localized concentration of PE and peptide could enhance oral peptide absorption. In this study, we aimed to develop a 3D-printed two-compartment capsular device with controlled pulsatile release of peptide and sodium caprate (C10). 3D-printed two-compartment capsular device was fabricated using a fused deposition modeling method. This device was then filled with LY peptide and C10. The release profile was modulated by changing the thickness and polymer type of the capsular device. USP apparatus II dissolution test was used to evaluate the impacts of device thickness and polymer selection on release profile in vitro. An optimal device was then enteric coated with HPMCAS. A strong linear relationship between the thickness of capsular devices and the delay in the release onset time was observed. An increase in the device thickness or the use of PLA decreased the release rate. The capsular device with compartment 1, compartment 2 and fence thickness of 0.4; 0.95 and 0.5mm, respectively, and the use of PVA achieved desired pulsatile release profiles of both peptide and C10. Furthermore, enteric-coated capsular devices with HPMCAS had similar pulsatile release profiles compared to non-enteric coated devices. These findings suggest potential application of 3D-printing techniques in the formulation development for complex modified drug release products.

Corked Microcapsules Enabling Controlled Ultrasound-Mediated Protein Delivery.

While ultrasound represents a facile, portable, and noninvasive trigger for drug delivery vehicles, most reported ultrasound-triggered drug delivery vehicles predominately present "burst" release profiles that are hard to control after the initial activation stimulus. Herein, we report a submerged electrospraying technique to fabricate protein-loaded microcapsules in which silica "corks" are embedded within the microcapsule shell. Upon the application of an ultrasound trigger, the corks can be perturbed within the shell, allowing for the release of the protein payload through a phantom tissue mimic to a degree proportional to the number/time of pulses applied. Specifically, multiple ultrasound pulses were shown to enable a 15- to 23-fold increase in the rate of release of the model bovine serum albumin protein payload relative to no ultrasound being applied, with release returning to a lower level when the ultrasound stimulus was removed. Coupled with the low cytotoxicity of the vehicle components, the corked microcapsules show promise for expanding the potential to use ultrasound to facilitate both on-demand and pulsatile release profiles.

Pulsatile Drug Delivery System: A Review

As modern technologies advance, new methods of drug delivery systems are constantly being developed. Pulsatile drug delivery system is becoming increasingly popular because it can deliver the drug at the correct location, time, and dosage, improving patient adherence. These technologies are designed to align with the body's inherent circadian rhythm. Pulsatile drug release is mainly preferred when continuous drug release is not needed. Understanding the circadian clock's design, illness rhythm pathophysiology, and chrono pharmacology’s medication knowledge helps create and utilize chronotherapeutic dosage forms for effective disease treatment, reducing side effects, improving targeted drug delivery, and maintaining consistent dosing. Proper design of pulsatile drug delivery enhances patient adherence, targets drug distribution, and decreases side effects. Like many other medical conditions, the outlook for chronotherapy using pulsatile drug delivery seems very optimistic. Pulsatile drug delivery systems can utilize either one or multiple mechanisms to administer medication at a specific time and location. Formulation of pulsatile flow is achieved by incorporating different polymers, with the thickness of the coating layer dictating the speed of release of the active medicinal ingredient.

Pregnancy induction with pulsatile gonadotropin releasing hormone pump (GNRH) therapy in a patient with a KISS1 receptor mutation associated normosmic congenital hypogonadotropic hypogonadism and a very low anti-mullerian hormone: a case study

Pregnancy induction with pulsatile gonadotropin releasing hormone pump (GNRH) therapy in a patient with a KISS1 receptor mutation associated normosmic congenital hypogonadotropic hypogonadism and a very low anti-mullerian hormone: a case study

Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances.

Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1ARH) neurons are responsible for the pulsatile release of Gonadotropin-releasing Hormone (GnRH). In females, the behavior of Kiss1ARH neurons, expressing Kiss1, Neurokinin B (NKB), and Dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17β-estradiol (E2) reduces peptide expression but increases Vglut2 mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current and that contribute to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of Canonical Transient Receptor Potential (TPRC) 5 and G protein-coupled K+ (GIRK) channels. When TRPC5 channels in Kiss1ARH neurons were deleted using CRISPR, the slow excitatory postsynaptic potential (sEPSP) was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of the Kiss1ARH neuron, suggesting that E2 modifies ionic conductances in Kiss1ARH neurons, enabling the transition from high frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1ARH neurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons.

Stimulation Therapy to Induce Mothers: Protocol for a Multicenter Randomized Controlled Trial.

More than 1 million women have their labor induced in the United States each year, and synthetic oxytocin infusion is the most common method used. However, compared to spontaneous labor, medical induction is resource intensive, has increased obstetric risks, and is associated with less successful breastfeeding. In contrast to the endogenous oxytocin hormone, which is released in a pulsatile fashion in the brain, synthetic oxytocin is continuously infused intravenously, resulting in important limitations related to efficacy, safety, and cost. Akin to spontaneous labor contractions, infant suckling of the breast nipple is known to stimulate the pulsatile release of endogenous oxytocin from the posterior pituitary gland. Nipple stimulation therapy via an electric breast pump similarly stimulates endogenous oxytocin release and may be a favorable inpatient method for patients undergoing labor induction. This study aims to examine whether inpatient nipple stimulation therapy is an efficacious labor induction method that increases the likelihood of spontaneous vaginal delivery and sustained breastfeeding and determine whether it is a cost-effective approach. This is a multicenter, pragmatic, open-label, parallel-group randomized controlled trial of nulliparous patients with singleton gestations ≥36 weeks undergoing labor induction. This trial compares inpatient nipple stimulation therapy via an electric breast pump versus immediate synthetic oxytocin infusion without nipple stimulation. This trial including 988 nulliparas will provide adequate statistical power to detect clinically meaningful differences in delivery mode and breast milk as the sole source of nutrition for newborns at hospital discharge or 72 hours after birth. The project received pilot funding in 2021 and full funding in 2023. Enrollment for this study began in November 2021 at a single site, and as of May 2024, recruitment is underway at 3 study sites. It is anticipated that enrollment will be completed by late 2026. Successful completion of this trial will provide rigorous data to determine whether inpatient nipple stimulation therapy with an electric breast pump can improve the way we induce labor and positively impact breastfeeding success and early infant nutrition through lactation. ClinicalTrials.gov NCT05079841; https://clinicaltrials.gov/study/NCT05079841. DERR1-10.2196/63463.

Formulation, Optimization, and Evaluation of Ezetimibe for Chronotherapeutic Drug Delivery using Compression-Coating Technology

Objectives: The purpose of the present study was to Formulation, optimization and evaluation of drug for chronotherapeutic drug delivery using compression coating technology for hypercholesterolemia. Material and Methods: The drug delivery system was designed to deliver the drug at a time when it could be needed for the most in the early morning (4 to 6 a.m.) for patients in case of hypercholesterolemia. The pulsatile concept was applied to the dosage form by having a lag phase followed by an immediate release. The prepared system consisted of two parts: a core tablet containing the active ingredient and fracture outer shell with delay-release polymer having diffusion characteristics. Solid dispersion was carried out by screening of betacyclodextrin, Polyvinyl pyrrolidone (PVP K30), and HPMC using three different drug complex ratios 1:1, 1:2, and 1:3 by a solvent evaporation method through spray dryer. The immediate-release core tablet (IRCT) was prepared by using a superdisintegrant with active ingredients. Screening of IRCT was carried out by pre and post compression parameters, disintegration time and an in-vitro dissolution study. The pulsatile release tablet (PRT) of optimized IRCT was made by Glyceryl Behenate and Dibasic Calcium Phosphate. Optimization of polymer concentration of PRT was carried out by pre and post-compression parameters, pulsatile lag time, and an in-vitro dissolution study. A 32 factorial design was employed to optimize the PRT. The design consisted of two dependent variables R1, and R2 independent variables X1 and X2. The two independent formulation variables selected for the study including Concentration of coating polymer and Concentration of lubricant. The dependent variables are Lag Time and Thickness. Results: XRD, DSC and FTIR spectra showed that solid dispersion was formed by the drug and PVP K30 complex. IRCT batch RR1 containing 22mg croscarmellose sodium to achieve good 30sec disintegration time and 98.34% drug release at the end of 20 minutes of Ezetimibe respectively. PRT formulation DR6 showed good pre and post-compression parameters with a satisfactory drug release of 98.34% for Ezetimibe respectively with a lag time of 6 hours. The 32 factorial design was used for the optimization of PRT parameters. A total of 9 experiments were performed for two factors at three levels each. The optimized batch showed 98.27% DR for Ezetimibe in 6.2 hrs (within 20 min after lag time) with pulsatile lag time up to 6.0 hrs and thickness of 5.10 kp. Conclusion: It was concluded that tablet within the tablet, pulsatile drug delivery of Ezetimibe (BCS class-II drugs) was successfully formulated with the advantage of enhanced solubility, and pulsatile release behavior and had an added benefit of suitable for chronopharmacotherapy of diseases that show circadian rhythms in their pathophysiology.

Estrogen receptor-α signaling in tanycytes lies at the crossroads of fertility and metabolism

BackgroundEstrogen secretion by the ovaries regulates the hypothalamic-pituitary-gonadal axis during the reproductive cycle, influencing gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion, and also plays a role in regulating metabolism. Here, we establish that hypothalamic tanycytes—specialized glia lining the floor and walls of the third ventricle—integrate estrogenic feedback signals from the gonads and couple reproduction with metabolism by relaying this information to orexigenic neuropeptide Y (NPY) neurons. MethodsUsing mouse models, including mice floxed for Esr1 (encoding estrogen receptor alpha, ERα) and those with Cre-dependent expression of designer receptors exclusively activated by designer drugs (DREADDs), along with viral-mediated, pharmacological and indirect calorimetric approaches, we evaluated the role of tanycytes and tanycytic estrogen signaling in pulsatile LH secretion, cFos expression in NPY neurons, estrous cyclicity, body-weight changes and metabolic parameters in adult females. ResultsIn ovariectomized mice, chemogenetic activation of tanycytes significantly reduced LH pulsatile release, mimicking the effects of direct NPY neuron activation. In intact mice, tanycytes were crucial for the estrogen-mediated control of GnRH/LH release, with tanycytic ERα activation suppressing fasting-induced NPY neuron activation. Selective knockout of Esr1 in tanycytes altered estrous cyclicity and fertility in female mice and affected estrogen's ability to inhibit refeeding in fasting mice. The absence of ERα signaling in tanycytes increased Npy transcripts and body weight in intact mice and prevented the estrogen-mediated decrease in food intake as well as increase in energy expenditure and fatty acid oxidation in ovariectomized mice. ConclusionsOur findings underscore the pivotal role of tanycytes in the neuroendocrine coupling of reproduction and metabolism, with potential implications for its age-related deregulation after menopause. Significance statementOur investigation reveals that tanycytes, specialized glial cells in the brain, are key interpreters of estrogen signals for orexigenic NPY neurons in the hypothalamus. Disrupting tanycytic estrogen receptors not only alters fertility in female mice but also impairs the ability of estrogens to suppress appetite. This work thus sheds light on the critical role played by tanycytes in bridging the hormonal regulation of cyclic reproductive function and appetite/feeding behavior. This understanding may have potential implications for age-related metabolic deregulation after menopause.

Sirenian (manatees and dugongs) reproductive endocrinology

Reproductive hormones are essential to mating systems, behavior, fertility, gestation, parturition, and lactation in mammals and understanding the role of hormones in these processes is essential for species conservation. Sirenia is a unique order of marine mammals that include manatees, dugongs, and the extinct Steller’s sea cow. Extant Sirenian species are all listed as vulnerable due to habitat loss, cold stress, boat strike trauma, harmful algal bloom toxicity, entanglements, and illegal hunting. Therefore, successful reproduction is essential to maintaining and increasing Sirenian populations. Understanding Sirenian reproductive behavior, endocrinology, and mating strategies will aid conservation and management efforts to protect and provide the proper conditions for successful reproduction. The objectives of this review were to synthesize the current knowledge regarding reproductive cycles and endocrinology of Sirenians and identify knowledge gaps for future investigation. The current literature on Sirenian reproductive physiology reports reproductive seasonality, sexual maturation, estrous cyclicity and acyclicity, pregnancy, and sex differences. However, there remain significant knowledge gaps on the cyclicity and pulsatile release of gonadotropins, maturation in females, and characterization of pregnancy hormone profiles throughout gestation. To date, there is no explanation for confirmed pattern for ovarian acyclicity, nor understanding of the function of the numerous accessory corpus luteum described in manatees. Research including a greater number of longitudinal and postmortem studies on a wider variety of wild manatee populations are important first steps. Taken together, understanding the reproductive endocrinology of these vulnerable and threatened species is critical for policy and management decisions to better inform protection initiatives.

Sustained release system from PLGA particles co-encapsulated with inactivated influenza virus with natural killer T cell agonist α-galactosylceramide

Vaccines against influenza and many other infectious diseases require multiple boosters in addition to the primary dose to improve efficacy, but this approach is not ideal for compliance. The multiple doses could potentially be replaced by sustained or pulsatile release of antigens encapsulated in degradable microparticles (MPs). The efficacy of a vaccine is improved by adding an adjuvant, which can be co-delivered from the particles to enhance immunogenicity. Here, we developed degradable poly-lactic-co-glycolic acid (PLGA) (7–17 kDa) MPs capable of sustained release of ultraviolet killed influenza virus (A/PR/8/34) (kPR8) vaccine and the natural killer T (NKT) cell agonist alpha-galactosylceramide (α-GalCer) and tested their effectiveness at providing long-term protection against influenza virus infection in mice. Multiple formulations were developed for encapsulating the virus and adjuvant separately, and in combination. The MPs exhibited sustained release of both the virus and the adjuvant lasting more than a month. Co-encapsulation significantly increased the encapsulation efficiency (EE) of the vaccine but reduced the release duration. On the other hand, co-encapsulation led to a reduction in EE for the α-GalCer and a change in release profile to a higher initial burst followed by a linear release compared to a low initial burst and slower linear release. The α-GalCer also had considerably longer release duration compared to the vaccine. Mice injected with particle formulations co-encapsulating kPR8 and α-GalCer were protected from a lethal influenza virus infection 30 weeks after vaccination. This study demonstrates that PLGA MP based vaccines are promising for providing effective vaccination and possibly for replacing multiple doses with a single injection.

Time-Separated Pulse Release-Activation of an Enzyme from Alginate-Polyethylenimine Hydrogels Using Electrochemically Generated Local pH Changes.

β-Glucosidase (EC 3.2.1.21) from sweet almond was encapsulated into pH-responsive alginate-polyethylenimine (alginate-PEI) hydrogel. Then, electrochemically controlled cyclic local pH changes resulting from ascorbate oxidation (acidification) and oxygen reduction (basification) were used for the pulsatile release of the enzyme from the composite hydrogel. Activation of the enzyme was controlled by the very same pH changes used for β-glucosidase release, separating these two processes in time. Importantly, the activity of the enzyme, which had not been released yet, was inhibited due to the buffering effect of PEI present in the gel. Thus, only a portion of the released enzyme was activated. Both enzymatic activity and release were monitored by confocal fluorescence microscopy and regular fluorescent spectroscopy. Namely, commercially available very little or nonfluorescent substrate 4-methylumbelliferyl-β-d-glucopyranoside was hydrolyzed by β-glucosidase to produce a highly fluorescent product 4-methylumbelliferone during the activation phase. At the same time, labeling of the enzyme with rhodamine B isothiocyanate was used for release observation. The proposed work represents an interesting smart release-activation system with potential applications in biomedical field.

The role of neuroestrogens in the estrogen-induced gonadotropin surge in male monkeys.

Neuroestrogens locally synthesized in the brain are known to play a role in sexual behaviors. However, the question of whether neuroestrogens are involved in the regulation of the gonadotropin-releasing hormone (GnRH) release is just emerging. Because previous studies in this lab indicate that neuroestradiol is also important for the pulsatile release as well as the surge release of GnRH in female rhesus monkeys, in the present study, we examined whether neuroestradiol plays a role in the estrogen-induced LH surge in orchidectomized (ORX) male rhesus monkeys. Unlike in rodents, it is known that a high dose of estrogen treatment can result in the LH surge in ORX male rhesus monkeys. Results that the administration of the aromatase inhibitor, letrozole, failed to attenuate the estrogen-induced LH surge, suggest that unlike in ovariectomized females, neuroestrogens do not play a role in the LH surge experimentally induced by the exogenous estrogen treatment in ORX male monkeys.

Body Condition in Small Ruminants—Effects of Nutrition on the Hypothalamic–Pituitary–Gonad Axis and Ovarian Activity That Controls Reproduction

Nutritional status plays a vital role in regulating ovary activity. This regulation is mediated by the hypothalamus–pituitary–gonad axis and by effects exerted directly on the ovary. Therefore, to achieve the best reproductive performance, it is essential to know how the nutritional status affects the secretion of GnRH, gonadotrophins, and sex steroid hormones. Adequate body reserves and energy balance are critical for optimal reproductive performance in sheep and goats. However, over- or under-conditioned animals experience issues like extended anestrus, irregular ovarian cycles, and reduced conception. Body condition scoring allows for the evaluation of the relationships between adiposity, nutritional status, and fertility. Acute feed deficits briefly stimulate processes, but chronic restrictions suppress pulsatile LH release, disrupting ovarian function. The process of follicle development is a very complex one which involves intricate interactions between the pituitary gonadotrophins and metabolic hormones as well as between the locally produced factors by the ovarian somatic and germ cells including the IGF system and the TGF-β superfamily members. Genotype and nutrition are factors that have an impact on follicular development, and seasonal factors are also involved. This review will give a brief overview on how the body condition can be evaluated and the effects of nutrition on the hypothalamus–pituitary–gonad axis and ovarian activity, which are responsible for reproductive regulation. This paper presents a clear and reasonable summary of the pathway that runs from the nutritional status of small ruminants to ovarian activity through the hypothalamic–pituitary–gonadal axis. This review summarizes methods for body condition evaluation in small ruminants and evidence regarding acute versus prolonged nutritional impacts on the hypothalamic–pituitary–gonadal axis and ovarian activity controlling reproduction.

Pulsatile gonadotropin releasing hormone therapy for spermatogenesis in congenital hypogonadotropic hypogonadism patients who had poor response to combined gonadotropin therapy.

Both pulsatile gonadotropin-releasing hormone (GnRH) and combined gonadotropin therapy are effective to induce spermatogenesis in men with congenital hypogonadotropic hypogonadism (CHH). This study aimed to evaluate the effect of pulsatile GnRH therapy on spermatogenesis in male patients with CHH who had poor response to combined gonadotropin therapy. Patients who had poor response to combined gonadotropin therapy ≥ 6 months were recruited and shifted to pulsatile GnRH therapy. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, testosterone, and testicular volume were used for data analysis. A total of 28 CHH patients who had poor response to combined gonadotropin (HCG/HMG) therapy for 12.5 (6.0, 17.75) months were recruited and switched to pulsatile GnRH therapy for 10.0 (7.25, 16.0) months. Sperm was detected in 17/28 patients (60.7%). The mean time for the appearance of sperm in semen was 12.0 (7.5, 17.5) months. Compared to those who could not achieve spermatogenesis during pulsatile GnRH therapy, the successful group had a higher level of LH60min (4.32 vs. 1.10 IU/L, P = 0.043) and FSH60min (4.28 vs. 1.90 IU/L, P = 0.021). Testicular size increased during pulsatile GnRH therapy, compared to previous HCG/ HMG therapy (P < 0.05). For CHH patients with prior poor response to one year of HCG/ HMG therapy, switching to pulsatile GnRH therapy may induce spermatogenesis.

3D printing of multi-unit gastro-retentive tablets for the pulsatile release of artesunate

Pulsatile drug delivery is hardly achieved by conventional gastro-retentive dosage forms. Artesunate as a typical anti-malaria medicine needs oral pulsatile release. Here, artesunate-loaded pulsatile-release multi-unit gastro-retentive tablets (APGTs) were prepared with a semi-solid extrusion three-dimensional (3D) printing method. An APGT was composed of three units: artesunate-loaded immediate and delayed release units and a block unit. The matrix of the immediate/delayed release units consisted of polyvinylpyrrolidone (PVP) K30 and croscarmellose sodium, which improved the rapid release of artesunate when contacting water. The block unit consisted of octadecanol, hydroxypropyl methyl cellulose K15M, PVP K30, and poloxamer F68. APGTs showed multi-phase release in simulated gastric liquids (SGLs). The first immediate release phase continued for 1 h followed by a long block phase for 7 h. The second rapid release phase was initiated when the eroded holes in the block unit extended to the inner delayed release unit, and this phase continued for about 14 h. Low-density APGTs could ensure their long-term floating in the stomach. Oral APGTs remained in the rabbit stomach for about 20 h. 3D printing provides a new strategy for the preparation of oral pulsatile-release tablets.

Engineered shapes using electrohydrodynamic atomization for an improved drug delivery.

The shapes of micro- and nano-products have profound influences on their functional performances, which has not received sufficient attention during the past several decades. Electrohydrodynamic atomization (EHDA) techniques, mainly include electrospinning and electrospraying, are facile in manipulate their products' shapes. In this review, the shapes generated using EHDA for modifying drug release profiles are reviewed. These shapes include linear nanofibers, round micro-/nano-particles, and beads-on-a-string hybrids. They can be further divided into different kinds of sub-shapes, and can be explored for providing the desired pulsatile release, sustained release, biphasic release, delayed release, and pH-sensitive release. Additionally, the shapes resulted from the organizations of electrospun nanofibers are discussed for drug delivery, and the shapes and inner structures can be considered together for developing novel drug delivery systems. In future, the shapes and the related shape-performance relationships at nanoscale, besides the size, inner structure and the related structure-performance relationships, would further play their important roles in promoting the further developments of drug delivery field. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Effect of intra-uterine administration of Lactobacillus bacteria on the steroid hormone profile in sub-clinical endometritis affected cows

Infertility in bovines is a major cause of serious economic loss to the dairy farmers. A major reason for infertility is sub-clinical, retrograde uterine infections. Sub-clinical endometritis is endometrial inflammation without apparent clinical manifestation and usually without signs of infection. This condition may be due to uterine infections or an extended inflammatory period that exists after elimination of bacteria. At present, infertility treatment is mainly done with intrauterine antibacterials, antiseptics and less commonly by hormones. These days, the major problem faced by animal reproductive health workers is the multiple drug resistance pathogens because of the indiscriminate use of antibiotics.Therefore, a different approach for more effective treatment of subclinical endometritis with Lactobacilli and its role on the steroid hormone profile was studied. In the present study, estradiol-17 β values were lower in the sub-clinical endometritis affected cows. Whereas, intra-uterine administration of Lactobacillus bacteria caused significant increase in estradiol level in a cycle after treatment in cross- bred cows. Similarly, the circulating serum progesterone concentration was also found to be low in subclinical endometritis affected cows. These findings could be used for clinical and experimental interpretations. Further, the information on pulsatile release of gonadotropins and steroid hormones status, receptors and its control, the close relationship among hormones could be necessary for better understanding of the role of steroid hormones in sub-clinical uterine infections.

Oxytocin and women's health in midlife.

Menopause marks the cessation of fertility and the transition to post-reproductive years. Nearly 1 million US women experience menopause annually, but despite the significant impact it has on their physical and mental health, menopause has been insufficiently studied. Oxytocin is a neurohormone that regulates emotionality, social behaviors, and fundamental physiological systems. Localization of oxytocin receptors in the brain, reproductive tissues, bone, and heart support their role in mental health and potentially sleep, along with reproductive and cardiovascular functions. While experimental data linking oxytocin to behavior and physiology in animals are largely consistent, human data are correlative and inconclusive. As women transition into menopause, oxytocin levels decrease while their susceptibility to mood disorders, poor sleep, osteoporosis, and cardiovascular diseases increases. These concurrent changes highlight oxytocin as a potential influence on the health and mood of women along their reproductive life span. Here, we summarize experimental rodent and non-human primate studies that link oxytocin to reproductive aging and metabolic health and highlight the inconclusive findings in studies of women. Most human studies relied on a single oxytocin assessment in plasma or on intranasal oxytocin administration. The pulsatile release and short half-life of plasma oxytocin limit the validity of these methods. We discuss the need for oxytocin assessments in stable bio-samples, such as urine, and to use valid assays for assessment of associations between changing oxytocin levels and well-being across the reproductive life span. This work has the potential to guide therapeutic strategies that will one day alleviate adverse health outcomes for many women.

Stiffness Modulation and Pulsatile Release in Dual Responsive Hydrogels.

Inspired by nature, self-regulation can be introduced in synthetic hydrogels by incorporating chemo-mechanical signals or coupled chemical reactions to maintain or adapt the material's physico-chemical properties when exposed to external triggers. In this work, we present redox and light dual stimuli responsive hydrogels capable of rapidly adapting the polymer crosslinking network while maintaining hydrogel stability. Upon irradiation with UV light, polymer hydrogels containing redox responsive disulfide crosslinks and light responsive ortho-nitrobenzyl moieties show a release of payload accompanied by adaptation of the hydrogel network towards higher stiffness due to in situ crosslinking by S-nitrosylation. Whereas the hydrogel design allows the network to either become softer in presence of reducing agent glutathione or stiffer upon UV irradiation, simultaneous application of both stimuli induces network self-regulation resulting in a pulsatile form of payload release from the hydrogel. Finally, adaptive stiffness was used to make tunable hydrogels as substrates for different cell lines.