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Background The aim of this report was to describe a case of pregnancy after drug-free in vitro activation (IVA) of follicles and fresh tissue autotransplantation in primary ovarian insufficiency (POI) patient and to review the pertinent literature. Methods We present a case in wich a 32 - years old patient with POI became pregnant after IVA without tissue culture and with ovarian tissue transplantation. We also reviewed the literature using Pubmed database. Case presentation Pretreatment with estradiol/progesterone stopped the day before surgery. The removal of the ovarian cortex and autotransplantation were performed by laparoscopy in the same surgical act. Ovarian fragments were transplanted in contralateral ovary and peritoneal pocket near to the ovary. Immediately after surgery GnRH agonist together HMG injections started, leading the growth of 3 preovulatory follicles and the retrieval of two mature eggs. After IVF two embryos were transferred and singleton pregnancy was established and currently she is 25 weeks pregnant. Results A total of 51 patients with POI in whom an in vitro activation of ovarian tissue was performed, were collected from the revieew of the literature. In 29.4% of them, follicular development was obtained and in 4 of them a pregnancy . In all of them, a combined technique (fragmentation and activation) was performed in two laparoscopies . No case has been reported successfully after drug-free in vitro activation. Conclusions This is the first report about a case with pregnancy after drug-free in vitro activation of follicles and fresh tissue autotransplantation in POI patient.

Drug-Free IVA has been recently introduced as a therapeutic option for patients with Primary Ovarian Insufficiency (POI). Despite the existing limited results, it can be considered as a promising option for these patients to achieve their own offspring. Here we report the case of a 35-year-old woman diagnosed with POI at 30 years of age. Drug-Free IVA was performed at age 33 and pregnancy was achieved by IVF 10 months after grafting. Unfortunately, she had a preterm delivery with neonatal death due to prematurity complications. After delivery, she recovered spontaneous ovarian function and one mature oocyte was retrieved 20 months after Drug-Free IVA. Following IVF, one embryo was transferred, and she is currently 33 weeks pregnant, suggesting that Drug-free IVA could lead to long-term ovarian function.

In vitro activation (IVA) represents a new frontier in the treatment of women with primary ovarian insufficiency as well as patients with cancer desiring fertility preservation. Here, we review the biological basis of IVA and the recent translation of IVA to humans by targeting Hippo and Akt-signaling pathways. We then provide a new integrated viewpoint on IVA, highlighting basic science research on the aspects of follicular development and ovarian tissue transplantation which may potentially optimize future translational research on IVA. Specific topics discussed include cryopreservation techniques, additional IVA pathway targets, the roles of actin polymerization, paracrine and endocrine factors, and the role of mechanical signaling and associated tissue rigidity in controlling ovarian follicular activation. Further research and improved understanding is needed to optimize success of IVA.

Skin wounds are common in accidental injuries, and the intricacies of wound repair are closely linked to endogenous electric fields. Electrical stimulation plays a pivotal role in the restorative processes of skin injuries, encompassing collagen deposition, angiogenesis, inflammation, and re-epithelialization. Employing electrical stimulation therapy replicates and enhances the effects of endogenous wound electric fields by applying an external electric field to the wound site, thereby promoting skin wound healing. In this study, we developed a self-powered repetitive mechanical impacts-electrical stimulation (RMI-ES) system utilizing a BaTiO 3 /polydimethylsiloxane (PDMS) piezoelectric composite film. Compared to conventional electrical stimulation devices, the fabricated piezoelectric composite film efficiently harvests energy from the pressure applied by the stimulation device and the tensile force occurring during natural rat activities. The results demonstrated that piezoelectric stimulation generated by the composite membrane expedited the cell cycle, promoting fibroblast proliferation. Additionally, piezoelectric stimulation induced favorable changes in fibroblast gene expression, including increased expression of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), collagen 1, collagen 3, vascular endothelial growth factor (VEGF), and alpha-smooth muscle actin (α-SMA), while reducing interleukin-6 (IL-6) expression. Transcriptome analysis revealed that piezoelectric stimulation may induce fibroblast migration, proliferation, and collagen expression by influencing PI3K/AKT serine/threonine kinase (AKT) pathways. Further confirmation through the addition of the PI3K inhibitor LY294002 validated that piezoelectric stimulation can regulate the repair process after skin injury through the pathway. Importantly, in vivo results demonstrated that the electric field at the wound site effectively promoted wound healing, reduced inflammation, and stimulated collagen deposition and neovascularization. This study emphasizes the role of the piezoelectric membrane as an effective, safe, and battery-free electrical stimulator crucial for skin wound healing.

A noninvasive deep brain stimulation via temporal interference (TI) electric fields is a novel neuromodulation technology, but few advances about TI stimulation effectiveness and mechanisms have been reported. One hundred twenty-six mice were selected for the experiment by power analysis. In the present study, TI stimulation was proved to stimulate noninvasively primary motor cortex (M1) of mice, and 7-day TI stimulation with an envelope frequency of 20 Hz (∆f =20 Hz), instead of an envelope frequency of 10 Hz (∆f =10 Hz), could obviously improve mice motor performance. The mechanism of action may be related to enhancing the strength of synaptic connections, improving synaptic transmission efficiency, increasing dendritic spine density, promoting neurotransmitter release, and increasing the expression and activity of synapse-related proteins, such as brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), and glutamate receptor protein. Furthermore, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and its upstream BDNF play an important role in the enhancement of locomotor performance in mice by TI stimulation. To our knowledge, it is the first report about TI stimulation promoting multiple motor performances and describing its mechanisms. TI stimulation might serve as a novel promising approach to enhance motor performance and treat dysfunction in deep brain regions.

Metabolic triggers are important inducers of the inflammatory processes in gout. Whereas the high serum urate levels observed in patients with gout predispose them to the formation of monosodium urate (MSU) crystals, soluble urate also primes for inflammatory signals in cells responding to gout-related stimuli, but also in other common metabolic diseases. In this study, we investigated the mechanisms through which uric acid selectively lowers human blood monocyte production of the natural inhibitor IL-1 receptor antagonist (IL-1Ra) and shifts production toward the highly inflammatory IL-1β. Monocytes from healthy volunteers were first primed with uric acid for 24 h and then subjected to stimulation with lipopolysaccharide (LPS) in the presence or absence of MSU. Transcriptomic analysis revealed broad inflammatory pathways associated with uric acid priming, with NF-κB and mammalian target of rapamycin (mTOR) signaling strongly increased. Functional validation did not identify NF-κB or AMP-activated protein kinase phosphorylation, but uric acid priming induced phosphorylation of AKT and proline-rich AKT substrate 40 kDa (PRAS 40), which in turn activated mTOR. Subsequently, Western blot for the autophagic structure LC3-I and LC3-II (microtubule-associated protein 1A/1B-light chain 3) fractions, as well as fluorescence microscopy of LC3-GFP–overexpressing HeLa cells, revealed lower autophagic activity in cells exposed to uric acid compared with control conditions. Interestingly, reactive oxygen species production was diminished by uric acid priming. Thus, the Akt–PRAS40 pathway is activated by uric acid, which inhibits autophagy and recapitulates the uric acid-induced proinflammatory cytokine phenotype.

Objective Theta-burst stimulation, including intermittent (iTBS) and continuous (cTBS) protocols, is a promising neuromodulatory intervention for autism spectrum disorder (ASD). This study aims to elucidate the therapeutic mechanisms of iTBS and cTBS for ASD. Methods Prenatal valproic acid-induced ASD rats were established and were randomized into VPA, VPA + iTBS, and VPA + cTBS groups, with a saline group as control. Core and comorbid ASD behaviors in rats were assessed. Multi-omics analyses included 16 S rRNA sequencing of cecal contents, non-targeted fecal metabolomics, and prefrontal cortex transcriptomics. Key pathways were validated via Western blot, ELISA, and immunofluorescence. Integrative analyses correlated multi-omics data with neuroendocrine findings. Results Behavioral assessments demonstrated that both iTBS and cTBS significantly ameliorated social deficits and repetitive behaviors in VPA-exposed rats. However, protocol-specific effects on comorbidities were observed: cTBS, but not iTBS, effectively alleviated anxiety-like behaviors, whereas iTBS, but not cTBS, significantly improved learning and memory. The multi-omics approach demonstrated that iTBS primarily modulated inflammatory immune responses and energy metabolism, while cTBS predominantly regulated oxidative stress, lipid metabolism, and nucleotide metabolism. Both interventions suppressed the hyperactivated PI3K/AKT/mTOR signaling pathway, an effect potentially linked to the normalization of hypothalamic-pituitary axis function. Furthermore, we identified a potential interplay between the GH/IGF-1 axis and the gut microbiome in ASD, which was differentially modulated by iTBS and cTBS. Conclusion iTBS modulated inflammatory-immune responses and energy metabolism, while cTBS regulated oxidative stress, lipid metabolism, and nucleotide metabolism. The inhibition of the central GH/PI3K/AKT/mTOR pathway by both protocols may involve their specific regulation of distinct gut microbiota communities. Graphical Abstract

Metabolic pathways that regulate T-cell function show promise as therapeutic targets in diverse diseases. Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cells. Despite having low resting metabolic rates, naive T-cells respond to TCR stimulation with robust and rapid increases in glycolysis and OXPHOS. This early metabolic switch requires Akt activity to support increased rates of glycolysis and STAT5 activity for amino acid biosynthesis and TCA cycle anaplerosis. Importantly, both STAT5 inhibition and disruption of TCA cycle anaplerosis are associated with reduced IL-2 production, demonstrating the functional importance of this early metabolic program. Our results define STAT5 as a key node in modulating the early metabolic program following activation in naive CD4+ T-cells and in turn provide greater understanding of how cellular metabolism shapes T-cell responses. T-cell subsets differ in metabolic requirements for particular tasks. Here the authors characterize metabolic fluxes in naïve human CD4+ cells upon activation, and identify a role of Stat5 in glutaminolysis linked to IL-2 production.

Neurodegeneration implies progressive neuronal loss and neuroinflammation further contributing to pathology progression. It is a feature of many neurological disorders, most common being Alzheimer’s disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation which modulates excitability of stimulated brain areas through magnetic pulses. Numerous studies indicated beneficial effect of rTMS in several neurological diseases, including AD, however exact mechanism are yet to be elucidated. We aimed to evaluate the effect of intermittent theta burst stimulation (iTBS), an rTMS paradigm, on behavioral, neurochemical and molecular level in trimethyltin (TMT)-induced Alzheimer’s-like disease model. TMT acts as a neurotoxic agent targeting hippocampus causing cognitive impairment and neuroinflammation, replicating behavioral and molecular aspects of AD. Male Wistar rats were divided into four experimental groups –controls, rats subjected to a single dose of TMT (8 mg/kg), TMT rats subjected to iTBS two times per day for fifteen days and TMT sham group. After three weeks, we examined exploratory behavior and memory, histopathological and changes on molecular level. TMT-treated rats exhibited severe and cognitive deficit. iTBS-treated animals showed improved cognition. iTBS reduced TMT-induced inflammation and increased anti-inflammatory molecules. We examined PI3K/Akt/mTOR signaling pathway which is involved in regulation of apoptosis, cell growth and learning and memory. We found significant downregulation of phosphorylated forms of Akt and mTOR in TMT-intoxicated animals, which were reverted following iTBS stimulation. Application of iTBS produces beneficial effects on cognition in of rats with TMT-induced hippocampal neurodegeneration and that effect could be mediated via PI3K/Akt/mTOR signaling pathway, which could candidate this protocol as a potential therapeutic approach in neurodegenerative diseases such as AD.

Background Atrophy of the masseter muscle can result in an aged facial appearance and diminished chewing function. Electrical stimulation (ES) is known for its ability to facilitate tissue healing and functional recovery, but its precise role in the repair of atrophic masseter muscles remains incompletely understood. Methods We induced masseter muscle atrophy in rats through botulinum toxin (BTX) injection and subsequently treated the animals with or without ES. Single‐nucleus sequencing (sn‐RNA seq) was conducted to analyse the changes in macrophages of masseter muscles between control, BTX and BTX + ES groups. The role and mechanism of macrophage phenotypic transformation in the process of ES promoting the recovery of atrophied masseter muscles were both verified through in vivo and in vitro experiments. Results Our results indicate that ES treatment within defined current parameters significantly ameliorated muscle condition by reducing atrophy‐related gene expression (MuRF1: BTX: 10.15 ± 1.69; BTX + ES: 1.05 ± 0.06; Fbxo32: BTX: 8.62 ± 1.19, BTX + ES: 1.19 ± 0.07, p < 0.0001) and enhancing vascularisation (Vegf positive area: BTX: 6.60 ± 2.87%, BTX + ES: 27.23 ± 1.70%, p < 0.001). Analysis conducted with sn‐RNA seq demonstrated increased infiltration of M1 macrophages during muscle atrophy, with a subsequent transition to M2 macrophages following ES treatment (M1 macrophage portion: Ctrl: 15.2%, BTX: 25.8%, BTX + ES: 14.7%; M2 macrophages: Ctrl: 67.9%, BTX: 46.9%, BTX + ES: 70.5%). Further investigations demonstrated that ES reduced M1 macrophage infiltration (five‐fold lower of CD86+ cell number, BTX: 30 ± 2; BTX + ES: 6 ± 2, p < 0.0001) while increasing M2 macrophage presence (3.3‐fold higher of CD163+cell, BTX: 10 ± 3; BTX + ES: 33 ± 8, p < 0.01), potentially via activation of the PI3K‐Akt pathway (p‐Akt/Akt ratio, BTX:0.58 ± 0.20%; BTX + ES:1.03 ± 0.07%, p < 0.05). Depletion of macrophages using clodronate liposomes reversed the beneficial effects of ES on induced masseter atrophy (MuRF1: BTX + ES: 2.20 ± 0.16; BTX + ES + CL: 12.93 ± 0.98, p < 0.0001), highlighting the involvement of macrophages in the therapeutic process. In vitro studies demonstrated that ES promoted the transition from M1 to M2 macrophages and enhanced proliferation and differentiation of myogenic cells. Conclusions Our findings suggest that ES can enhance masseter muscle tissue repair by modulating macrophage polarisation, offering valuable insights into the potential of ES in noninvasive tissue regeneration strategies for treating masseter muscle atrophy.