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Paediatric Drugs May 2024Necrotizing enterocolitis (NEC) is a life-threatening disease predominantly affecting premature and very low birth weight infants resulting in inflammation and necrosis... (Review)
Review
Necrotizing enterocolitis (NEC) is a life-threatening disease predominantly affecting premature and very low birth weight infants resulting in inflammation and necrosis of the small bowel and colon and potentially leading to sepsis, peritonitis, perforation, and death. Numerous research efforts have been made to better understand, treat, and prevent NEC. This review explores a variety of factors involved in the pathogenesis of NEC (prematurity, low birth weight, lack of human breast milk exposure, alterations to the microbiota, maternal and environmental factors, and intestinal ischemia) and reports treatment modalities surrounding NEC, including pain medications and common antibiotic combinations, the rationale for these combinations, and recent antibiotic stewardship approaches surrounding NEC treatment. This review also highlights the effect of early antibiotic exposure, infections, proton pump inhibitors (PPIs), and H receptor antagonists on the microbiota and how these risk factors can increase the chances of NEC. Finally, modern prevention strategies including the use of human breast milk and standardized feeding regimens are discussed, as well as promising new preventative and treatment options for NEC including probiotics and stem cell therapy.
Topics: Humans; Enterocolitis, Necrotizing; Infant, Newborn; Milk, Human; Anti-Bacterial Agents; Probiotics; Risk Factors; Infant, Premature
PubMed: 38564081
DOI: 10.1007/s40272-024-00626-w -
European Journal of Pharmacology Jul 2023DL-3-n-butylphthalide (NBP) and edaravone dexborneol (Eda-Dex) are two promising reagents for stroke treatment. However, the impacts of NBP and Eda-Dex on poststroke...
INTRODUCTION
DL-3-n-butylphthalide (NBP) and edaravone dexborneol (Eda-Dex) are two promising reagents for stroke treatment. However, the impacts of NBP and Eda-Dex on poststroke mental deficits are still poorly understood. In this study, we aimed to investigate and compare the influences of NBP and Eda-Dex on neurological function and cognitive behavior in rats with ischemic stroke.
METHODS
An ischemic stroke model was established by middle cerebral artery occlusion (MCAO). After peritoneal administration of the drugs, the rats were subjected to neurological deficit evaluation, cerebral blood flow (CBF) assays, cerebral infarct area evaluations or behavioral tests. Brain tissues were collected and further analyzed by enzyme-linked immunosorbent assay (ELISA), western blotting or immunohistochemistry.
RESULTS
NBP and Eda-Dex significantly decreased the neurological score, reduced the cerebral infarct area and improved CBF. Behavioral changes as assessed in the sucrose preference test, novel object recognition test, and social interaction test were significantly alleviated by NBP and Eda-Dex in rats with ischemic stroke. Moreover, NBP and Eda-Dex significantly suppressed inflammation by targeting the nuclear factor kappa-B/inducible nitric oxide synthase (NF-κB/iNOS) pathway and significantly inhibited oxidative stress by targeting the kelch-1ike ECH-associated protein l/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) pathway. In addition, NBP and Eda-Dex distinctly suppressed the activation of microglia and astrocytes and improved neuronal viability in the ischemic brain.
CONCLUSIONS
NBP and Eda-Dex improved neurological function and alleviated cognitive disorders in rats with ischemic stroke by synergistically inhibiting inflammation and oxidative stress.
Topics: Rats; Animals; Edaravone; Neuroprotective Agents; Kelch-Like ECH-Associated Protein 1; Ischemic Stroke; NF-E2-Related Factor 2; Stroke; Infarction, Middle Cerebral Artery; NF-kappa B; Inflammation; Brain Ischemia
PubMed: 37207969
DOI: 10.1016/j.ejphar.2023.175801 -
Journal of Visualized Experiments : JoVE Jul 2023Early diagnosis of mesenteric ischemia remains challenging because mesenteric ischemia presents with no key symptoms or physical findings, and no laboratory data...
Early diagnosis of mesenteric ischemia remains challenging because mesenteric ischemia presents with no key symptoms or physical findings, and no laboratory data specifically indicates intestinal tissue ischemic status before necrosis develops. While computed tomography is the standard for diagnostic imaging, there are several limitations: (1) repeated assessments are associated with increased radiation exposure and risk of renal damage; (2) the computed tomography findings can be misleading because necrosis occasionally occurs despite opacified mesenteric arteries; and (3) computed tomography is not necessarily available within the golden time of salvaging the intestines for those patients in the operating room or at a place far from the hospital. This article describes a challenge to overcome such limitations using ultrasonography and near-infrared light, including clinical studies. The former is capable of providing not only morphologic and kinetic information of the intestines but also perfusion of the mesenteric vessels in real-time without transferring the patient or exposing them to radiation. Transesophageal echocardiography enables precise assessment of mesenteric perfusion in the OR, ER, or ICU. Representative findings of mesenteric ischemia in seven aortic dissection cases are presented. Near-infrared imaging with indocyanine green helps visualize the perfusion of vessels and intestinal tissues although this application requires laparotomy. Findings in two cases (aortic aneurysm) are shown. Near-infrared spectroscopy demonstrates oxygen debt in the intestinal tissue as digital data and can be a candidate for early detection of mesenteric ischemia without laparotomy. The accuracy of these assessments has been confirmed by intraoperative inspections and postoperative course (prognosis).
Topics: Humans; Mesenteric Ischemia; Multimodal Imaging; Mesenteric Arteries; Mesentery; Perfusion
PubMed: 37590532
DOI: 10.3791/65095 -
The Canadian Journal of Cardiology Aug 2023The pericardium plays several homeostatic roles to support and maintain everyday cardiac function. Recent advances in techniques and experimental models have allowed for... (Review)
Review
The pericardium plays several homeostatic roles to support and maintain everyday cardiac function. Recent advances in techniques and experimental models have allowed for further exploration into the cellular contents of the pericardium itself. Of particular interest are the various immune cell populations present in the space within the pericardial fluid and fat. In contrast to immune cells of the comparable pleura, peritoneum and heart, pericardial immune cells appear to be distinct in their function and phenotype. Specifically, recent work has suggested these cells play critical roles in an array of pathophysiological conditions including myocardial infarction, pericarditis, and post-cardiac surgery complications. In this review, we spotlight the pericardial immune cells currently identified in mice and humans, the pathophysiological role of these cells, and the clinical significance of the immunocardiology axis in cardiovascular health.
Topics: Humans; Mice; Animals; Pericardium; Pericarditis; Myocardial Infarction; Pericardial Effusion
PubMed: 37270165
DOI: 10.1016/j.cjca.2023.05.017 -
Clinical Nephrology. Case Studies 2023We present two atypical cases of calciphylaxis presenting with ocular ischemic pathology - both without the hallmark cutaneous manifestations - to raise awareness of...
PURPOSE
We present two atypical cases of calciphylaxis presenting with ocular ischemic pathology - both without the hallmark cutaneous manifestations - to raise awareness of this rare yet highly disabling condition.
OBSERVATIONS
We report two cases of ophthalmic calciphylaxis presenting as (1) anterior ischemic optic neuropathy (AION) and cilioretinal artery occlusion in a 76-year-old woman with pre-dialysis kidney failure, and (2) AION with contralateral central retinal artery occlusion (CRAO) in a 44-year-old man on hemodialysis.
CONCLUSION AND IMPORTANCE
These cases highlight the need for judicious clinical suspicion of calciphylaxis in patients with kidney failure, presenting with microvascular ischemic ophthalmic pathology such as AION or CRAO. Confirmation with temporal artery biopsy is essential to direct targeted individualized multi-disciplinary treatment of calciphylaxis and avoid unnecessary steroid exposure in cases masquerading as giant cell arteritis (GCA).
PubMed: 38169875
DOI: 10.5414/CNCS111088 -
Journal For Immunotherapy of Cancer Nov 2023Peritoneal carcinomatosis is an advanced stage of cancer in which the disease has spread to the peritoneal cavity. In order to restore antitumor immunity subverted by...
Intraperitoneal administration of a modified vaccinia virus Ankara confers single-chain interleukin-12 expression to the omentum and achieves immune-mediated efficacy against peritoneal carcinomatosis.
BACKGROUND
Peritoneal carcinomatosis is an advanced stage of cancer in which the disease has spread to the peritoneal cavity. In order to restore antitumor immunity subverted by tumor cells in this location, we evaluated intraperitoneal administrations of modified vaccinia virus Ankara (MVA) engineered to express single-chain interleukin 12 (scIL-12) to increase antitumor immune responses.
METHODS
MVA encoding scIL-12 (MVA.scIL-12) was evaluated against peritoneal carcinomatosis models based on intraperitoneal engraftment of tumor cells. CD8-mediated immune responses, elucidated antitumor efficacy, and safety were evaluated following intravenous, intratumoral, or intraperitoneal administration of the viral vector. The immune response was measured by ELISpot (enzyme-linked immunosorbent spot), RNA sequencing, flow cytometry, intravital microscopy, and depletion of lymphocyte subsets with monoclonal antibodies. Safety was assessed by body-weight follow-up and blood testing. Tissue tropism on intravenous or intraperitoneal administration was assessed by bioluminescence analysis using a reporter MVA encoding luciferase.
RESULTS
Intraperitoneal or locoregional administration, but not other routes of administration, resulted in a potent immune response characterized by increased levels of tumor-specific CD8 T lymphocytes with the ability to produce both interferon-γ and tumor necrosis factor-α. The antitumor immune response was detectable not only in the peritoneal cavity but also systemically. As a result of intraperitoneal treatment, a single administration of MVA.scIL-12 encoding scIL-12 completely eradicated MC38 tumors implanted in the peritoneal cavity and also protected cured mice from subsequent subcutaneous rechallenges. Bioluminescence imaging using an MVA encoding luciferase revealed that intraperitoneal administration targets transgene to the omentum. The omentum is considered a key tissue in immune protection of the peritoneal cavity. The safety profile of intraperitoneal administration was also better than that following intravenous administration since no weight loss or hematological toxicity was observed when the vector was locally delivered into the peritoneal cavity.
CONCLUSION
Intraperitoneal administration of MVA vectors encoding scIL-12 targets the omentum, which is the tissue where peritoneal carcinomatosis usually begins. MVA.scIL-12 induces a potent tumor-specific immune response that often leads to the eradication of experimental tumors disseminated to the peritoneal cavity.
Topics: Animals; Mice; Interleukin-12; Peritoneal Neoplasms; Omentum; Vaccinia virus; Luciferases
PubMed: 37918917
DOI: 10.1136/jitc-2023-006702 -
European Journal of Pharmacology Sep 2023Peritoneal adhesion is a common abdominal surgical complication that induces abdominal haemorrhage, intestinal obstruction, infertility, and so forth. The high morbidity...
Peritoneal adhesion is a common abdominal surgical complication that induces abdominal haemorrhage, intestinal obstruction, infertility, and so forth. The high morbidity and recurrence rate of this disease indicate the need for novel therapeutic approaches. Here, we revealed the protective roles of tetrahydroberberrubine (THBru), a novel derivative of berberine (BBR), in preventing peritoneal adhesion and identified its underlying mechanism in vivo and in vitro. Abrasive surgery was used to create a peritoneal adhesion rat model. We found that THBru administration markedly ameliorated peritoneal adhesion, as indicated by a lowered adhesion score and ameliorated caecal tissue damage. By comparison, THBru exhibited more potent anti-adhesion effects than BBR at the same dose. Mechanistically, THBru inhibited inflammation and extracellular matrix (ECM) accumulation in the microenvironment of adhesion tissue. THBru suppressed the expression of inflammatory cytokines including interleukin-1β (IL-1β), IL-6, transforming growth factor β (TGF-β), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1), by regulating the transforming growth factor beta-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK) and TAK1/nuclear factor κB (NF-κB) signaling pathways. However, THBru promoted the activation of MMP-3 by directly blocking the TIMP-1 activation core and subsequently decreased collagen deposition. Taken together, this study identifies THBru as an effective anti-adhesion agent that regulates diverse mechanisms, thereby outlining its potential therapeutic implications for the treatment of peritoneal adhesion.
Topics: Rats; Animals; Berberine; Inflammation; NF-kappa B; Transforming Growth Factor beta; Extracellular Matrix; Intercellular Adhesion Molecule-1
PubMed: 37295764
DOI: 10.1016/j.ejphar.2023.175803 -
Clinical Immunology (Orlando, Fla.) Sep 2023Metrnl play an immunocytokine-like role in several diseases, which is also known as meteorin-like because it is homologous to the neurotrophic factor meteorin (Metrn)....
Protective role of the novel cytokine Metrnl/ interleukin-41 in host immunity defense during sepsis by promoting macrophage recruitment and modulating Treg/Th17 immune cell balance.
BACKGROUND
Metrnl play an immunocytokine-like role in several diseases, which is also known as meteorin-like because it is homologous to the neurotrophic factor meteorin (Metrn). Although the expression and function of Metrnl, including neurotrophic, immunomodulatory, and insulin resistance functions in different tissues have been extensively studied, its role in sepsis has remained largely limited.
METHODS
The present work analyzed the levels of Metrnl and cytokines in the circulation, such as tumor necrosis factor (TNF-α), interleukin (IL-1)β, IL-6, IL-8, together with IL-10 among septic adult patients. Clinical information was obtained from such patients, including sofa score, procalcitonin(PCT)count, and C-reactive count (CRP) within 24 h when entering the intensive care unit (ICU). We constructed a sepsis model in Metrnl-deficient or normal wild-type mice using cecal ligation and perforation to study its functions in bacterial burden, survival, cytokine/chemokine generation, peritoneal lavage fluid neutrophils, macrophage and lymphocyte recruitment, and Treg/Th17 immune cell balance after CLP-induced sepsis.
RESULTS
The expression of Metrnl was remarkably elevated in the early phase of sepsis clinically. Its serum content in patients dying of sepsis slightly decreased relative to that in survivors. Furthermore, the concentration of Metrnl in septic cases when entering the ICU independently predicted the 28-day mortality. For septic patients who had low serum Metrnl content (≤ 274.40 pg/mL), the death risk increased by 2.3 folds relative to those who had a high serum content. It is reported that Metrnl is probably insufficient among patients dying of sepsis. Additionally, the content of Metrnl in the serum of septic patients when entering the ICU is markedly and negatively related to the levels of TNF-α, IL-1β, IL-6, IL-8, IL-17, PCT, and Sofa score. Collectively, Metrnl could be a potential therapeutic target for sepsis. A low-lethality non-severe sepsis (NSS) model was constructed, which suggested that Metrnl insufficiency elevated the death rate and reduced bacterial clearance during sepsis. For Metrnl-deficient mice, impaired sepsis immunity defense might be related to decreased macrophage recruitment and Treg/Th17 lymphocyte imbalance. Recombinant Metrnl administered to Metrnl-deficient mice abolished the immunity defense impairment following NSS while protecting the high-lethality severe sepsis (SS) model in wild-type (WT) mice. In addition, Metrnl-induced sepsis prevention was intricately associated with the increased recruitment of peritoneal macrophages and modulation of the Treg/TH17 immune cell balance. Furthermore, CCL3 exposure in Metrnl-deficient mice reduced peritoneal bacterial loads while improving survival during sepsis partially by promoting the recruitment of peritoneal macrophages. Furthermore, Metrnl regulated the polarization of M1 macrophages through the ROS signaling pathway and promoted macrophage phagocytosis, thereby killing Escherichia coli.
CONCLUSIONS
The present proof-of-concept work suggests that Metrnl-mediated recruitment of macrophages significantly affects sepsis defense in the host and modulates the Treg/Th17 immune cell balance. Findings in this work shed more light on the development of host-directed treatments that can be used to manipulate host immunity to treat sepsis.
Topics: Animals; Mice; Cytokines; Interleukin-6; Interleukin-8; Interleukins; Macrophages; Sepsis; T-Lymphocytes, Regulatory; Th17 Cells; Tumor Necrosis Factor-alpha
PubMed: 37423488
DOI: 10.1016/j.clim.2023.109690 -
Frontiers in Immunology 2023C-reactive protein (CRP) levels are elevated in patients with abdominal aortic aneurysms (AAA). However, it has not been investigated whether CRP contributes to AAA...
BACKGROUND
C-reactive protein (CRP) levels are elevated in patients with abdominal aortic aneurysms (AAA). However, it has not been investigated whether CRP contributes to AAA pathogenesis.
METHODS
CRP deficient and wild type (WT) male mice were subjected to AAA induction via transient intra-aortic infusion of porcine pancreatic elastase. AAAs were monitored by measurements of maximal infrarenal aortic external diameters immediately prior to and 14 days following elastase infusion. Key AAA pathologies were assessed by histochemical and immunohistochemical staining procedures. The influence of CRP deficiency on macrophage activation was evaluated in peritoneal macrophages .
RESULTS
CRP protein levels were higher in aneurysmal than that in non-aneurysmal aortas. Aneurysmal aortic dilation was markedly suppressed in CRP deficient (aortic diameter: 1.08 ± 0.11 mm) as compared to WT (1.21 ± 0.08 mm) mice on day 14 after elastase infusion. More medial elastin was retained in CRP deficient than in WT elastase-infused mice. Macrophage accumulation was significantly less in aneurysmal aorta from CRP deficient than that from WT mice. Matrix metalloproteinase 2 expression was also attenuated in CRP deficient as compared to WT aneurysmal aortas. CRP deficiency had no recognizable influence on medial smooth muscle loss, lymphocyte accumulation, aneurysmal angiogenesis, and matrix metalloproteinase 9 expression. In assays, mRNA levels for tumor necrosis factor α and cyclooxygenase 2 were reduced in lipopolysaccharide activated peritoneal macrophages from CRP deficient as compared to wild type mice.
CONCLUSION
CRP deficiency suppressed experimental AAAs by attenuating aneurysmal elastin destruction, macrophage accumulation and matrix metalloproteinase 2 expression.
Topics: Humans; Male; Animals; Mice; Swine; Matrix Metalloproteinase 2; C-Reactive Protein; Elastin; Aortic Aneurysm, Abdominal; Aorta, Abdominal
PubMed: 37753091
DOI: 10.3389/fimmu.2023.1233807 -
Biotechnology and Applied Biochemistry Oct 2023M2 macrophages are the most prevalent type in the tumor microenvironment and their polarization to M1 type can be used as a potential cancer immunotherapy. Here, we...
M2 macrophages are the most prevalent type in the tumor microenvironment and their polarization to M1 type can be used as a potential cancer immunotherapy. Here, we investigated the role of tumor microenvironment and particularly purified exosomes in M2 to M1 macrophage polarization. Rapamycin treatment on triple-negative breast cancer cells (TNBC) was performed. Tumor cells-derived exosomes (called texosomes) were isolated and characterized using scanning electron microscopy, transmission electron microscopy, dynamic light scattering, high-performance liquid chromatography, Fourier transform infrared, and Western blot assays. M2 mouse peritoneal macrophages were treated with rapamycin or rapamycin-texosome. Then, M1/M2 phenotype-specific marker genes and proteins were measured to assess the degree of M2 to M1 polarization. Finally, nitric oxide (NO) production, phagocytosis, and efferocytosis assays were assessed to verify the functionality of the polarized macrophages. Purified rapamycin-texosomes significantly increased the expression of the M1 markers (Irf5, Nos2, and CD86) and decreased M2 markers (Arg, Ym1, and CD206). In addition, the levels of M1-specific cytokines tumor necrosis factor alpha and interleukin 1β (IL-1β) were increased, whereas the levels of M2 specific cytokines IL-10 and transforming growth factor beta were declined. Furthermore, texosome treatment increased NO concentration and phagocytosis and decreased efferocytosis indicating M1 polarization. These findings suggest rapamycin-texosomes can induce M2 to M1 macrophages polarization as a potential immunotherapy for TNBC.
Topics: Humans; Mice; Animals; Sirolimus; Exosomes; Triple Negative Breast Neoplasms; Macrophages; Cytokines; Phenotype; Tumor Microenvironment; Interferon Regulatory Factors
PubMed: 37254633
DOI: 10.1002/bab.2473