Tissue Damage Effects Research Articles

Histopathological and histochemical analysis of the digestive tract of adult horseshoe crabs under mercury stress.

Mercury (Hg) contamination is a major environmental concern that continuously impacts marine organisms, including the mangrove horseshoe crab (Carcinoscorpius rotundicauda). As a vulnerable species, C. rotundicauda holds significant ecological and evolutionary value, making it particularly susceptible to Hg pollution and deserving of focused conservation efforts. This study presents the first comprehensive histopathological and histochemical analysis of mercury toxicity in the digestive tract of adult C. rotundicauda. Through both qualitative and quantitative analyses of histopathological and histochemical alterations, we evaluated the effects of acute Hg exposure (0.5 mg/L and 5 mg/L) on the esophagus, stomach, and intestines over time. The results revealed significant dose- and time-dependent tissue damage, with the stomach exhibiting the most pronounced alterations, including epithelial detachment, vacuolation caused by fibers degradation in the loose connective tissue, and muscle layer disruption, followed by the esophagus and intestines. Additionally, mucous cell density in the hindgut submucosa decreased by 30 % after 96 h of acute Hg exposure (0.5 and 5 mg/L HgCl2), indicating a weakened protective barrier. The tissue damage of the digestive tract may further have a negative impact on the health of the adult horseshoe crab, thus threatening the survival of C. rotundicauda population and reducing the biodiversity of the mangrove ecosystem. These findings underscore the critical threat posed by Hg pollution to the digestive system of C. rotundicauda and offer novel insights into the toxicological impact on marine invertebrates. Considering the tissue-damaging effects of Hg on adult horseshoe crabs, this study underscores the importance of regular monitoring of Hg contamination in natural habitats. The results offer valuable guidance for future habitat restoration and effective management of existing habitats.

Histopathological characterization of skin and muscle lesions induced by lionfish (Pterois volitans) venom in a murine experimental model.

Fish venoms have been poorly characterized and the available information about their composition suggests they are uncomplicated secretions that, combined with epidermal mucus, could induce an inflammatory reaction, excruciating pain, and, in some cases, local tissue injuries. In this study, we characterized the 24-hour histopathological effects of lionfish venom in a mouse experimental model by testing the main fractions obtained by size exclusion-HPLC. By partial proteomics analysis, we also correlated these in vivo effects with the presence of some potentially toxic venom components. We observed a strong lesion on the skin and evident necrosis in the skeletal muscle. None of the tissue-damaging effects were induced by the fraction containing cytolysins, membrane pore-forming toxins ubiquitously present in species of scorpionfish, stonefish, and lionfish, among others. On the contrary, injuries were associated with the presence of other components, which have remained practically ignored so far. This is the case of an abundant protein, present in venom, with homology to a Golgi-associated plant pathogenic protein 1-like (GAPR1), which belongs to the same protein superfamily as venom CRISPs and insect allergens. This GAPR1-like protein and the hyaluronidase are probably responsible for the hemostasis impairment and hemorrhagic lesions observed in mouse skin, whereas muscle injuries can be indirectly caused by a combination of inflammatory and hemorrhagic events. More information is required to establish the components accountable for the myonecrotic effect.

A deep learning framework for in silico screening of anticancer drugs at the single-cell level.

Tumor heterogeneity plays a pivotal role in tumor progression and resistance to clinical treatment. Single-cell RNA sequencing (scRNA-seq) enables us to explore heterogeneity within a cell population and identify rare cell types, thereby improving our design of targeted therapeutic strategies. Here, we use a pan-cancer and pan-tissue single-cell transcriptional landscape to reveal heterogeneous expression patterns within malignant cells, precancerous cells, as well as cancer-associated stromal and endothelial cells. We introduce a deep learning framework named Shennong for in silico screening of anticancer drugs for targeting each of the landscape cell clusters. Utilizing Shennong, we could predict individual cell responses to pharmacologic compounds, evaluate drug candidates' tissue damaging effects, and investigate their corresponding action mechanisms. Prioritized compounds in Shennong's prediction results include FDA-approved drugs currently undergoing clinical trials for new indications, as well as drug candidates reporting anti-tumor activity. Furthermore, the tissue damaging effect prediction aligns with documented injuries and terminated discovery events. This robust and explainable framework has the potential to accelerate the drug discovery process and enhance the accuracy and efficiency of drug screening.

Innovative Use of Nanomaterials in Treating Retinopathy of Prematurity

Background/Objectives: Retinopathy of prematurity (ROP) is a severe condition primarily affecting premature infants with a gestational age (GA) of 30 weeks or less and a birth weight (BW) of 1500 g or less. The objective of this review is to examine the risk factors, pathogenesis, and current treatments for ROP, such as cryotherapy, laser photocoagulation, and anti-VEGF therapy, while exploring the limitations of these approaches. Additionally, this review evaluates emerging nanotherapeutic strategies to address these challenges, aiming to improve ROP management. Methods: A comprehensive literature review was conducted to gather data on the pathogenesis, traditional treatment methods, and novel nanotherapeutic approaches for ROP. This included assessing the efficacy and safety profiles of cryotherapy, laser treatment, anti-VEGF therapy, and nanotherapies currently under investigation. Results: Traditional treatments, while effective in reducing disease progression, exhibit limitations, including long-term complications, tissue damage, and systemic side effects. Nanotherapeutic approaches, on the other hand, have shown potential in offering targeted drug delivery with reduced systemic toxicity, improved ocular drug penetration, and sustained release, which could decrease the frequency of treatments and enhance therapeutic outcomes. Conclusions: Nanotherapies represent a promising advancement in ROP treatment, offering safer and more effective management strategies. These innovations could address the limitations of traditional therapies, reducing complications and improving outcomes for premature infants affected by ROP. Further research is needed to confirm their efficacy and safety in clinical practice.

Use of arthroscopy in management of tibial plateau fractures

Introduction Tibial plateau fractures are periarticular injuries of the proximal tibia often associated with soft tissue injury. They account for 1-2% of all fractures. Their impact on the articular surfaces and the development of osteoarthritis make them an interesting research topic in the orthopaedic field. With the development of arthroscopic treatment methods, many are thinking of ways to incorporate less invasive methods in the reduction and fixation of these injuries. Review methods English-language scientific literature found in PubMed and Google Scholar was used for the review. Articles were searched based on keywords. Each article was analyzed for knowledge currency and relevance for use in the review. Description of the State of Knowledge After searching the articles, 35 articles were selected for final analysis. The collected data provided the latest information on treatment of tibial plateau fractures (TPF) using arthroscopic tools with studies diving deep into both the technique and longer-term results. Summary The use of arthroscopy in treatment of tibial plateau fractures grows year by year with more and more clinicians being interested in limiting the soft tissue damage and other adverse effects of ORIF Keywords: Schatzker, arthroscopy, tibial plateau fracture

Efficacy of interstitial photodynamic therapy using talaporfin sodium and a semiconductor laser for a mouse allograft glioma model

To investigate the therapeutic potential of photodynamic therapy (PDT) for malignant gliomas arising in unresectable sites, we investigated the effect of tumor tissue damage by interstitial PDT (i-PDT) using talaporfin sodium (TPS) in a mouse glioma model in which C6 glioma cells were implanted subcutaneously. A kinetic study of TPS demonstrated that a dose of 10 mg/kg and 90 min after administration was appropriate dose and timing for i-PDT. Performing i-PDT using a small-diameter plastic optical fiber demonstrated that an irradiation energy density of 100 J/cm2 or higher was required to achieve therapeutic effects over the entire tumor tissue. The tissue damage induced apoptosis in the area close to the light source, whereas vascular effects, such as fibrin thrombus formation occurred in the area slightly distant from the light source. Furthermore, when irradiating at the same energy density, irradiation at a lower power density for a longer period of time was more effective than irradiation at a higher power density for a shorter time. When performing i-PDT, it is important to consider the rate of delivery of the irradiation light into the tumor tissue and to set irradiation conditions that achieve an optimal balance between cytotoxic and vascular effects.

Toxicity Evaluation and Tissue Damaging Effects of Lead in Labeo Rohita

Heavy metal contamination of aquatic ecosystems due to industrialization and anthropogenic activities has become a serious global issue. Toxic effects of these heavy metals are posing a major threat to the aquatic organisms especially fish. Fishes exposed to lead (Pb), exhibit a wide-range of effects including muscular and neurological degeneration and destruction, growth inhibition, mortality, reproductive problems, and paralysis. Many fish species are used as food source by man. Bio magnification of these metals makes them hazardous for humans. Objective: To evaluate the acute toxicity (96-hr LC50 and lethal concentrations) of Pb in Labeo rohita and the effect of various sub-lethal doses of Pb on different organs (Gills, Liver, and Muscles) of fish. Methods: Live fish samples (150) were shifted from hatchery to laboratory. To measure metal (Pb), accumulation in fish body inductively coupled Plasma mass spectrometry (ICP-MS) was performed. Results: Acute toxicity (96-hr LC50) of Pb was observed as 52.20 mg/l, while Pb accumulation was noted more in gills as compared to liver and muscles. Conclusions: This study will provide baseline information for the control of aquatic pollution and conservation of aquatic organisms

Abstract 6831: Single-cell-based epigenetic and transcriptomic analysis in the KPC pancreatic cancer mouse model revealed dynamiccharacteristic subtypes of cancer-associated fibroblasts

Abstract Pancreatic cancer features robust fibrosis, with 40-80% fibrotic tissue and a dense stroma, highlighting the crucial need to grasp cellular interactions in the cancer microenvironment. In this study, we used single-cell RNA sequencing (scRNA-seq) to analyze pancreatic tissues from 60-day-old normal mouse (n=1) (GSE125588) and KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) cancer model with tumor diameter of 1-2 cm (n=2) (GSE129455). By examining fibroblast clusters, we identified distinct subtypes of cancer-associated fibroblasts (CAFs), and revealed four clusters: normal fibroblasts cluster, inflammatory CAFs (iCAFs) cluster marked by increased expression of IL6 and other cytokines, myofibroblast CAFs (myCAFs) cluster solely in the KPC model, and antigen-presenting CAFs (apCAFs) cluster expressing Mesothelin. We found that expression pattern of iCAFs in the KPC appeared similar to normal cells than myCAFs, suggesting a potential role in inhibiting cancer. it is reported that mesothelial cells might transition to apCAFs under the influence of IL6 and TGFβ due to tissue damage and inflammatory effects. This transition was visualized in our apCAF cluster, suggesting a potential pathway for the transformation of mesothelial cells into apCAFs. Next, in order to analyze epigenetic profiles of fibroblasts, we conducted single-cell Assay for Transposase-Accessible Chromatin with high-throughput sequencing (scATAC-seq) using 90-day-old KPC mice (n=2) and a wild-type mouse (n=1).scATAC-seq showed that there are mainly two clusters of fibroblasts, one cluster corresponded to myCAF, enriched with PDPN, while the other represented iCAF cluster, enriched with COL1A2. These data suggest that in terms of the epigenetic state, myCAF contain several different CAFs and have the potential to differentiate into either myCAFs or other type of based on certain stimulation. Ultimately, CAF differentiated into three distinct subtypes as revealed by scRNA-seq. This highlights that despite similar epigenetic states, various transcription factors characterize the functionality of these fibroblast subtypes. Further exploration of the underlying mechanism that lead to different CAF subtypes might help in controlling the microenvironment of pancreatic cancer. Citation Format: Keita Sasaki, Keiko Shinjo, Xingxing Wang, Kohei Kumegawa, Reo Raruyama, Shinji Mii, Yoshiteru Murofushi, Miho Suzuki, Atsushi Enomoto, Yutaka Kondo. Single-cell-based epigenetic and transcriptomic analysis in the KPC pancreatic cancer mouse model revealed dynamiccharacteristic subtypes of cancer-associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6831.

The mammary gland is intolerant to bacterial intrusion

Mammals depend on the secretion of milk to rear their offspring, which exposes the organ in charge of the function, the mammary gland (MG), to bacterial threat. The essential driving force that conditions the interactions of bacteria with the MG is the abundant secretion of milk, a nutritious fluid which endows the common mastitis-causing pathogens with a doubling time of less than 30 min. From this angle, mammals rely on a potential bacterial bioreactor for the survival of their offspring. The MG is lined with a two-layered epithelium devoid of protective mucus. This means that the mammary epithelium is exposed directly to bacteria once they have passed through the opening lactiferous canal. To cope with the threat, the MG resorts to neutrophilic inflammation to check bacterial proliferation in its lumen and at its epithelial lining. Promptness of neutrophil recruitment is a necessity, which requires a low threshold of activation on the part of the mammary epithelium. Constrained by natural selection, the MG has evolved an innate and adaptive immunity intolerant to bacteria regardless of their level of virulence. The evolutionary issue has been to find a compromise between the deleterious tissue-damaging side effects of inflammation and the maintenance of the secretory function indispensable for the offspring’s survival. It appears that the MG relies mainly on neutrophilic inflammation for its protection and is regulated by type 3 immunity. Advances in knowledge of type 3 immunity in the MG will be necessary to induce immune protection adapted to the physiology of this peculiar organ.

Pathogenetic Bases of Systemic Morphological Manifestations of Coal Worker’s Pneumoconiosis: A Review

Introduction: Miners are at increased risk of developing pneumoconiosis that poses a serious threat to their health. Progressive pneumosclerosis and bronchial mucosa atrophy are typical pathological changes in this disease. At the same time, there is evidence of systemic manifestations of pneumoconiosis. In this regard, a deeper understanding of how long-term exposure to coal dust affects pathophysiological processes not only in the target organ, but also in the whole body is required. Objective: To generalize and systematize ideas about the pathogenetic foundations of systemic morphological manifestations of black lung disease. Materials and methods: To obtain information, we have carried out a search for relevant studies published in 1995–2022 in Scopus, PubMed, and RISC databases using the following keywords: pneumoconiosis, miners, morphological changes, pathogenesis, free radical oxidation, inflammation, immune response, cytokines, growth factors, and endothelial dysfunction. We selected 59 full-text publications presenting the results of completed studies on the mechanisms of development of systemic morphological changes in coal miner’s pneumoconiosis. The systematic review was made according to PRISMA guidelines and using certain PICO(S) criteria. Results: It has been shown that long-term exposure to coal dust causes activation of macrophage-related inflammation in the respiratory system, free radical oxidation, modulation of intracellular signaling pathways, and programmed cell death. Numerous studies have demonstrated the role of inflammation as the main pathogenetic factor of pneumoconiosis, which is closely related to oxidative stress and immune response. Inflammatory mediators ensure the immune response, regeneration and sclerosis of damaged tissues. In case of high cumulative doses of coal dust, these processes begin to have a destructive and tissue-damaging effect in both the lungs and other organs due to the systemic action of the above mediators. The key role of the endothelium in the development, course and outcome of inflammation is noted.

Abstract 15: Pharmacological Activation of Efferocytosis Prevents Intracranial Aneurysm Rupture

Introduction: Efferocytosis is the clearance process of dead or dying cells that reduces the tissue-damaging effects of excessive apoptotic cells. The accumulation of apoptotic cells at higher levels in ruptured aneurysms than in unruptured aneurysms suggests impaired efferocytosis. Mer receptor tyrosine kinase (MerTK), a receptor on macrophages, is essential for efferocytosis. Growth arrest-specific gene 6 (Gas6) is a small molecule that binds to and promotes MerTK-mediated efferocytosis. Our previous study suggested that MerTK knockout mice increased the rupture rate of intracranial aneurysms due to impaired efferocytosis. In this study, we investigated the effect of pharmacological activation of MerTK-mediated efferocytosis using the Gas6 in intracranial aneurysms. Methods: We used 10-week-old male C57BL/6J mice. We induced intracranial aneurysms by a combination of elastase injection and hypertension. After aneurysm induction, we started treatment with Gas6 or PBS as a vehicle. We compared the aneurysm formation and rupture rates, and the survival curve between the two groups. Results: The aneurysm rupture rate was significantly lower in the Gas6 group than in the control group (85.0% versus 50.0%, P <0.05, Fig. A and B). There was no statistical difference in the rate of aneurysm formation between the Gas6 and control groups (80.0% versus 100%, P =0.07). The Gas6 group had a better survival rate than the control group ( P <0.05, Fig. C). Conclusions: Pharmacological activation of MerTK-mediated efferocytosis prevents intracranial aneurysm rupture. Our findings suggest that efferocytosis and MerTK may serve as novel therapeutic targets for the prevention of aneurysm rupture.

Abstract A019: Neoplastic co-option of epithelial-immune interactions in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is initiated by a complex interplay between genetic and environmental insults that induce a marked remodeling of the pancreatic epithelium and its immune cell landscape. These tissue changes are highly reminiscent of wound healing responses, yet they critically contribute to disease pathogenesis. How regenerative tissue plasticity is co-opted to drive PDAC pathogenesis remains poorly understood. Our recent work identified cancer-associated chromatin alterations in the pre-malignant pancreatic epithelium that are induced by cooperative effects of mutant KRAS and tissue damage (inflammation). These synergistic processes aberrantly activate several cell communication factors, such as IL-33, that establish an expansive communication network among selective KRAS-mutant subpopulations and their immune environment that contributes to tumor development (Alonso-Curbelo et al., Nature 2021; Burdziak*, Alonso-Curbelo* et al., Science 2023). These epigenetically-activated communication networks are not shared with physiological regenerative processes, and represent a molecular groundwork to understand (onco)gene-environment cooperation and identify early, tumor-specific cancer mechanisms. They also provide new opportunities at the intersection of cancer biology, epigenetics and immuno-oncology for exploiting cell-cell communication traits of early KRAS-mutant cells and their niches to block the emergence and progression of neoplastic lineages. To address these questions, we are integrating single-cell genomics profiling, functional perturbations, and multiplexed tissue analyses to identify early molecular programs responsible for co-opting immune responses in PDAC, define how these shape influence tumor evolution, and identify crosstalk networks sustaining disease maintenance. Ultimately, a deeper mechanistic understanding of how early epigenetic dysregulation directs regenerative immune responses towards cancer will expose new therapeutic concepts to selectively target pro-tumor inflammation without impairing homeostatic tissue responses. Citation Format: Direna Alonso-Curbelo. Neoplastic co-option of epithelial-immune interactions in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A019.

Biocompatibility and efficacy of prostatic urethral lift in benign prostate hyperplasia: an in vivo and in vitro study

The study aimed to assess the biocompatibility and efficacy of a prostatic urethral lift (PUL) for benign prostatic hyperplasia (BPH). Human BPH-1 cells were co-cultured with implant anchors and sutures, and cytotoxicity was measured. Scanning electron microscopy (SEM) was used to observe adhesion and growth of cells and to evaluate implant biocompatibility. Fifteen male beagle dogs were randomly assigned to the surgical (n = 9) or sham-operated (n = 6) groups. The surgical group underwent cystotomy, and PUL was used to insert two implants in each lobe of the prostate to compress the enlarged prostate and dilate the urethra; the sham group underwent cystotomy without implant insertion. Compared with the control group, no significant difference in cell viability among the groups with different co-culture times of implant anchors and sutures (P > 0.05) was observed. SEM revealed good adhesion and growth of prostate cells on the implants. Improvements in urine flow rates remained stable at 7, 28, and 180 days after surgery, and the urethral diameter in the prostate region was significantly increased compared with that before surgery. PUL is a biocompatible and effective treatment for BPH, improving the urine flow rate without causing inflammation, tissue damage, or cytotoxic effects. Here, the basis for further PUL application was provided.

Micropulse Laser Therapy as an Integral Part of Eye Disease Management.

Ocular diseases can significantly impact vision and quality of life through pathophysiological alterations to the structure of the eye. The management of these conditions often involves a combination of pharmaceutical interventions, surgical procedures, and laser therapy. Laser technology has revolutionized many medical fields, including ophthalmology, offering precise and targeted treatment options that solve some of the unmet needs of other therapeutic strategies. Conventional laser techniques, while effective, can generate excessive thermal energy, leading to collateral tissue damage and potential side effects. Compared to conventional laser techniques, micropulse laser therapy delivers laser energy in a pulsed manner, minimizing collateral damage while effectively treating target tissues. The present paper highlights the advantages of micropulse laser therapy over conventional laser treatments, presents the implications of applying these strategies to some of the most prevalent ocular diseases, and highlights several types and mechanisms of micropulse lasers. Although micropulse laser therapy shows great potential in the management of ocular diseases, further research is needed to optimize treatment protocols, evaluate long-term efficacy, and explore its role in combination therapies.

Brain and cognitive reserve mitigate balance dysfunction in multiple sclerosis.

Approximately two-thirds of patients with multiple sclerosis (MS) complain different degrees of balance dysfunction, but some of them are able to withstand considerable disease burden without an overt balance impairment. Here, we tested the hypothesis that brain and cognitive reserve lessen the effect of MS-related tissue damage on balance control. We measured the postural sway of 148 patients and 74 sex- and age-matched healthy controls by force platform under different conditions reflecting diverse neuro-pathological substrates of balance dysfunction: eyes opened (EO), eyes closed (EC), and while performing the Stroop test, i.e., dual-task (DT). Lesion volumes on T2-hyperintense and T1-hypointense sequences, and normalized brain volume provided estimations of MS-related tissue damage in patients with MS. Hierarchical linear regressions explored the protective effect against the MS-related tissue damage of intracranial volume and educational attainment (proxies for brain and cognitive reserve, respectively) on balance. Larger intracranial volume and high educational attainment mitigated the detrimental effect of MS-related tissue damage on postural sway under EO (adjusted-R2=0.20 and 0.27, respectively, p<0.01) and DT (adjusted-R2=0.22 and 0.30, respectively, p<0.06) conditions. Neither educational level nor brain size was associated with postural sway under EC condition. Our findings suggest a protective role of brain and cognitive reserve even on balance, an outcome that relies on both motor control and higher order processing resources. The lack of a protective effect on postural sway under EC condition confirms that this latter outcome is closer associated with spinal cord rather than brain damage.

Thymoquinone protects against 5-Fluorouracil-induced mucositis by NF-κβ and HIF-1 mechanisms in mice.

Mucositis is among the most common side effects of 5-Fluorouracil (5-FU) and other cancer therapeutic drugs. Thymoquinone (TQ), a bioactive constituent extracted from Nigella sativa, has antioxidant and anti-inflammatory properties and can modify acute gastrointestinal injury. To investigate the effects of TQ on mucositis induced by 5-FU, studied animals were divided into four groups: control, 5-FU unit dose (300 mg/kg) to cause oral and intestinal mucositis (OM and IM), TQ (2.5 mg/kg) and TQ (2.5 mg/kg) plus 5-FU. Due to The molecular mechanisms, it was confirmed that the expression of NF-κβ and HIF-1 increases in OM. The serum levels of malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD), as well as pathological parameters, were assessed. Based on our results, the nuclear factor-kappa β gene expression in the tongue was downregulated significantly in the 5-FU + TQ compared to the 5-FU. TQ treatment can diminish MDA, and a reduction in oxidative stress was shown. TQ could also reduce the severity of tissue destruction and damaging effects induced by 5-FU on the tongue and intestine. We also observed lower villus length and width in the intestine of the 5-FU group compared to the control group. According to our research's pathological, biochemical, and molecular results, treatment with TQ as an anti-inflammatory and antioxidant compound may be the potential to improve and treat 5-FU-induced OM and IM, and TQ could be used against cancer treatment drugs and exhibit fewer adverse effects.

Protective influence of the zinc complex of 1-butylvioluric acid on the development of the liver tissue culture in the presence of convulsive poisons

Introduction. Currently, the actual problem is the search for substances that can be used as drugs for the pharmacological correction of the effects of cytostatic damage by convulsive poisons. It is known that the liver is the first organ to encounter any foreign molecule carried by the portal bloodstream, and it is the most damaged. The aim of this work was to study the effect of the zinc complex of 1-butylvioluric acid on the development of an organotypic culture of rat liver tissue after poisoning with 2-(dimethylaminomethyl)phenyl ester of dimethylcarbamic acid hydrochloride. Material and methods. White 3-month-old male Wistar rats were used in the experiment. To study the effects of the test substances, liver tissue was selected and the method of organotypic cultivation was applied. Poisoning with convulsive poisons was modeled using 2-(dimethylaminomethyl)phenyl ester of dimethylcarbamic acid hydrochloride and the zinc complex of 1-butylvioluric acid was used as a drug for pharmacological correction of the effects of liver tissue damage. Results. The data obtained indicate that under the action of 2-(dimethylaminomethyl) phenyl ester of dimethylcarbamic acid hydrochloride, which simulates the effect of convulsive poisons on liver cells, their cell proliferation is inhibited. It was also found that the zinc complex of 1-butylvioluric acid eliminates the inhibitory effect of 2-(dimethylaminomethyl)phenyl ester of dimethylcarbamic acid hydrochloride on the proliferation of liver tissue culture. Research limitations. The study was performed on a culture of rat liver cells; to extrapolate data to the whole organism, it is necessary to take into account the data of toxicodynamics and toxicokinetics. Conclusion. Thus, the data obtained in the experiments prove the effectiveness of the use of the zinc complex of 1-butylvioluric acid as a drug for the pharmacological correction of the consequences of exposure to convulsive poisons, and also create a basis for its further study.

Immunological priming of mesenchymal stromal/stem cells and their extracellular vesicles augments their therapeutic benefits in experimental graft-versus-host disease via engagement of PD-1 ligands.

Mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) exert profound anti-inflammatory and regenerative effects in inflammation and tissue damage, which makes them an attractive tool for cellular therapies. In this study we have assessed the inducible immunoregulatory properties of MSCs and their EVs upon stimulation with different combinations of cytokines. First, we found that MSCs primed with IFN-γ, TNF-α and IL-1β, upregulate the expression of PD-1 ligands, as crucial mediators of their immunomodulatory activity. Further, primed MSCs and MSC-EVs, compared to unstimulated MSCs and MSC-EVs, had increased immunosuppressive effects on activated T cells and mediated an enhanced induction of regulatory T cells, in a PD-1 dependent manner. Importantly, EVs derived from primed MSCs reduced the clinical score and prolonged the survival of mice in a model of graft-versus-host disease. These effects could be reversed in vitro and in vivo by adding neutralizing antibodies directed against PD-L1 and PD-L2 to both, MSCs and their EVs. In conclusion, our data reveal a priming strategy that potentiates the immunoregulatory function of MSCs and their EVs. This concept also provides new opportunities to improve the clinical applicability and efficiency of cellular or EV-based therapeutic MSC products.

Crocin treatment exerts anti-inflammatory and anti-oxidative effects in liver tissue damage of pinealectomized diabetic rats.

Diabetes mellitus (DM) is a chronic metabolic disorder with an increasing global prevalence that leads to significant morbidity and mortality. The liver plays a vital role in glycemic regulation in physiological and pathological conditions such as DM. Free radical formation and inhibition of antioxidant defense systems play a role in the liver damage pathogenesis in diabetic patients The antioxidant, anti-diabetic, anti-inflammatory, and radical scavenging properties of crocin are known. This study was designed to determine the possible protective effects of crocin against liver tissue damage in pinealectomized diabetic rats. Sixty rats were divided into six groups: Control, Sham+streptozotocin (STZ), Pinealectomy (PINX), PINX+STZ, PINX+Crocin, and PINX+STZ+Crocin. PNX procedure was carried out on the first day of the experiment. Intraperitoneal (i.p.) injection of 50 mg/kg STZ was performed on the 30th day of the experiment to induce DM. Crocin (50 mg/kg; i.p.) was applied for 15 days after the pinealectomy procedure and induction of DM. Crocin decreased the markers (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), interleukin-1β (IL-1β), and malondialdehyde (MDA)) of liver damage and increased antioxidant enzyme levels and tissue total antioxidant status. Histological results showed that the administration of crocin exhibited a protective effect against liver damage caused by STZ. These results indicate that crocin evidence protection against liver injury caused by STZ.

Vestibular Drop Attacks and Meniere’s Disease as Results of Otolithic Membrane Damage—A Numerical Model

Meniere’s disease (MD) is a condition of the inner ear with symptoms affecting both vestibular and hearing functions. Some patients with MD experience vestibular drop attacks (VDAs), which are violent falls caused by spurious vestibular signals from the utricle and/or saccule. Recent surgical work has shown that patients who experience VDAs also show disrupted utricular otolithic membranes. The objective of this study is to determine if otolithic membrane damage alone is sufficient to induce spurious vestibular signals, thus potentially eliciting VDAs and the vestibular dysfunction seen in patients with MD. We use a previously developed numerical model to describe the nonlinear dynamics of an array of active, elastically coupled hair cells. We then reduce the coupling strength of a selected region of the membrane to model the effects of tissue damage. As we reduce the coupling strength, we observe large and abrupt spikes in hair bundle position. As bundle displacements from the equilibrium position have been shown to lead to depolarization of the hair-cell soma and hence trigger neural activity, this spontaneous activity could elicit false detection of a vestibular signal. The results of this numerical model suggest that otolithic membrane damage alone may be sufficient to induce VDAs and the vestibular dysfunction seen in patients with MD. Future experimental work is needed to confirm these results in vitro.