Histological Changes In Tissues Research Articles

Investigation of the Efficacy of Zonisamide in Alcohol Induced Hepatotoxicity

Subject: This research aims to evaluate the histological changes in liver tissue induced by alcohol consumption and to assess the effectiveness of zonisamide in treating alcohol-related hepatotoxicity. Materials and Methods: The study utilized 40 adult Wistar albino rats, divided into four groups: a control (sham), an ethanol group, a zonisamide group, and a combination of ethanol and zonisamide (ethanol+zonisamide). Each group underwent a four-day binge drinking protocol to mimic excessive alcohol intake observed in humans. Zonisamide was administered at a dose of 100 mg/kg daily. Post-treatment, the liver tissues were collected, stained with hematoxylin and eosin, and examined for histopathological changes. Results: The control and zonisamide-only groups showed no abnormal liver or vascular alterations, indicating zonisamide's safety. In contrast, the ethanol group displayed significant liver damage, including vascular dilatation, congestion, and extensive cellular degeneration. Conversely, the ethanol+zonisamide group exhibited substantial histological improvements with noticeable reductions in vascular impairments and signs of hepatocyte regeneration, suggesting that zonisamide mitigates the detrimental effects of alcohol on the liver. Conclusion: The study concludes that zonisamide has a protective effect against alcohol-induced liver damage. It appears to preserve the structural integrity of hepatocytes and supports cellular survival, potentially through its anti-inflammatory and antioxidant properties. These promising results advocate for further exploration of zonisamide as a therapeutic option for managing liver injuries associated with alcohol abuse. This study contributes significant insights into the therapeutic potential of zonisamide, encouraging more comprehensive investigations into its clinical applications in hepatology. Keywords: Alcohol, Zonisamide, Hepatotoxicity

Protective effects of the bioactive peptide from maggots against skin flap ischemia‒reperfusion injury in rats

Ischemia‒reperfusion (I/R) injury is a frequently observed complication after flap surgery, and it affects skin flap survival and patient prognosis. Currently, there are no proven safe and effective treatment options to treat skin flap I/R injury. Herein, the potential efficacies of the bioactive peptide from maggots (BPM), as well as its underlying mechanisms, were explored in a rat model of skin flap I/R injury and LPS- or H2O2-elicited RAW 264.7 cells. We demonstrated that BPM significantly ameliorated the area of flap survival, and histological changes in skin tissue in vivo. Furthermore, BPM could markedly restore or enhance Nrf2 and HO-1 levels, and suppress the expression of pro-inflammatory cytokines, including TLR4, p-IκB, NFκB p65, p-p65, IL-6, and TNF-α in I/R-injured skin flaps. In addition, BPM treatment exhibited excellent biocompatibility with an adequate safety profile, while it exhibited superior ROS-scavenging ability and the upregulation of antioxidant enzymes in vitro. Mechanistically, the above benefits related to BPM involved the activation of Nrf2/HO-1 and suppression of TLR4/NF-κB pathway. Taken together, this study may provide a scientific basis for the potential therapeutic effect of BPM in the prevention of skin flap I/R injury and other related diseases.

A rat model of adenoid hypertrophy constructed by using ovalbumin and lipopolysaccharides to induce allergy, chronic inflammation, and chronic intermittent hypoxia.

Adenoid hypertrophy (AH) is a common pediatric disease that significantly impacts the growth and quality of life of children. However, there is no replicable and valid model for AH. An AH rat model was developed via comprehensive allergic sensitization, chronic inflammation induction, and chronic intermittent hypoxia (CIH). The modeling process involved three steps: female Sprague-Dawley rats (aged 4-5 weeks) were used for modeling. Allergen sensitization was induced via intraperitoneal administration and intranasal provocation using ovalbumin (OVA); chronic nasal inflammation was induced through intranasal lipopolysaccharide (LPS) administration for sustained nasal irritation; CIH akin to obstructive sleep apnea/hypopnea syndrome was induced using an animal hypoxia chamber. Postmodel establishment, behaviors, and histological changes in nasopharynx-associated lymphoid tissue (NALT) and nasal mucosa were assessed. Arterial blood gas analysis and quantification of serum and tissue levels of (interleukin) IL-4 and IL-13, OVA-specific immunoglobulin E (sIgE), eosinophil cationic protein (ECP), tumor necrosis factor (TNF-α), IL-17, and transforming growth factor (TGF)-β were conducted for assessment. The treatment group received a combination of mometasone furoate and montelukast sodium for a week and then was evaluated. Rats exhibited notable nasal symptoms and hypoxia after modeling. Histopathological analysis revealed NALT follicle hypertrophy and nasal mucosa inflammatory cell infiltration. Elevated IL-4, IL-13, IL-17, OVA-sIgE, ECP, and TNF-α levels and reduced TGF-β levels were observed in the serum and tissue of model-group rats. After a week of treatment, the treatment group exhibited symptom and inflammatory factor improvement. The model effectively simulates AH symptoms and pathological changes. But it should be further validated for genetic, immunological, and hormonal backgrounds in the currently used and other strains and species.

Effect of Curcuma longa extract on reproduction function in mice and testosterone production in Leydig cells.

Curcuma longa, best known for its culinary application as the main constituent of curry powder, has shown potential impact on the reproductive system. This study aimed to investigate the efficacy of Curcuma longa extract (CLE) on Kidney-Yang deficiency mice induced by hydrocortisone and the possible roles in testosterone secretion in Leydig cells. We evaluated male sexual behaviour, reproductive organ weight, testosterone levels, and histological tissue changes in hydrocortisone-induced mice. CLE effectively reversed hydrocortisone-induced Kidney-Yang deficiency syndrome by improving sexual behaviour, testis and epididymis weight, testosterone levels and reducing pathological damage. Our invitro study further indicated that CLE stimulated testosterone production via upregulating the mRNA and protein expression of steroidogenic enzymes in Leydig cells. It significantly improved H89-inhibited protein expression of StAR and cAMP-response element-binding (CREB), as well as melatonin-suppressed StAR protein expression. The data obtained from this study suggest that CLE could alleviate Kidney-Yang deficiency symptoms and stimulate testosterone production by upregulating the steroidogenic pathway. This research identifies CLE as a potential nutraceutical option for addressing testosterone deficiency diseases.

In vivo antimalarial effect of 1-hydroxy-5,6,7-trimethoxyxanthone isolated from Mammea siamensis T. Anders. flowers: pharmacokinetic and acute toxicity studies

BackgroundThe potent antiplasmodial activity of 1-hydroxy-5,6,7-trimethoxyxanthone (HTX), isolated from Mammea siamensis T. Anders. flowers, has previously been demonstrated in vitro. However, its in vivo activity has not been reported. Therefore, this study aimed to investigate the antimalarial activity and acute toxicity of HTX in a mouse model and to evaluate the pharmacokinetic profile of HTX following a single intraperitoneal administration.MethodsThe in vivo antimalarial activity of HTX was evaluated using a 4-day suppressive test. Mice were intraperitoneally injected with Plasmodium berghei ANKA strain and given HTX daily for 4 days. To detect acute toxicity, mice received a single dose of HTX and were observed for 14 days. Additionally, the biochemical parameters of the liver and kidney functions as well as the histopathology of liver and kidney tissues were examined. HTX pharmacokinetics after intraperitoneal administration was also investigated in a mouse model. Liquid chromatography triple quadrupole mass spectrometry was used to quantify plasma HTX and calculate pharmacokinetic parameters with the PKSolver software.ResultsHTX at 10 mg/kg body weight significantly suppressed parasitemia in malaria-infected mice by 74.26%. Mice treated with 3 mg/kg HTX showed 46.88% suppression, whereas mice treated with 1 mg/kg displayed 34.56% suppression. Additionally, no symptoms of acute toxicity were observed in the HTX-treated groups. There were no significant alterations in the biochemical parameters of the liver and kidney functions and no histological changes in liver or kidney tissues. Following intraperitoneal HTX administration, the pharmacokinetic profile exhibited a maximum concentration (Cmax) of 94.02 ng/mL, time to attain Cmax (Tmax) of 0.5 h, mean resident time of 14.80 h, and elimination half-life of 13.88 h.ConclusionsHTX has in vivo antimalarial properties against P. berghei infection. Acute toxicity studies of HTX did not show behavioral changes or mortality. The median lethal dose was greater than 50 mg/kg body weight. Pharmacokinetic studies showed that HTX has a long elimination half-life; hence, shortening the duration of malaria treatment may be required to minimize toxicity.

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis.

Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms. This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis. Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1β, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models. SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Exosomes Derived from Mouse Breast Carcinoma Cells Facilitate Diabetic Wound Healing.

Exosomes derived from breast cancer have been reported to play a role in promoting cell proliferation, migration, and angiogenesis, which has the potential to accelerate the healing process of diabetic wounds. The aim of this investigation was to examine the function of exosomes originating from 4T1 mouse breast carcinoma cells (TEXs) in the process of diabetic wound healing. The assessment of primary mouse skin fibroblastscell proliferation and migration was conducted through the utilization of CCK-8 and wound healing assays, while the tube formation of HUVECs was evaluated by tube formation assay. High-throughput sequencing, RT-qPCR and cell experimentswere used to detect the roles ofmiR-126a-3pin HUVECsfunctions in vitro. The in vivo study employed a model of full-thickness excisional wounds in diabetic subjects to explore the potential therapeutic benefits of TEXs. Immunohistochemical and immunofluorescent techniques were utilized to evaluate histological changes in skin tissues. The findings suggested that TEXs facilitate diabetic wound healing through the activation of cell migration, proliferation, and angiogenesis. An upregulation of miR-126a-3p has been observed in TEXs, and it has demonstrated efficient transferability from 4T1 cells to HUVEC cells. The activation of the PI3K/Akt pathway has been attributed to miR-126a-3p derived from TEXs. The promotion of chronic wound healing can be facilitated by TEXs through the activation of cellular migration, proliferation, and angiogenesis. The activation of the PI3K/Akt pathway by miR-126a-3p originating from TEXs has been discovered, indicating a potential avenue for enhancing the regenerative capabilities of wounds treated with TEXs.

Monotropein Alleviates Ovalbumin-Induced Asthma in Mouse Model by Inhibiting AKT/NF-κB Pathway

Introduction: Clinical management of asthma remains as a prevalent challenge. Monotropein (MON) is a naturally occurring cyclic enol ether terpene glycoside with medical application potential. This study aims to evaluate the potential therapeutic effects of MON in the mouse model of chronic asthma. Methods: An ovalbumin (OVA)-induced asthmatic mouse model was established to evaluate the therapeutic effect of MON at different doses (20, 40, and 80 mg/kg). The potential involvement of protein kinase B (AKT)/nuclear factor kappa B (NF-κB) pathway in the effect of MON was investigated by the administration of an AKT activator SC79. Histological changes in pulmonary tissues were examined by hematoxylin and eosin staining. The profiles of inflammatory cytokines (interleukin [IL]-4, IL-5, IL-13, and tumor necrosis factor [TNF]-α) in bronchoalveolar lavage fluid (BALF), and OVA-specific IgE in blood samples were analyzed by enzyme-linked immunosorbent assay (ELISA). The oxidative stress in the lung tissues was determined by measuring malondialdehyde level. The phosphorylation activation of AKT and NF-κB was examined by immunoblotting in the lung tissues. Results: MON treatment suppressed the infiltration of inflammatory cells in the airways of OVA-induced asthma mice and reduced the thickness of the bronchial wall and smooth muscle layer in a dose-dependent manner. MON treatment also reduced the levels of OVA-specific IgE in serum and cytokines in BALF in asthma-induced mice, and attenuated the oxidative stress in the lung tissues. OVA induced the phosphorylation of AKT and NF-κB proteins in the lung tissues of asthmatic mice, which was significantly suppressed by MON treatment. The co-administration of AKT activator SC79 impaired the therapeutic effect of MON on asthma-induced mice. Conclusion: Our data demonstrated the potential therapeutic effect of MON on asthmatic mouse model, suggesting that MON attenuated the inflammatory and oxidative damages in ling tissues by dampening the AKT/NF-κB signaling pathway.

The effect of bisphenol A on antioxidant defense and the structure and function of the liver of Siberian sturgeon (Acipenser baerii).

The present study was conducted to investigate the biochemical and histological changes of liver tissue in Siberian sturgeon (Acipenser baerii) exposed to different doses of bisphenol A (BPA). One hundred and eighty pieces of 1-year-old A. baerii with an average weight of 200-250 g bought and randomly distributed in 18 tanks (n = 10). After 2 weeks of adaptation, the fish received intraperitoneal injections of 1, 10, and 100 μg/g/week BPA and μg/g/week of 17β-estradiol intraperitoneally. The solvent control group received only peanut oil, while the control group did not receive any injections. In order to investigate histological changes of the liver, after 2 weeks the liver samples were taken, fixed in 10% formalin solution and slides prepared by routine histological methods. For assaying antioxidant defense status, the liver tissue from three fish of each replicates was captured and after homogenization, activity of catalase, superoxide dismutase, and glutathione peroxidase and malondialdehyde measured. The most important histological changes observed in the liver tissue were: vacuolation of hepatocytes, nuclear hypertrophy, necrosis of liver cells, expansion of sinusoids, and accumulation of fat cells. In the highest dose, the intensity of tissue changes increased. Activity of antioxidant enzymes and malondialdehyde content increased in fish exposed to 100 μg/g/week BPA in compare with other groups (p < .05). According to our findings, it could be concluded that liver histology was affected by BPA and tissue damage had occurred, which had led to changes in blood parameters. Also, the obtained results showed that the high concentrations of BPA used in this study stimulate the antioxidant defense. RESEARCH HIGHLIGHTS: BPA evoke oxidative stress in Siberian sturgeons in high dose of exposure. Severity of liver histologic lesions was dose dependent.

Spleen and Pancreatic Tissue Change after Genetically Modified Soybean Oil Consumption Among Male Wistar Rats

&lt;strong data-sider-select-id="b8bf10e1-996e-4fe0-a16e-f65aaaaf6a6c"&gt;Background: Over the past 20 years, the increased consumption of transgenic products for humans and animals led to the conduction of nutritional studies in this regard. However, these studies were limited, and they did not find a definitive answer to the possible health hazards of transgenic products. Therefore, this study was designed to evaluate the effects of a diet containing transgenic soybean oil on rats. &lt;strong data-sider-select-id="0d24514e-9731-4303-8701-71ae0f71f52c"&gt;Methods: Accordingly, male Wistar rats (N=6/group) were given a nutritionally moderate purified diet with 10% genetically modified soybean oil for 90 days. Two control groups receiving nongenetically modified soybean oil and a standardized diet were also enrolled. One-way analysis of variance (ANOVA) followed by Tuky post hoc analysis was used to compare the values between groups and to detect the effects of transgenic soybean oil. &lt;strong data-sider-select-id="6e6a93c9-227f-45c1-a050-9f3b96ecc42d"&gt;Results: Rats fed on transgenic soybean oil demonstrated several histologic changes in pancreas tissues, including changes in severe congestion, the presence of inflammatory cells, and changes in the Langerhans islands. However, no changes were observed in the spleen, except for negligible congestion in all treatment groups. Regarding blood indicators, hemoglobin levels in the transgenic soybean oil group decreased compared to the other two groups (P&lt;0.05). &lt;strong data-sider-select-id="103c4ab9-7a19-4a38-8077-e5b11eb6caee"&gt;Conclusion: According to our results, a 90-day treatment with transgenic soy-based oil caused significant organ changes in the pancreas tissue of rats. Further studies evaluating the long-term effects are also needed to better elucidate these effects.

Cyanidin prevents cardiomyocyte apoptosis in mice after myocardial infarction.

Myocardial infarction is a worldwide disease with high morbidity and mortality and a major cause of chronic heart failure, seriously affecting patients' quality of life. Natural medicine has been used to cure or prevent cardiovascular disease for decades. As a natural flavonoid, anthocyanidin has been used to treat many diseases due to its antioxidative, anti-inflammatory, and other properties. A mouse model (C57BL/6) weighing 30-40g was utilized to induce myocardial infarction by ligating the left anterior descending coronary artery. Cyanidin (30mg/kg) was administered orally to mice for four weeks. A variety of assessments were used to evaluate cardiac function. The gene expression was measured using RNAseq and Western blot. Histological changes in myocardial tissue were assessed using staining techniques, including Masson, Hematoxylin Eosin (HE), and transmission electron microscopy. Tunnel staining was implemented as a method to detect cellular apoptosis. For the quantification of B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in the serum, an enzyme-linked immunosorbent assay (ELISA) was employed. Furthermore, autodock simulation was executed in order to assess the interaction between cyanidin and a subset of genes. Cyanidin treatment inhibited myocardial cell apoptosis, improved cardiac function, and reduced serum concentrations of BNP and atrial natriuretic peptide ANP, as well as mitigated histological cardiac tissue damage. Cyanidin also inhibited the activity of matrix metalloproteinases (MMP2/9) and Fibronectin 1 (Fn1). Cyanidin improves heart function and reduces myocardial damage in mice after MI. Furthermore, cyanidin can prevent cardiomyocyte apoptosis. These effects are most likely caused by suppression of MMP9/2 and control of the Akt signaling pathway, suggesting an appropriate therapeutic target.

MEDAG expression in vitro and paeoniflorin alleviates bone loss by regulating the MEDAG/AMPK/PPARγ signaling pathway in vivo

ObjectivesOsteoporosis (OP) is characterized by reduced bone mass and impaired bone microstructure. Paeoniflorin (PF) is isolated from peony root with anti-inflammatory, immunomodulatory, and bone-protective effects. Up to now, the mechanism of anti-OP in PF has not been completely clarified. MethodsThe expression of MEDAG in osteoclasts, osteoblasts and adipocytes was detected by RT-qPCR. The OVX mouse model was constructed, and oral administration of PF was performed for 15 weeks. Bone microstructure was detected by H&E staining and a micro-CT system, and expression of signaling proteins examined by Western blot and immunohistochemical staining. ELISA and biochemical kits were used to quantify serum metabolite levels. Key findingsMEDAG were upregulated in osteoclasts and adipocytes, and downregulated in osteoblasts. PF administration effectively alleviated OVX-induced bone loss, and histological changes in femur tissues. Moreover, PF significantly reduced serum TRAP, CTX-1, P1NP, BALP, and LDL-C levels and increased HDL-C. In addition, PF inhibited the expression of MEDAG, cathepsin K, NFATc1, PPARγ, and C/EBPα and increased p-AMPKα, OPG and Runx2. ConclusionsMEDAG is a potential target for bone diseases, and PF might attenuate OVX-induced osteoporosis via MEDAG/AMPK/PPARγ signaling pathway.

Interplay between dental pulp tissue osteoprotegerin and TNF-α levels with micromorphological changes in the teeth of patients with chronic pulpitis

Background/Aim. Chronic pulpitis (CP) is an inflammatory dental pulp disorder associated with various pathophysiological mechanisms in its origin. The aim of the study was to evaluate the changes in the pulp tissue of osteoprotegerin (OPG) and tumor necrosis factor (TNF)-? and establish their relationship with the histological changes of pulp tissue, as well as with the micromorphological changes, occurring in the mineralized tissue. Methods. The study examined the dental pulp of 41 patients with CP and 12 healthy individuals. The group of the diseased subjects was subdivided based on the presence of communication of the pulp with the oral cavity, i.e., open (n = 22) or closed (clausa) (n = 19) CP. Results. The levels of TNF-? were statistically significantly increased, while OPG levels were decreased in the pulp of patients with CP, compared to the control group. TNF-? levels were almost the same in the pulp of patients with closed CP and the control group, while values were significantly increased in those with open CP compared to control. Histopathological analysis showed a significant increase in the number of mononuclear inflammatory cells in the diseased pulp. Scanning electron microscopy showed distinct changes, which correlate with internal resorption. Conclusion. The results indicate a much greater and intensified process of root resorption in patients with closed CP, which is unassociated with dental pulp OPG and TNF-? level changes.

Phytochemical constituents of bark essential oils of Cinnamomum zeylanicum Blume and effects on liver tissue of rats

Cinnamomum zeylanicum Blume is an evergreen tropical tree belonging to the Lauraceae family; it is a useful plant in traditional and modern medicines. Essential oils of Cinnamomum zeylanicum were prepared and identified using gas chromatography–mass spectrometry (GC-MS). For histological study 80 adult male rats were employed in this study. It is the same weight (30 ±5 gm) and 75 days in age. The animals were divided into 4 groups, with ten rats in each group. The results indicated that C. zeylanicum bark contained 27 different phytochemical components. The main components included Cinnamaldehyde (2-Propenal, 3-phenyl-) (46.46%), 9-Methoxybicyclo, [6.1.0] nona-2,4,6-triene (31.31%), alpha-, Muurolene (7.14%) and Copaene (1.63%). Sections of livers were examined for histological abnormalities, such as the breakdown of the liver architecture and increased inflammation, in comparison to control samples, some hepatocytes were swollen with pyknotic, large nuclei and dilated sinusoids. As well as in the rats treated with noticed sever congestion of central vein (CV), degeneration and sluggish of endothelial lining larger, Bile ducts hyperplasia and necrotic hepatocytes. It can be deduced that the main component of cinnamon bark oil is cinnamaldehyde and the liver displayed some tissue changes, including hepatocyte necrosis and the existence of steatosis foci. Histological and cellular changes in liver tissue were dramatically attenuated by C. zeylanicum essential oil.

Mobilization of Circulating Tumor Cells after Short- and Long-Term FOLFIRINOX and GEM/nab-PTX Chemotherapy in Xenograft Mouse Models of Human Pancreatic Cancer.

Mobilization of CTCs after various types of therapy, such as radiation therapy, has been reported, but systematic study of CTCs after chemotherapy remained quite limited. In this study, we sequentially examined CTC numbers after single-dose and repetitive-dose chemotherapy, including FORFIRINOX (FFX) and Gemcitabine and nab-Paclitaxel (GnP) using two pancreatic cancer xenograft models. CTC was detected by the immunocytology-based microfluidic platform. We further examined the dynamic change in the histology of primary tumor tissues during chemotherapy. We confirmed a transient increase in CTCs 1-2 weeks after single-dose and repetitive-dose of FFX/GnP chemotherapy. Histological examination of the primary tumors revealed that the peak period of CTC at 1-2 weeks after chemotherapy corresponded to the maximal destructive phase consisting of cell cycle arrest, apoptosis of tumor cells, and blood vessel destruction without secondary reparative tissue reactions and regeneration of tumor cells. These findings indicate that mobilization of CTCs early after chemotherapy is mediated by the shedding of degenerated tumor cells into the disrupted blood vessels driven by the pure destructive histological changes in primary tumor tissues. These results suggest that sequential CTC monitoring during chemotherapy can be a useful liquid biopsy diagnostic tool to predict tumor chemosensitivity and resistance in preclinical and clinical settings.

Residual nasal polyp tissue following dupilumab therapy is associated with periostin-associated fibrosis.

Dupilumab, an anti-interleukin-4 receptor alpha monoclonal antibody, is a new treatment for severe uncontrolled chronic rhinosinusitis with nasal polyps. However, data on the effect of dupilumab on histological changes in nasal polyp tissue are lacking. We aimed to investigate the effect of dupilumab on real-life clinical conditions and nasal polyp tissues from patients with eosinophilic chronic rhinosinusitis (ECRS), which is a refractory subtype. We conducted an open-label, prospective, observational, single-centre study on 63 patients with refractory ECRS on the basis of the criteria of the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study. These patients had a history of surgery and received dupilumab for 24weeks. Patient-reported sinonasal symptoms, T&T olfactometry and nasal polyp scores were prospectively evaluated. In 23 patients with residual nasal polyps following dupilumab treatment, changes in systemic and local periostin expression, and total collagen deposition in nasal polyp tissues were investigated before and after dupilumab administration. Dupilumab rapidly improved sinonasal symptoms and reduced the nasal polyp score 24weeks after initiation. 40 (63.5%) patients had resolution of nasal polyps, but the reduction was limited in the remaining 23 (36.5%) patients. Periostin expression in serum and nasal lavage fluid was decreased, whereas periostin and the total collagen deposition area in subepithelial tissues in residual nasal polyps were enhanced after dupilumab administration. Dupilumab improves sinonasal symptoms and reduces the nasal polyp score in refractory ECRS. Periostin-associated tissue fibrosis may be involved in the differential effect of dupilumab on nasal polyp reduction.

Effect of atorvastatin on muscle tissues of dermatomyositis and antisynthetase syndrome patients with dyslipidemia.

In a recent study, we have shown that atorvastatin is clinically safe for dermatomyositis (DM) and antisynthetase syndrome (ASS) patients with dyslipidemia. Herein, we showed in an unprecedented way, the safety of atorvastatin on the muscular tissues of these patients. Transcriptome analysis was performed on samples of the vastus lateralis muscle obtained at baseline and after 12 weeks of atorvastatin (20 mg/day) intervention in DM or ASS patients with dyslipidemia [6DM and 5ASS received atorvastatin, and 2DM and 3ASS received placebo]. The results were analyzed considering differences in expression fold change before and after treatment. Histological and histochemical analyses were also performed. In both groups, no significant changes were observed in genes related to the mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways. Histological analysis showed a slight variability in the fiber size that was preserved after the intervention. In addition, the mosaic of muscle fibers was preserved in the internal architecture of the fibers and all histological regions. No fiber necrosis or atrophy, focal failures, subsarcolemmal accumulation, lipids, areas of fibrosis, or alterations in mitochondrial activity were observed. All muscle fibers were labeled for MHC I. Atorvastatin did not promote significant changes in the expression of genes related to mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways in the muscle tissues of DM and ASS patients with dyslipidemia. Atorvastatin did not also promote histological and histochemical changes in muscle tissues. Our results reinforce the safety of the administration of atorvastatin to treat dyslipidemia in patients with DM and ASS.

The Effectiveness of Time in Treatment with Vitamin C and Broccoli Extract on Cadmium Poisoning in Mice: Histological Changes of Testicular Tissue and Cell Apoptotic Index.

The growth rate of reproductive system disorders caused by heavy metals is undeniable. The effect of time and interfering compounds are also of paramount importance. The main objective of this study was to compare the effects of broccoli extract and vitamin C in the context of cadmium poisoning on various reproductive parameters in mice, with a specific focus on the influence of time. A total of one hundred and forty-four male mice were randomly assigned to six groups. The control (C) group received only water and a standard diet without any interventions. The Cd group received a single intraperitoneal dose of cadmium chloride at 1.5 mg/kg. The cadmium intervention groups were administered broccoli extract at dosages of 100 mg/kg (Cd + B100), 200 mg/kg (Cd + B200), and 300 mg/kg (Cd + B300), respectively. Additionally, the Cd + VC group was treated with cadmium and vitamin C at 200 mg/kg intraperitoneally for a duration of 28 days. At the end of each week (four stages), five animals were randomly chosen from each group. Epididymal sperm were subjected to analysis for sperm parameters, while testicular tissue sections were examined for histological studies, apoptosis index, and markers of oxidative stress. The influence of time on body and testis weight gain was notably significant in the Cd + B300 and Cd + VC groups (p = 0.001). In all groups, except for Cd + B100, there were marked increases in spermatogenic cell lines and the Johnson coefficient compared to the Cd group (p = 0.001). These changes were particularly pronounced in the Cd + VC and Cd + B300 groups with respect to time (p < 0.001). Furthermore, there was a discernible positive impact of time on sperm count in the high-dose broccoli and vitamin C groups, although this effect did not reach significance in terms of sperm motility and vitality. Over time, the levels of superoxide dismutase (SOD) and catalase (CAT) enzymes increased, while malondialdehyde (MDA) levels decreased in the Cd + VC, Cd + B200, and Cd + B300 groups (p = 0.001). The apoptosis index in testicular tissue reached its highest level in the Cd group and its lowest level in the Cd + B300 and Cd + VC groups during the fourth week (p < 0.05). Linolenic acid, indole, and sulforaphane were identified as the most potent compounds in broccoli during this intervention. Consequently, vitamin C and broccoli extract at a dosage of 300 mg/kg demonstrated significant enhancements in reproductive performance in cases of cadmium poisoning. Overall, the influence of time significantly amplified the process of spermatogenesis and sperm production, with no observable changes in sperm viability and motility.

MAPK1 knockdown ameliorated immune and inflammatory abnormalities in a mouse model of refractory asthma

Purpose: To evaluate the potential molecular mechanisms involved in refractory asthma in an animal model, and the potential therapeutic effect of MAPK1 knockdown on the disease.Methods: Eighteen female Institute of Cancer Research (ICR) mice, aged 8 - 10 weeks, were randomly divided into three groups: control, asthma model and refractory asthma, with 6 mice in each group. The expression of MAPK1 was knocked down in mice using an adenoviral vector. Subsequently, the methylation levels of MAPK1 promoter in mouse lung tissue were determined using methylation assays. Hematoxylin and eosin (H&amp;E) staining and Periodic Acid-Schiff (PAS) staining were used to determine inflammatory and histological changes in lung tissues. Levels of immune cells were determined using flow cytometry, while Western blotting was used to measure the protein expression levels of ERK1/2, JNK, MEK1/2 and p38.Results: Methylation assay results show that mean methylation level of cg11335969 locus was significantly reduced in the refractory asthma mouse model (p &lt; 0.05). The levels of IgG1 and IgM in refractory asthmatic mice were reduced after MAPK1 knockdown. There was a significantly reduced degree of lung lesions in mice (p &lt; 0.05), as was reflected in effectively decreased histopathological changes. Protein levels of ERK1/2, JNK, MEK1/2 and p38, and the levels of neutrophils, dendritic cells, and macrophages were significantly decreased (p &lt; 0.05).Conclusion: There is hypermethylated modification of MAPK1 at cg11335969 site in refractory asthma mouse model. Knockdown of MAPK1 attenuates inflammation and tissue damage, and reverses abnormal immune cell numbers in refractory asthma mice. Thus, MAPK1 inhibition may be a novel strategy for ameliorating immune abnormalities in refractory asthma.

In Silico Assessment of Naphthalene Interaction with Glutathione Reductase and Histological Changes in Naphthalene Exposed Rats Tissues

Naphthalene (NA), a bicyclic aromatic compound that is widely used in various commercial and industrial applications including lavatory scent disks and mothballs, is known to be readily absorbed into the systemic circulation following either inhalation or ingestion and may cause systemic toxicity. This study examined the histopathological changes in some tissues (lung, liver and kidney) of NA-exposed Wistar rats. Twenty-four rats (175-250 g) were randomly divided into six groups of four rats each. The rats in all groups were given food and water while in addition rats in the experimental groups were exposed to NA at 0.75 mg/m3 and 1.50 mg/m3 for 2 h and 4 h. Rats were sacrificed at 24 h after the last hour of NA exposure. The tissues were excised for histological examination. The effects of NA and some selected metabolites using the rat glutathione reductase homology model were examined via molecular docking and dynamic simulation. From this study, exposure of rats to NA resulted in hepatocyte necrosis at 0.75 mg/m3 for 2 h, dilation of the alveolar duct of the lung at 0.75 mg/m3 and severe epithelial hyperplasia and chronic infiltration of inflammatory cells in the lung at 1.50 mg/m3 for 4 h. Also, vascular congestion was observed in the kidneys at 0.75 mg/m3 for 2 h and 1.50 mg/m3 for 4 h. The in silico study revealed the NA metabolite toxic potential, and NA showed the lowest binding score (-5.40± 0.00 kcal/mol). Therefore, the study concludes that NA exposure irrespective of duration can lead to hepatic and alveolar damage in the absence of mechanisms that can ameliorate its toxic effects.