-
Journal of Ovarian Research Jun 2024This study aimed to investigate the mitigating effect of N-acetylcysteine (NAC) on doxorubicin (DOX)-induced ovarian and uterine toxicity in rats using laboratory tests,...
BACKGROUND
This study aimed to investigate the mitigating effect of N-acetylcysteine (NAC) on doxorubicin (DOX)-induced ovarian and uterine toxicity in rats using laboratory tests, ultrasonographic (US) imaging, and histopathology analysis.
METHODS
Forty-eight rats were divided into six groups (n = 8) as follows: Group A (control) (0.5 mL saline administered intraperitoneally [IP]), Group B (a single 10 mg/kg dose of DOX administered IP on day 1), Group C (a single 10 mg/kg dose of DOX administered IP 24 h before sacrifice), Group D (100 mg/kg of NAC administered IP for 21 days), Group E ( a single 10 mg/kg dose of DOX administered IP on day 1 and 100 mg/kg of NAC administered IP for 21 days), and Group F (100 mg/kg of NAC administered IP for 21 days and a single 10 mg/kg dose of DOX administered IP 24 h before sacrifice). The ovaries were examined using B-mode US on days 1, 14, and 21, and the histopathological examinations of the ovaries and the uterus were undertaken after sacrifice on day 22.
RESULTS
Histomorphological analyses showed that ovarian weight decreased after DOX administration in Group B but not in Group E. US revealed a transient increase in ovarian size in Group B and E, reverting to baseline levels over time, as well as a progressive increase in peritoneal fluid in Groups B and E. Group B exhibited a significant decrease in the thickness of the endometrium and myometrium and uterine cornual length, which was not observed in Group E. Histopathological examination showed that DOX caused a decline in follicular count, especially in primordial, secondary, and Graafian follicles, and resulted in follicular atresia, predominantly in Group B. Destructive degeneration/necrosis and vascular changes were most prominently seen in the corpus luteum of Groups C and B. In NAC-treated rats (Groups E and F), although germ cell damage was present, atretic follicles and vascular changes, such as hyperemia and congestion, were reduced. The anti-müllerian hormone (AMH) level was the highest in Group F.
CONCLUSIONS
NAC, an antioxidant, attenuated DOX-induced gonadotoxicity in rats.
Topics: Animals; Female; Doxorubicin; Acetylcysteine; Rats; Ovary; Ultrasonography; Uterus; Antibiotics, Antineoplastic
PubMed: 38943148
DOI: 10.1186/s13048-024-01459-4 -
Modern Pathology : An Official Journal... Jun 2024PLAG1 gene fusions were recently identified in a subset of uterine myxoid leiomyosarcomas (M-LMS). However, we have encountered cases of PLAG1-rearranged uterine...
PLAG1 gene fusions were recently identified in a subset of uterine myxoid leiomyosarcomas (M-LMS). However, we have encountered cases of PLAG1-rearranged uterine sarcomas (PLAG1-US) lacking M-LMS-like morphology and/or any expression of smooth muscle markers. To better characterize their clinicopathological features, we performed a multi-institutional search which yielded 11 cases. The patients ranged in age from 34-72 years (mean: 57). All tumors arose in the uterine corpus, ranging in size from 6.5-32 cm (mean: 15). The most common stage at presentation was pT1b (n=6), three cases had stage pT1 (unspecified) and one case each presented in stage pT2a and pT3b. Most were treated only by hysterectomy with adnexectomy. The follow-up (range: 7-71 months; median: 39 months) was available for 7 patients. Three cases (7-21 months of follow-up) had no evidence of disease. Three out of 4 remaining patients died of disease within 55-71 months, while the last developed peritoneal spread and was transferred for palliative care at 39 months. Morphologically, the tumors showed a high inter- and intratumoral heterogeneity. M-LMS-like and epithelioid LMS-like morphology was present in 3 and 5 primary tumors, respectively, the rest mostly presented as non-descript ovoid/spindle cell sarcomas. Unusual morphological findings included prominently hyalinized stroma (n=3), adipocytic differentiation with areas mimicking myxoid liposarcoma (n=2), osteosarcomatous differentiation (n=1) and undifferentiated pleomorphic sarcoma-like areas (n=1). The mitotic activity ranged from 3-24 mitoses/10 high-power fields (mean: 9), 3/10 cases showed necrosis. In 3/11 cases, no expression of SMA, h-caldesmon or desmin was noted, whereas 5/5 cases expressed PLAG1. By RNA-sequencing, the following fusion partners were identified: PUM1, CHCHD7 (each n=2), C15orf29, CD44, MYOCD, FRMD6, PTK2 and TRPS1 (each n=1). One case only showed PLAG1 gene break by FISH. Our study documents a much broader morphological spectrum of PLAG1-US than previously reported, encompassing but not limited to M-LMS-like morphology with occasional heterologous (particularly adipocytic) differentiation. Since it is currently difficult to precisely define their line of differentiation, for the time being, we suggest using a descriptive name PLAG1-rearranged uterine sarcoma.
PubMed: 38942115
DOI: 10.1016/j.modpat.2024.100552 -
Journal of Hepatology Jun 2024Gut bacterial translocation contributes to immune dysfunction and spontaneous bacterial peritonitis (SBP) in cirrhosis. We hypothesized that exposure of peritoneal...
BACKGROUND & AIMS
Gut bacterial translocation contributes to immune dysfunction and spontaneous bacterial peritonitis (SBP) in cirrhosis. We hypothesized that exposure of peritoneal macrophages (PMs) to bacterial DNA results in type-I interferon (IFN) production, shaping subsequent immune responses, inflammasome activation, and the release of damage-associated molecular patterns (DAMPs).
METHODS
PMs from patients with cirrhosis were stimulated with E. coli single-stranded DNA (ssDNA), lipopolysaccharide LPS, and IFN or infected with E. coli, S. aureus, and Group B streptococcus in vitro. Cytokine release, inflammasome activation, and DAMP release were quantified by quantitative-PCR, ELISA, western blots, and reporter cells employing primary PMs, monocytes, and caspase-deficient THP-1 macrophages. Serum progranulin concentration was correlated with transplant-free survival in 77 patients with SBP.
RESULTS
E. coli ssDNA induced strong type-I IFN activity in PMs and monocytes, priming them for enhanced LPS-mediated tumor necrosis factor production without toll-like receptor 4 tolerance induction. During in vitro macrophage bacterial infection, type-I IFN release aligned with upregulated expression of IFN-regulatory factors (IRF)1/2 and guanylate binding proteins (GBP)2/5. PMs upregulated inflammasome-associated proteins and type-I IFN upon E. coli ssDNA exposure and released interleukin-1β upon bacterial infection. Proteomic screen in mouse macrophages revealed progranulin as being caspase-11-dependent during E. coli infection. PMs and THP-1 macrophages released significant amounts of progranulin when infected with S. aureus or E. coli via gasdermin-D in a type-I IFN and caspase-5-dependent manner. During SBP, PMs upregulated IRF1, GBP2/5 and caspase-5 and higher serum progranulin concentrations were indicative of lower 90-day transplant-free survival after SBP.
CONCLUSIONS
Type-I IFN shapes peritoneal immune responses and regulates caspase-5-mediated progranulin release during SBP.
IMPACT AND IMPLICATIONS
Patients with cirrhosis exhibit impaired immune responses and increased susceptibility to bacterial infections. This study reveals that type-I interferon responses, triggered by pathogen-associated molecular patterns, are crucial in regulating macrophage activation and priming them for inflammatory responses. Additionally, we elucidate the mechanisms by which type-I interferons promote the release of progranulin from macrophages during spontaneous bacterial peritonitis. Our findings enhance understanding of how bacterial translocation affects immune responses, identify novel biomarkers for inflammasome activation during infections, and point to potential therapeutic targets.
PubMed: 38936554
DOI: 10.1016/j.jhep.2024.06.019 -
Combinatorial Chemistry & High... Jun 2024The occurrence of acute lung injury (ALI) caused by lipopolysaccharide (LPS) is prevalent and perilous among older individuals. Inflammation and oxidative stress are...
BACKGROUND
The occurrence of acute lung injury (ALI) caused by lipopolysaccharide (LPS) is prevalent and perilous among older individuals. Inflammation and oxidative stress are vital factors in the progression of ALI in this population. Dayuan Yin (DYY) is a classic Chinese herbal formula used for treating pulmonary diseases. Therefore,this situation can be well simulated by selecting suitable aged rats and induced by LPS, which is helpful to evaluate the role of DYY.
OBJECTIVE
The objective of this study is to assess the therapeutic efficacy of DYY in reducing pulmonary inflammation and oxidative stress injury in aged rats induced by LPS.
METHODS
In elderly male Sprague Dawley (SD) rats, the ALI model was induced by injecting LPS into the peritoneal cavity. The therapeutic effect of the DYY group was evaluated after 3 days of oral administration. Lung tissue damage was assessed using hematoxylin-eosin staining and the lung wet/dry (W/D) ratio. Inflammatory reaction in lung tissue was analyzed by counting inflammatory agents, measuring total protein (TP), and examining the concentration of inflammatory components in bronchoalveolar lavage fluid (BALF). Lung oxidative stress was assessed by measuring malondialdehyde (MDA), inducible nitric oxide synthase (iNOS), and superoxide dismutase (SOD) levels in BALF. The impact of DYY on the phosphorylation of PI3K, AKT, and NF-κBp65 protein was analyzed using Western Blot (WB).
RESULTS
The administration of DYY exhibited a dose-dependent reduction in the severity of lung injury caused by LPS, leading to a reversal of the LPS-induced lung W/D ratio. Furthermore, DYY treatment resulted in decreased levels of leukocytes, eosinophils, neutrophils, macrophages, lymphocytes, and total protein in BALF. Additionally, DYY significantly inhibited the upregulation of Interleukin -6, Interleukin -10, and Interleukin -1β (IL-6, IL-10, IL-1β) as well as Tumor necrosis factor-α(TNF-α) induced by LPS (P<0.01). The lungs experienced oxidative stress due to LPS, leading to the production of MDA and iNOS, as well as a decrease in SOD activity. DYY reduced oxidative stress in the lungs and inhibited the activation of p-PI3K, p-Akt, and p-NF-κBp65, with a greater effect at higher doses.
CONCLUSION
In a dose-dependent manner, DYY suppresses the inflammatory response and oxidative stress in the lung tissue of elderly rats, thereby reducing ALI caused by LPS. This effect may be attributed to the inhibition of the PI3K/AKT/NF-κB pathway activation.
PubMed: 38920065
DOI: 10.2174/0113862073294620240527102409 -
The American Journal of Emergency... Jun 2024Pediatric digestive volvulus is a serious condition that carries with it a high rate of morbidity and mortality. (Review)
Review
INTRODUCTION
Pediatric digestive volvulus is a serious condition that carries with it a high rate of morbidity and mortality.
OBJECTIVE
This review highlights the pearls and pitfalls of pediatric digestive volvulus, including the presentation, diagnosis, and management in the emergency department (ED) based on current evidence.
DISCUSSION
Pediatric digestive volvulus is a deadly condition most commonly associated with malrotation. It occurs when the stomach or small intestine twists on itself, resulting in ischemia and potentially strangulation with necrosis and perforation. Presentation differs based on the gastrointestinal (GI) segment affected, degree of twisting, and acuity of the volvulus. Gastric volvulus most commonly presents with retching with or without nonbilious emesis and epigastric distension with pain, while midgut volvulus typically presents with bilious emesis in infants. Patients with GI necrosis and perforation may present with hemodynamic compromise and peritonitis. If suspected, emergent consultation with the pediatric surgery specialist is necessary, and if this is not available, transfer to a center with a pediatric surgeon is recommended. Imaging includes plain radiography, ultrasound, or upper GI series, while treatment includes resuscitation, administration of antibiotics, and emergent surgical decompression and detorsion of the involved segments.
CONCLUSION
An understanding of pediatric digestive volvulus and its many potential mimics can assist emergency clinicians in diagnosing and managing this deadly disease.
PubMed: 38908340
DOI: 10.1016/j.ajem.2024.06.012 -
Animals : An Open Access Journal From... Jun 2024An 8-month-old intact male domestic shorthair cat was referred to the Emergency Service of the Veterinary Teaching Hospital (VTH) of the Department of Veterinary Science...
An 8-month-old intact male domestic shorthair cat was referred to the Emergency Service of the Veterinary Teaching Hospital (VTH) of the Department of Veterinary Science of the University of Parma (Italy) from the Parma municipal multi-cat shelter, during the winter season (January 2023), for lethargy, anorexia, hypothermia, and hypoglycemia. At the VTH, upon cardiologic examination, an increase in heart rate, under normal blood pressure conditions, was detected. Signalment, clinical history, basal metabolic panel (BMP), ultrasound investigations, and cytological findings were all consistent with a diagnosis of feline infectious peritonitis (FIP). FIP was confirmed in the effusive abdominal fluid by a molecular genetic test (real-time PCR for feline coronavirus RNA). The molecular genetic investigation also detected an FCoV gene single-nucleotide mutation: biotype M1058L. At necropsy, an effusive collection was recorded in the abdomen, thoracic cavity, and pericardium sac. White parenchymal nodules, of about 1 mm diameter, were found on the surface and deep in the lungs, liver, kidneys, and heart. Histopathology revealed the typical FIP pyogranulomatous vasculitis and IHC confirmed the presence of the FIP virus (FIPV) antigen. The most relevant histopathological finding was the myocarditis/myocardial necrosis associated with the presence of the gene-mutated FCoV (M1058L biotype). This is the first case of myocarditis in a cat positive for the FCoV/FIP M1058L biotype. Further studies are necessary to support the mutated FCoV M1058L biotype, as an uncommon, but possible, causative pathogen of myocarditis in FCoV/FIP-positive cats. Studies including several FCoV/FIP M1058L-positive cases could allow us to make a correlation with heart gross pathology, histopathology, and immunolocalization of the FCoV/FIP M1058L biotype in the myocardium. The investigation will potentially allow us to determine the effective tropism of the FCoV/FIP M1058L biotype for myocardiocytes or whether myocardiocyte lesions are evident in the presence of concomitant causes related to the patient, its poor condition, or external environmental distress such as cold season, and whether the aforementioned concomitant events are correlated.
PubMed: 38891720
DOI: 10.3390/ani14111673 -
Aging Jun 2024Microbial infection-induced sepsis causes excessive inflammatory response and multiple organ failure. An effective strategy for the treatment of sepsis-related syndromes...
Microbial infection-induced sepsis causes excessive inflammatory response and multiple organ failure. An effective strategy for the treatment of sepsis-related syndromes is still needed. Rosuvastatin, a typical β-hydroxy β-methylglutaryl-CoA reductase inhibitor licensed for reducing the levels of low-density lipoprotein cholesterol in patients with hyperlipidemia, has displayed anti-inflammatory capacity in different types of organs and tissues. However, its effects on the development of sepsis are less reported. Here, we found that the administration of Rosuvastatin reduced the mortality of sepsis mice and prevented body temperature loss. Additionally, it inhibited the production of inflammatory cytokines such as tumor necrosis factor (TNF-α), Interleukin-6 (IL-6), interleukin-1β (IL-1β), and migration inhibitory factor (MIF) in peritoneal lavage supernatants of animals. The increased number of mononuclear cells in the peritoneum of sepsis mice was reduced by Rosuvastatin. Interestingly, it ameliorated lung inflammation and improved the hepatic and renal function in the sepsis animals. Further experiments show that Rosuvastatin inhibited lipopolysaccharide (LPS)-induced production of proinflammatory cytokines in RAW 264.7 macrophages by preventing the activation of nuclear factor kappa-B (NF-κB). Our findings demonstrate that the administration of Rosuvastatin hampered organ dysfunction and mitigated inflammation in a relevant model of sepsis.
PubMed: 38885061
DOI: 10.18632/aging.205937 -
Cureus May 2024The torsion of a dilated sigmoid colon around its own mesenteric axis is the cause of sigmoid volvulus, which frequently results in constipation and intestinal...
The torsion of a dilated sigmoid colon around its own mesenteric axis is the cause of sigmoid volvulus, which frequently results in constipation and intestinal obstruction. The clinical presentation of sigmoid volvulus can be observed as nausea, constipation, abdominal distension, and abdominal pain. It is also reported to be insidious. Additionally, it causes blood obstruction, resulting in necrosis, bowel ischemia, and even intestinal perforation if not addressed on time. Physical symptoms might vary depending on the course of the disease but are usually observed as the classical trio of abdominal distension, abdominal pain, and constipation. Computed tomography imaging presents the sign of an inverted U, or classic coffee bean, aiding in the diagnosis of the sigmoid volvulus. A 38-year-old male was admitted to the emergency department of our tertiary care center with significant complaints of obstipation and abdominal pain. The medical history and physical examination revealed peritoneal symptoms, which warranted a prompt radiological imaging diagnosis. The patient was subjected to computed tomography, which was suggestive of sigmoid volvulus. The patient underwent an emergency laparotomy and sigmoidectomy, which were uneventful with no postoperative complications.
PubMed: 38883052
DOI: 10.7759/cureus.60508 -
Biochemical Pharmacology Jun 2024Nephrotoxicity is a major constraint of cisplatin application in many solid tumors. Since the lack of preventive strategies, the necessity exists to identify critical...
Nephrotoxicity is a major constraint of cisplatin application in many solid tumors. Since the lack of preventive strategies, the necessity exists to identify critical molecular targets involved in cisplatin nephrotoxicity. The Purinergic ligand-gcotedion channel 7 receptor (P2X7R) is a ligand-gated ion channel that is predominantly implicated in inflammation and cell death. Our aim is to investigate the role P2X7R in cisplatin-induced acute and chronic kidney injury, as well as the underlying mechanism. In this study, we found that cisplatin can cause an increase in the expression of P2X7R in mouse kidney tissue, and P2X7R knockout can alleviate acute renal function damage caused by cisplatin, as well as the expression of kidney injury molecule 1 (KIM-1) and interleukin-18 (IL-18). Cisplatin can cause an increase in the expression of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in mouse kidney tissue. Compared with wild-type mice, P2X7R -/- mice showed decreased expression of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved Caspase-1, and cleaved IL-1β in kidney tissue after cisplatin administration, and the apoptosis of renal tubular epithelial cells were also decreased. In addition, we also found that NLRP3 knockout can improve cisplatin induced degeneration, detachment, and necrosis of renal tubular epithelial cells. Furthermore, P2X7R -/- mice also showed reduced renal fibrosis and better long-term renal prognosis. In conclusion, our study identified that P2X7R knockout can improve cisplatin induced acute renal injury and chronic renal fibrosis by inhibiting the activation of NLRP3 inflammasome.
PubMed: 38880358
DOI: 10.1016/j.bcp.2024.116369 -
International Journal of Reproductive... Mar 2023Endometriosis is a chronic estrogen-related inflammatory disorder that is known by proliferating endometrial cells in a place outside the uterus. The high presence of...
Human V 7.2-J 33 mucosal-associated invariant T cells in endometrial ectopic tissues tend to produce interferon-gamma: A new player in endometriosis etiology: A case-control study.
BACKGROUND
Endometriosis is a chronic estrogen-related inflammatory disorder that is known by proliferating endometrial cells in a place outside the uterus. The high presence of immune cells in the peritoneal fluid of women with endometriosis confirms the involvement of the immune system in the pathogenesis of the disease. Mucosal-associated invariant T (MAIT) cells play an undeniable impact on mucosal immunity by the production of interleukin-17, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha. The function of the cells in the pathogenesis of endometriosis is less investigated.
OBJECTIVE
This study aims to investigate the infiltration of MAIT cells by using the determination levels of gene expression in eutopic and ectopic tissue of endometriosis lesions.
MATERIALS AND METHODS
In this case-control study, the tested samples include 20 eutopic and 20 ectopic tissues of women with endometriosis and 20 uterine endometrial tissues of women in the control group. Expressions of the tumor necrosis factor-alpha, interleukin-17A, and -γ genes were analyzed by quantitative reverse transcriptase-polymerase chain reaction.
RESULTS
According to the results, gene expression did not show substantial elevation in the uterine and eutopic endometrial tissues compared to internal gene control as well as in ectopic tissues. Correlation analysis approved a positive relationship between expression genes and -γ levels in ectopic tissues.
CONCLUSION
Considering the low-expression specific gene of MAIT cells in ectopic tissue, it can be concluded that these cells are present in the endometriotic environment to a certain extent, and there is a possibility of their role in the progression of endometriosis by secreting IFN- .
PubMed: 38868448
DOI: 10.18502/ijrm.v22i3.16168