Reparative Mechanisms Research Articles

Ethnic variations in post ST elevation myocardial infarction inflammatory kinetics

Abstract Introduction Sterile inflammation post myocardial infarction (MI) is essential to activation reparative mechanisms. However, excessive inflammation contributes to detrimental recovery and adverse outcomes(1). Several studies have reported an association between elevated leucocyte subpopulations and neutrophil-lymphocyte ratio (NLR) with poor prognosis after MI(2). In healthy volunteers, it is known that black individuals have a lower diurnal neutrophil, basophil, and monocyte count and the term ‘benign ethnic neutropenia’ has been used(3). However, the effect of ethnicity on leucocyte counts after MI is not known. Purpose We aimed to assess the interaction between ethnicity and leucocyte subpopulations and NLR. Understanding post-MI inflammation and its interaction with ethnicity is essential in providing personalised patient management and prognostication. Methods We conducted a single centre retrospective observational study of consecutive patients presenting with ST-segment elevation MI (STEMI) between 2016 and 2022. Patients were divided into white and other ethnic groups combined (‘ethnic minorities’) based on self-reported ethnicity. Leucocyte subpopulations, neutrophil and monocyte lymphocyte ratios (NLR and MLR, respectively) at baseline and for 4 days post admission were compared. Baseline variables were analysed with Shapiro-Wilk testing and presented as median (IQR). Area under the curve (AUC) was used to analyse magnitude of change in longitudinal analysis with smoothed conditional means (LOESS) to display trends in the data. Univariate and multivariate linear regression analyses were used to investigate for an association between ethnicity and baseline clinical variables. Results We included 1933 STEMI patients, of whom 1477 (76%) were white and 456 (24%) were from ethnic minority groups. Baseline neutrophils (7.73 [5.9-10] vs 9.04 [6.7-11.9] x109/L), monocytes (0.52 [0.38-0.69] vs 0.6 [0.44-0.82] x109/L), basophils (0.03 [0.02-0.04] vs 0.04 [0.02-0.06] x109/L), NLR (4.47 [2.93-7.19] vs 5.61 [3.64-8.89]) and MLR (0.3 [0.21-0.43] vs 0.36 [0.26-0.53]) were significantly lower (all p<0.001) in ethnic minority vs white patients. There were no differences in peak troponin T or CRP. Longitudinal assessment of leucocyte subgroups and NLR showed that white patients had a significantly higher AUC and difference between minimum and maximum values (delta) for neutrophils, monocytes, basophils and NLR (Panel 1). After correction, we observed a negative association between being in the ethnic minority group and baseline NLR (p=0.005) and basophil count (p<0.001). Conclusions Despite baseline differences in leucocyte subgroups and NLR according to ethnicity, there is a distinct interaction among patients with STEMI suggesting an ethnicity-specific inflammatory profile. Blunting of the magnitude and duration of leucocyte response is novel, and future work will focus on the implications for prognosis and tailored therapy.

Immunomodulatory hydrogel orchestrates pro-regenerative response of macrophages and angiogenesis for chronic wound healing

Chronic wound healing often encounters challenges characterized by prolonged inflammation and impaired angiogenesis. While the immune response plays a pivotal role in orchestrating the intricate process of wound healing, excessive inflammation can hinder tissue repair. In this study, a bilayer alginate hydrogel system encapsulating polyelectrolyte complex nanoparticles (PCNs) loaded with anti-inflammatory cytokines and angiogenic growth factors is developed to address the challenges of chronic wound healing. The alginate hydrogel is designed using two distinct crosslinking methods to achieve differential degradation, thereby enabling precise spatial and temporal controlled release of PCNs. Initially, interleukin-10 (IL-10) is released to mitigate inflammation, while unsaturated PCNs bind and remove accumulated pro-inflammatory cytokines at the wound site. Subsequently, angiogenic growth factors, including vascular endothelial growth factor and platelet-derived growth factor, are released to promote vascularization and vessel maturation. Our results demonstrate that the bilayer hydrogel exhibits distinct degradation kinetics between the two layers, facilitating the staged release of multiple signaling molecules. In vitro experiments reveal that IL-10 can activate the Jak1/STAT3 pathway, thereby suppressing pro-inflammatory cytokines and chemokines while down-regulating inflammation-related genes. In vivo studies demonstrate that application of the hydrogel in chronic wounds using diabetic murine model promotes healing by positively modulating multiple integral reparative mechanisms. These include reducing inflammation, promoting macrophage polarization towards a pro-regenerative phenotype, enhancing keratinocyte migration, stimulating angiogenesis, and expediting wound closure. In conclusion, our hydrogel system effectively mitigates inflammatory responses and provides essential physiological cues by inducing a synergistic angiogenic effect, thus offering a promising approach for the treatment of chronic wounds.

Returns, Marches and Countermarches: The Agony for Truth and Justice

The present research aims to describe and characterize the actions in the reparation processes of Grandmothers of Plaza de Mayo, and Mothers and Relatives of Disappeared Detainees, in Argentina and Uruguay respectively, in the period from 2005 to 2015, in the face of the effects of political violence and state terrorism. It is proposed to make visible what the organizations' actions have been to influence advances in reparations, with special emphasis on concrete actions in contexts of self-styled "progressive" governments. A qualitative research is proposed, with the substantive use of the technique of documentary analysis and in-depth interviews for data collection, and for the analysis of said data we proceeded through discourse analysis. The results indicate that the central axes linked to comprehensive reparation in each organization are oriented towards: psychosocial reparation, accompaniment in the search process, progress at the legal level, recognition by the State of its responsibility before the crimes committed, the clarification of the truth, especially in the awareness of young people, with an educational paradigm that encourages education for memory. Reparatory mechanisms have manifested themselves in a similar way in the contexts of political progressivism, both in Argentina and Uruguay. However, the Argentine context has established a greater deployment of policies, with a special focus on the restitution of rights, and guarantees of non-repetition, developing an instituting policy promoted by the human rights movement. In the Uruguayan case, although progressivism enabled the creation of new institutions, providing new spaces and a budget to respond to the citizenship and mainly to the victims' relatives, for truth, justice and reparation, these have been poorly satisfactory measures, in where there is still a consolidation of policies, demanded by the human rights movement.

Recent advances in shape memory scaffolds and regenerative outcomes.

The advent of tissue engineering (TE) technologies has revolutionized human medicine over the last few decades. Despite splendid advances in the fabricating and development of different substrates for regenerative purposes, non-responsive static composites have been used to heal injured tissues. After being transplanted into the target sites, grafts will lose their original features, leading to a reduction in regenerative potential. Along with these statements, the use of shape memory polymers (SMPs), smart substrates with unique physicochemical properties, has been extended in different disciplines of regenerative medicine in recent years. These substrates are intelligent and they can easily change physicogeometry features such as stiffness, strain size, shape, etc. in response to external stimuli. It has been proposed that SMPs can easily acquire their original properties after deformation, even in the presence or absence of certain stimuli. It has been indicated that the application of distinct synthesis protocols is required to fabricate dynamically switchable surfaces with prominent cell-to-substrate interaction, resulting in better regulation of cell function, dynamic growth, and reparative mechanisms. Here, we aimed to scrutinize the prominent regenerative properties of SMPs in the TE and regenerative medicine fields. Whether and how SMPs can orchestrate certain cell behavior, with reconfigurable features and adaptability were discussed in detail.

Beyond Trauma-Induced Coagulopathy: Detection of Auto-Heparinization as a Marker of Endotheliopathy Using Rotational Thromboelastometry.

Background/Objectives: The complexity of trauma-induced coagulopathy (TIC) is a result of the unique interactions between the patient, trauma, and resuscitation-related causes. The main objective of trauma resuscitation is to create the optimal milieu for both the development of immediate reparatory mechanisms and the prevention of further secondary injuries. Endotheliopathy represents one of the hallmarks of trauma-induced coagulopathy, and comprises endothelial dysfunction, abnormal coagulation, and inflammation, all of which arise after severe trauma and hemorrhagic shock. Methods: We retrospectively and descriptively evaluated 217 patients admitted to the Bucharest Clinical Emergency Hospital who met the Berlin criteria for the diagnosis of multiple trauma. Patients with high suspicion of auto-heparinization were identified according to the dynamic clinical and para-clinical evolution and subsequently tested using rotational thromboelastometry (ROTEM). The ratio between the clot formation time (CT) was used, obtained on the two channels of interest (INTEM/HEPTEM). Results: Among the 217 patients with a mean age of 43.43 ± 15.45 years and a mean injury severity score (ISS) of 36.98 ± 1.875, 42 patients had a reasonable clinical and para-clinical suspicion of auto-heparinization, which was later confirmed by the INTEM/HEPTEM clotting time ratio in 28 cases (12.9% from the entire study population). A multiple linear regression analysis highlighted that serum lactate (estimated 0.02, p = 0.0098) and noradrenaline requirement (estimated 0.03, p = 0.0053) influenced the CT (INTEM/HEPTEM) ratio. Conclusions: There is a subset of multiple trauma patients in which the CT (INTEM/HEPTEM) ratio was influenced only by serum lactate levels and patients' need for vasopressor use, reinforcing the relationship between shock, hypoperfusion, and clotting derangements. This emphasizes the unique response that each patient has to trauma.

Transcending antibiotic resistance: The potential of mass Galla chinensis et camelliae Fermentata to Dismantle Helicobacter pylori biofilms and enhance anti-biotic activity

Ethnopharmacological relevanceHelicobacter pylori (H. pylori) infections are on the rise, presenting a significant global health challenge. Mass Galla chinesis et camelliae Fermentata (Chinese gall leaven, CGL), a traditional Chinese medicinal product made from the fermentation of Rhus chinensis Mill., is frequently employed to address digestive system ailments. Contemporary pharmacological research reveals that CGL exhibits anti-inflammatory, anti-diarrheal, and enzyme-inhibitory activities and holds potential as a treatment for H. pylori infections. However, the precise mechanisms underlying CGL's efficacy against H. pylori remain to be fully elucidated. AimThe objective of the study is to evaluate CGL's ability to disrupt the H. pylori biofilm and to explore its synergistic potential with antibiotics in targeting the biofilm-efflux pump system, a mechanism implicated in bacterial resistance. MethordsThe study determined the Minimum Inhibitory Concentration (MIC) of CGL and metronidazole against H. pylori and evaluated their effects on H. pylori biofilms using an in vitro model. Structural changes induced by drug interventions were compared to those in untreated and antibiotic-treated models through scanning electron microscopy and laser confocal microscopy. The accumulation of H33342 dye in planktonic and biofilm H. pylori before and after drug treatment was assessed to evaluate cell viability and biofilm disruption. The study also involved adding experimental drugs to a biofilm H. pylori medium containing D-glucose, measuring glucose concentrations post-intervention using the glucose oxidase method, and calculating changes in glucose uptake. Finally, the relative expression levels of several genes in planktonic and biofilm H. pylori treated with CGL alone or in combination with antibiotics were measured to understand the impact on the biofilm-efflux pump system. ResultsBoth CGL alone and in combination with metronidazole demonstrated effective disruption of H. pylori biofilms. The combination therapy was particularly effective in reducing the biofilm transfer-enhancing effect of metronidazole and decreasing SpoT expression in the 'SpoT-(p)ppGpp' pathway, especially in biofilms. It showed a greater inhibition of the 'σ54-gluP-sugar uptake' pathway, with significant reductions in rpoN and gluP expression under biofilm conditions compared to CGL or metronidazole alone. The treatment also suppressed H. pylori proliferation and may have altered glucose uptake mechanisms. Moreover, it significantly inhibited the 'hp0939/hp0497/hp0471-RND efflux pump' pathway, with a notable reduction in gene expression compared to the 1/2 MIC metronidazole treatment. ConclusionThis study demonstrates that CGL effectively hinders the development of drug resistance in H. pylori by targeting biofilm formation and critical molecular pathways associated with antibiotic resistance. The synergistic effect of combining CGL with metronidazole notably enhances biofilm disruption and inhibits the bacterium's metabolic and reparative mechanisms. Further in vivo studies are needed to confirm these results and to investigate additional mechanisms of CGL's action.

Impaired mitochondrial quality control in fibromyalgia: Mechanisms involved in skeletal muscle alteration

Fibromyalgia (FMS) is a persistent syndrome marked by widespread musculoskeletal pain and behavioural symptoms. Given the hypothesis linking FMS aetiology to mitochondrial dysfunction and oxidative stress, we examined the biochemical correlation among these factors by studying specific proteins associated with mitochondrial homeostasis in muscle. Additionally, this study investigated the role of Boswellia serrata gum resin extract (BS), known for its various functions, including the potent induction of antioxidant enzymes, in determining protective or reparative mechanisms in the muscle cells. Sprague–Dawley rats were injected with reserpine to induce FMS.These animals exhibited moderate changes in hind limb skeletal muscles, experiencing mobility difficulties. Additionally, there were noteworthy morphological and ultrastructural alterations, along with the expression of myogenin, mitochondrial enzymes and oxidative stress markers in the gastrocnemius muscle. Interestingly, BS demonstrated a reduction in spontaneous motor activity difficulties. Moreover, BS showed a positive impact on musculoskeletal morphostructural aspects, as well as a decrease in oxidative stress and mitochondrial alterations. In particular, BS restored the mRNA expression of citrate synthase and cytochrome-c oxidase subunit II and the activity of electron transfer chain complexes. BS also influenced mitochondrial biogenesis, upregulating PGC-1α expression and the related transcription factors (Nrf1, Tfam, Nrf2, FOXO3a, SIRT3, GCLC, NQO1, SOD2 and GPx4), oxidative stress (lipid peroxidation, GSH levels and GSH-Px activity) and mitochondrial dynamics and function (Mnf2 expression and CoQ10 levels). Overall, this study underlined the key role of the mitochondrial alteration in FMS and that BS had a very high antioxidant effect in these organelles and also in the cells.

Micro-needle mesotherapy in anti-aging prevention and skin rejuvenation - the importance of inflammation, healing and skin regeneration after the procedure

The skin serves numerous vital roles in the human body, such as protecting against physical, chemical, and mechanical injuries. Although skin aging is a natural phenomenon, it is still the subject of research by scientists seeking methods to delay the process. One of the innovative treatments in this field is micro-needle mesotherapy, referred to as collageninducing therapy. The study aimed to describe the features of the ageing skin, elucidate the alterations that occur with time, and investigate the reparative mechanisms triggered by micro-needle mesotherapy treatment. Microneedle-induced skin inflammation is a desirable process. It leads to the healing of damage and can significantly contribute to wrinkle shallowing, improved hydration and skin remodeling.

Role of Mesenchymal Stem/Stromal Cells (MSCs) and MSC-Derived Extracellular Vesicles (EVs) in Prevention of Telomere Length Shortening, Cellular Senescence, and Accelerated Biological Aging.

Biological aging is defined as a progressive decline in tissue function that eventually results in cell death. Accelerated biologic aging results when the telomere length is shortened prematurely secondary to damage from biological or environmental stressors, leading to a defective reparative mechanism. Stem cells therapy may have a potential role in influencing (counteract/ameliorate) biological aging and maintaining the function of the organism. Mesenchymal stem cells, also called mesenchymal stromal cells (MSCs) are multipotent stem cells of mesodermal origin that can differentiate into other types of cells, such as adipocytes, chondrocytes, and osteocytes. MSCs influence resident cells through the secretion of paracrine bioactive components such as cytokines and extracellular vesicles (EVs). This review examines the changes in telomere length, cellular senescence, and normal biological age, as well as the factors contributing to telomere shortening and accelerated biological aging. The role of MSCs-especially those derived from gestational tissues-in prevention of telomere shortening (TS) and accelerated biological aging is explored. In addition, the strategies to prevent MSC senescence and improve the antiaging therapeutic application of MSCs and MSC-derived EVs in influencing telomere length and cellular senescence are reviewed.

Exploring the Efficacy of Hydroxybenzoic Acid Derivatives in Mitigating Jellyfish Toxin-Induced Skin Damage: Insights into Protective and Reparative Mechanisms.

The escalation of jellyfish stings has drawn attention to severe skin reactions, underscoring the necessity for novel treatments. This investigation assesses the potential of hydroxybenzoic acid derivatives, specifically protocatechuic acid (PCA) and gentisic acid (DHB), for alleviating Nemopilema nomurai Nematocyst Venom (NnNV)-induced injuries. By employing an in vivo mouse model, the study delves into the therapeutic efficacy of these compounds. Through a combination of ELISA and Western blot analyses, histological examinations, and molecular assays, the study scrutinizes the inflammatory response, assesses skin damage and repair mechanisms, and investigates the compounds' ability to counteract venom effects. Our findings indicate that PCA and DHB significantly mitigate inflammation by modulating critical cytokines and pathways, altering collagen ratios through topical application, and enhancing VEGF and bFGF levels. Furthermore, both compounds demonstrate potential in neutralizing NnNV toxicity by inhibiting metalloproteinases and phospholipase-A2, showcasing the viability of small-molecule compounds in managing toxin-induced injuries.

Roles of airway and intestinal epithelia in responding to pathogens and maintaining tissue homeostasis.

Epithelial cells form a resilient barrier and orchestrate defensive and reparative mechanisms to maintain tissue stability. This review focuses on gut and airway epithelia, which are positioned where the body interfaces with the outside world. We review the many signaling pathways and mechanisms by which epithelial cells at the interface respond to invading pathogens to mount an innate immune response and initiate adaptive immunity and communicate with other cells, including resident microbiota, to heal damaged tissue and maintain homeostasis. We compare and contrast how airway and gut epithelial cells detect pathogens, release antimicrobial effectors, collaborate with macrophages, Tregs and epithelial stem cells to mount an immune response and orchestrate tissue repair. We also describe advanced research models for studying epithelial communication and behaviors during inflammation, tissue injury and disease.

Mandibular Overdenture Supported by Two or Four Unsplinted or Two Splinted Ti-Zr Mini-Implants: In Vitro Study of Peri-Implant and Edentulous Area Strains.

Clinical indications for the newly released Ti-Zr (Roxolid®) alloy mini-implants (MDIs) aimed for overdenture (OD) retention in subjects with narrow alveolar ridges are not fully defined. The aim of this study was to analyze peri-implant and posterior edentulous area microstrains utilizing models of the mandible mimicking a "real" mouth situation with two (splinted with a bar or as single units) or four unsplinted Ti-Zr MDIs. The models were virtually designed from a cone beam computed tomography (CBCT) scan of a convenient patient and printed. The artificial mucosa was two millimeters thick. After MDI insertion, the strain gauges were bonded on the oral and vestibular peri-implant sites, and on distal edentulous areas under a denture. After attaching the ODs to MDIs, the ODs were loaded using a metal plate positioned on the first artificial molars (posterior loadings) bilaterally and unilaterally with 50, 100, and 150 N forces, respectively. During anterior loadings, the plate was positioned on the denture's incisors and loaded with 50 and 100 N forces. Each loading was repeated 15 times. The means with standard deviations, and the significance of the differences (two- and three-factor MANOVA) were calculated. Variations in the MDI number, location, and splinting status elicited different microstrains. Higher loading forces elicited higher microstrains. Unilateral loadings elicited higher microstrains than bilateral and anterior loadings, especially on the loading side. Peri-implant microstrains were lower in the four-MDI single-unit model than in both two-MDI models (unsplinted and splinted). Posterior implants showed higher peri-implant microstrains than anterior in the four-MDI model. The splinting of the two-MDI did not have a significant effect on peri-implant microstrains but elicited lower microstrains in the posterior edentulous area. The strains did not exceed the bone reparatory mechanisms, although precaution and additional study should be addressed when two Ti-Zr MDIs support mandibular ODs.

Deinstitutionalization as Reparative Justice: A Commentary on the Guidelines on Deinstitutionalization, including in Emergencies

In this paper, I argue that the Committee on the Rights of Persons with Disabilities Guidelines on Deinstitutionalization, Including in Emergencies function as an instrument and template for reparative justice towards persons still in institutions and survivors of institutionalization. The Guidelines construct deinstitutionalization as a reparative process at both the systemic and individual levels, as well as calling for the creation of reparation and redress mechanisms. I examine the entire body of the Guidelines, highlight their reparative content, and point out where the text may fall short of this perspective and how the shortcomings might be remedied. This paper is grounded in the situation of psychiatric institutionalization and the concerns of people subjected to that system, emphasizing issues faced by this constituency and its human rights concerns for redress and legal and societal change. The issues addressed include the following: the strengthening of normative standards with regard to the abolition of psychiatric institutionalization and forced interventions and the obligation to immediately end these violations; a policy shift towards the de-medicalization of psychosocial disability; the implications of reparative justice in diminishing the role and authority of those that have operated institutions including the mental health system; the role of adult persons with disabilities as members of families and the role played by some family members in institutionalization; issues to be considered in designing reparations processes and mechanisms. Following some introductory remarks, this paper is structured to follow the outline of the Guidelines, quoting the text with interspersed comments and ending with a brief conclusion.

Influence of Implant Number on Peri-Implant and Posterior Edentulous Area Strains in Mandibular Overdentures Retained by the New Ti–Zr (Roxolid®) Mini-Implants as Single-Units: In Vitro Study

The new Ti–Zr (Roxolid®) mini-implants have not yet been fully researched. We analyzed peri-implant and posterior edentulous area microstrains during mandibular overdenture (OD) loading at different sites with different extents of forces when one-, two-, three-, or four- mini dental implants (MDIs) as single-units supported the respective ODs. The models were designed from cone beam computed tomography (CBCT) scans of an appropriate patient with narrow ridges. The mucosal thickness was 2 mm. Strain gauges were bonded on the vestibular and oral peri-implant sites, and in the distal edentulous area under the saddles. The loads were applied posteriorly bilaterally and unilaterally with 50, 100 and 150 N forces, and anteriorly with 50 and 100 N forces. Each loading was repeated 15 times. Statistical analysis included descriptive statistics, boxplots and the MANOVA. Higher forces induced higher peri-implant microstrains, as well as unilateral loadings, especially on the loaded side, in all models except the one-MDI model where anterior loads (100 N) elicited the highest peri-implant microstrain (1719.35 ± 76.0). The highest microstrains during unilateral posterior loading (right side) with 150 N force were registered from the right MDI in the two-MDI model (1836.64 ± 63.0). High microstrains were also recorded on the left side (1444.48 ± 54.6). By increasing the number of implants, peri-implant microstrains and those in the edentulous area decreased. In the three- and four-MDI models, higher microstrains were found in the posterior than in the anterior MDIs under posterior loadings. None of the recorded microstrains exceeded bone reparatory mechanisms, although precaution and additional research should be provided when only one or two MDIs support ODs.

Reactive Gliosis in Neonatal Disorders: Friend or Foe for Neuroregeneration?

A developing nervous system is particularly vulnerable to the influence of pathophysiological clues and injuries in the perinatal period. Astrocytes are among the first cells that react to insults against the nervous tissue, the presence of pathogens, misbalance of local tissue homeostasis, and a lack of oxygen and trophic support. Under this background, it remains uncertain if induced astrocyte activation, recognized as astrogliosis, is a friend or foe for progressing neonatal neurodevelopment. Likewise, the state of astrocyte reactivity is considered one of the key factors discriminating between either the initiation of endogenous reparative mechanisms compensating for aberrations in the structures and functions of nervous tissue or the triggering of neurodegeneration. The responses of activated cells are modulated by neighboring neural cells, which exhibit broad immunomodulatory and pro-regenerative properties by secreting a plethora of active compounds (including interleukins and chemokines, neurotrophins, reactive oxygen species, nitric oxide synthase and complement components), which are engaged in cell crosstalk in a paracrine manner. As the developing nervous system is extremely sensitive to the influence of signaling molecules, even subtle changes in the composition or concentration of the cellular secretome can have significant effects on the developing neonatal brain. Thus, modulating the activity of other types of cells and their interactions with overreactive astrocytes might be a promising strategy for controlling neonatal astrogliosis.

Paraprobiotic and postbiotic forms of Bacillus siamensis improved growth, immunity, liver and intestinal health in Lateolabrax maculatus fed soybean meal diet

Live commensal Bacillus siamensis LF4 showed reparative potentials against high SM-induced negative effects, but whether its paraprobiotic (heat-killed B. siamensis, HKBS) and postbiotic (cell-free supernatant, CFS) forms had reparative functions and potential mechanisms are not yet known. In this study, the reparative functions of HKBS and CFS were investigated by establishing an injured model of spotted seabass (Lateolabrax maculatus) treated with dietary high soybean meal (SM). The results showed that HKBS and CFS effectively mitigated growth suppression, immune deficiency, and liver injury induced by dietary high SM. Simultaneously, HKBS and CFS application positively shaped intestinal microbiota by increased the abundance of beneficial bacteria (Fusobacteria, Firmicutes, Bacteroidota, and Cetobacterium) and decreased harmful bacteria (Proteobacteria and Plesiomonasare). Additionally, HKBS and CFS improved SM-induced intestinal injury by restoring intestinal morphology, upregulating the expression of tight junction proteins, anti-inflammatory cytokines, antimicrobial peptides, downregulating the expression of pro-inflammatory cytokines and apoptotic proteins. Furthermore, HKBS and CFS intervention significantly activated TLR2, TLR5 and MyD88 signaling, and eventually inhibited p38 and NF-κB pathways. In conclusion, paraprobiotic (HKBS) and postbiotic (CFS) from B. siamensis LF4 can improve growth, immunity, repair liver and intestinal injury, and shape intestinal microbiota in L. maculatus fed high soybean meal diet, and TLRs/p38 MAPK/NF-κB signal pathways might be involved in those processes. These results will serve as a base for future application of paraprobiotics and postbiotics to prevent and repair SM-induced adverse effects in fish aquaculture.

Перспективи внутрішньоутробного лікування запальних змін евентрованих органів при гастрошизисі у плодів (огляд літератури)

Gastroschisis (GS) - is one of the most severe defects of newborns, which is characterized by congenital eventration of the abdominal organs outside the anterior abdominal wall into the amniotic fluid, due to a through defect of the anterior abdominal wall. The defect is adjacent to the normal, unaltered umbilical cord, usually to the right of the umbilicus, the umbilical ring is split, the eventrated organs are not covered by embryonic membranes or their remains. The frequency of gastroschisis is 0.31-4.72 per 10,000 births. Although, with the development of modern surgical approaches over the past 15 years, the mortality of newborns with gastroschisisis dynamically decreasing, however, this pathology remains a significant problem in neonatal and pediatric surgery, as it requires early surgery, associated with a significant risk of disability in children due to short bowel syndrome, abdominal cancer and recurrent esophageal disease, adhesive intestinal obstruction, etc. Purpose - to analyze, according to the literature, the prospects for the use of cellular technologies for the in utero treatment of inflammatory changes in the enteric organs in fetal GS in experimental conditions. The main reason for the unsatisfactory results of GS treatment is the pathological changes of the eventrated organs and their consequences. Therefore one of the ways to reduce mortality in GS is intrauterine treatment and the prevention of inflammatory changes of the eventrated organs in the fetuses. Modern regenerative medicine offers several new approaches for the treatment of fetal malformations, including the use of cell technology. Stem cells, from various sources, are one of the alternative therapies that can inhibit inflammatory processes in tissues, activate endogenous reparative mechanisms, and, ultimately, together with the implementation of preventive measures, reduce perinatal mortality and disability. The availability of domestic cell drugs, the development of technologies for their transplantation, and methods of delivery of pregnant women with GS in the fetus, with proven clinical efficacy, will significantly improve the comprehensive treatment of patients with congenital malformations, which is significant social and economic importance. Therefore, the study of regenerative potential and assessment of the prospects for the use of stem cells in obstetrics and perinatal medicine from various sources is of great scientific and practical interest. No conflict of interests was declared by the authors.

FAD mutants decrease brain neovascularization and neuronal survival by targeting angiogenic mechanisms of PS1/γ‐secretase

AbstractBackgroundThe cerebrovascular system is central to neuronal survival and function and emerging evidence suggests that vascular brain abnormalities are involved in the development of neurodegenerative disorders such as Alzheimer’s disease (AD). Angiogenesis, the generation of new blood vessels from existing vasculature, is crucial throughout adult life for maintaining brain blood circulation and for reparative mechanisms of toxic insults such as ischemia. Angiogenesis is controlled by growth factors including the Vascular Endothelial Growth Factor (VEGF). By binding to its receptor (VEGFR2), VEGF regulates extension of new blood vessels in damaged areas and maintains blood supply to tissues and organs. FAD variants of Presenilin1 (PS1), the catalytic subunit of γ‐secretase induce Familial AD (FAD) and can serve as systems where mechanisms of AD‐like neurodegeneration can be studied.MethodsMouse brain endothelial cells (ECs) expressing knock‐in PS1 FAD mutants were isolated and cultured and effects of PS1/γ‐secretase on angiogenic functions and processing of VEGFR2 were performed as in literature. VEGF‐induced phosphorylation of kinases downstream of VEGFR2 were determined on WBs. Middle cerebral artery occlusion (MCAO) was performed in mice as in literature. Isolated brains were sectioned using a mouse brain matrix and slices were stained with TTC and fixed with 4% PFA to detect infarct area. Cerebral blood flow (CBF) was assessed using perfusion MRI (pMRI) as in literature. Neurons were stained with anti‐NeuN and positive neurons in lesioned and contralateral areas were countedResultsPS1/γ‐secretase process VEGFR2 and regulate crucial functions of the brain VEGF/VEGFR2 system including receptor dimerization, internalization and downstream angiogenic signaling. Importantly, PS1 FAD mutants decrease the VEGF‐induced activation and angiogenic signaling of VEGFR2 and reduce brain neovascularization suggesting mechanisms by which PS1 FAD mutants may cause neuronal dysfunction and death. In this presentation we discuss the importance of the PS1/γ‐secretase on the VEGFA/VEGFR2‐mediated angiogenenic signaling and brain neovascularization and test effects of PS1FAD mutants in brain neoangiogenesis and neuronal survival.ConclusionsThe PS1/γ‐secretase system regulates brain angiogenesis and neovascularization by activating properties of the VEGF/VEGFR2 system. PS1 FAD mutants decrease brain angiogenesis, neovascularization and neuronal survival by targeting angiogenic mechanisms of PS1 and γ‐secretase.

LIPUS-induced neurogenesis:A potential therapeutic strategy for cognitive dysfunction in traumatic brain injury

Traumatic brain injury (TBI) precipitates cellular membrane degeneration, phospholipid degradation, neuronal demise, impaired brain electrical activity, and compromised neuroplasticity, ultimately leading to acute and chronic brain dysfunction. Low-intensity pulsed ultrasound (LIPUS) is an emerging brain therapy with the characteristics of non-invasive, high spatial resolution, and high stimulation depth. Herein, we established a controlled cortical impact model to investigate the potential reparative mechanisms of LIPUS in TBI, employing a multi-faceted research methodology encompassing behavioral assessments, immunofluorescence, neuroelectrophysiology, scratch detection of primary cortical neurons, metabolomics and transcriptomics. Our findings demonstrate that LIPUS promotes hippocampal neurogenesis following brain injury, accomplished through the elevation of phosphatidylcholine levels in the hippocampus of TBI mice. Consequently, LIPUS enhances neural electrical activity and augments neural plasticity within the CA1 subregion of the hippocampus, effectively restoring neuronal function and cognitive capabilities in TBI mice. These findings shed light on the promising role of LIPUS in TBI brain rehabilitation, offering new perspectives and theoretical foundations for future studies in this domain.

Dense dopaminergic innervation of the peri-infarct cortex despite dopaminergic cell loss after a pure motor-cortical stroke in rats.

After ischemic stroke, the cortex directly adjacent to the ischemic core (i.e., the peri-infarct cortex, PIC) undergoes plastic changes that facilitate motor recovery. Dopaminergic signaling is thought to support this process. However, ischemic stroke also leads to the remote degeneration of dopaminergic midbrain neurons, possibly interfering with this beneficial effect. In this study, we assessed the reorganization of dopaminergic innervation of the PIC in a rat model of focal cortical stroke. Adult Sprague-Dawley rats either received a photothrombotic stroke (PTS) in the primary motor cortex (M1) or a sham operation. 30 days after PTS or sham procedure, the retrograde tracer Micro Ruby (MR) was injected into the PIC of stroke animals or into homotopic cortical areas of matched sham rats. Thus, dopaminergic midbrain neurons projecting into the PIC were identified based on MR signal and immunoreactivity against tyrosine hydroxylase (TH), a marker for dopaminergic neurons. The density of dopaminergic innervation within the PIC was assessed by quantification of dopaminergic boutons indicated by TH-immunoreactivity. Regarding postsynaptic processes, expression of dopamine receptors (D1- and D2) and a marker of the functional signal cascade (DARPP-32) were visualized histologically. Despite a 25% ipsilesional loss of dopaminergic midbrain neurons after PTS, the number and spatial distribution of dopaminergic neurons projecting to the PIC was not different compared to sham controls. Moreover, the density of dopaminergic innervation in the PIC was significantly higher than in homotopic cortical areas of the sham group. Within the PIC, D1-receptors were expressed in neurons, whereas D2-receptors were confined to astrocytes. The intensity of D1- and DARPP-32 expression appeared to be higher in the PIC compared to the contralesional homotopic cortex. Our data suggest a sprouting of dopaminergic fibers into the PIC and point to a role for dopaminergic signaling in reparative mechanisms post-stroke, potentially related to recovery.