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Science Signaling Oct 2023Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung...
Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung transplantation. Here, we investigated the cellular mechanisms underlying lung IR-induced activation of endothelial TRPV4 channels, which play a central role in lung edema and dysfunction after IR. In a left lung hilar-ligation model of IRI in mice, we found that lung IRI increased the efflux of ATP through pannexin 1 (Panx1) channels at the endothelial cell (EC) membrane. Elevated extracellular ATP activated Ca influx through endothelial TRPV4 channels downstream of purinergic P2Y2 receptor (P2Y2R) signaling. P2Y2R-dependent activation of TRPV4 channels was also observed in human and mouse pulmonary microvascular endothelium in ex vivo and in vitro models of IR. Endothelium-specific deletion of P2Y2R, TRPV4, or Panx1 in mice substantially prevented lung IRI-induced activation of endothelial TRPV4 channels and lung edema, inflammation, and dysfunction. These results identify endothelial P2Y2R as a mediator of the pathological sequelae of IRI in the lung and show that disruption of the endothelial Panx1-P2Y2R-TRPV4 signaling pathway could be a promising therapeutic strategy for preventing lung IRI after transplantation.
Topics: Humans; Animals; Mice; TRPV Cation Channels; Receptors, Purinergic P2Y2; Lung; Reperfusion Injury; Endothelial Cells; Inflammation; Adenosine Triphosphate; Edema; Nerve Tissue Proteins; Connexins
PubMed: 37874885
DOI: 10.1126/scisignal.adg1553 -
British Medical Bulletin Sep 2023Transient bone osteoporosis (TBO) is characterized by persistent pain, loss of function, no history of trauma and magnetic resonance image (MRI) findings of bone marrow...
INTRODUCTION
Transient bone osteoporosis (TBO) is characterized by persistent pain, loss of function, no history of trauma and magnetic resonance image (MRI) findings of bone marrow edema.
SOURCE OF DATA
PubMed, Google scholar, EMABSE and Web of Science were accessed in February 2023. No time constrains were used for the search.
AREAS OF AGREEMENT
TBO is rare and misunderstood, typically affecting women during the third trimester of pregnancy or middle-aged men, leading to functional disability for 4-8 weeks followed by self-resolution of the symptoms.
AREAS OF CONTROVERSY
Given the limited evidence in the current literature, consensus on optimal management is lacking.
GROWING POINTS
This systematic review investigates current management of TBO.
AREAS TIMELY FOR DEVELOPING RESEARCH
A conservative approach leads to the resolution of symptoms and MRI findings at midterm follow-up. Administration of bisphosphonates might alleviate pain and accelerate both clinical and imaging recovery.
Topics: Male; Middle Aged; Pregnancy; Humans; Female; Osteoporosis; Magnetic Resonance Imaging; Diphosphonates; Bone Marrow Diseases; Edema
PubMed: 37328938
DOI: 10.1093/bmb/ldad012 -
Effects of the PI3K/Akt/HO-1 pathway on autophagy in a sepsis-induced acute lung injury mouse model.International Immunopharmacology Nov 2023Sepsis-induced lung injury is an acute hypoxic respiratory insufficiency caused by systemic infectious factors that results in alveolar epithelial cell and capillary...
Sepsis-induced lung injury is an acute hypoxic respiratory insufficiency caused by systemic infectious factors that results in alveolar epithelial cell and capillary endothelial cell injury, diffuse pulmonary interstitial edema, and alveolar edema. Heme oxygenase (HO)-1 is usually associated with inflammation and has anti-inflammatory effects. Autophagy is a degradation pathway that eliminates cellular metabolic waste and plays an important protective role during stress. The phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt) signaling pathway plays a key role in mediating cellular responses to inflammatory reactions. Therefore, we hypothesized that HO-1 is associated with autophagy and regulated by the PI3K/Akt signaling pathway in mice with sepsis-induced lung injury. Sepsis-induced lung injury was induced in mice using cecal ligation and puncture (CLP). Hemin or Sn-protoporphyrin IX (SnPP) was administered via intraperitoneal injection before surgery. Survival rates were observed during days 1-7 after the surgery; lung histology was discerned 24 h after the surgery; pro-inflammatory and anti-inflammatory factors in plasma and lung tissue were measured using enzyme-linked immunosorbent assay (ELISA); HO-1, Beclin-1, microtubule-associated protein 1 light chain 3B (LC3B)-II, p62 and lysosome associated membrane protein (LAMP)2 protein expression levels were measured 24 h after the surgery; HO-1 and LC3B-II protein expression levels were observed using immunofluorescence 24 h after the surgery; and autophagosomes were detected using electron microscopy 24 h after the surgery. Furthermore, when PI3K inhibitors LY294002, PI3K activators Recilisib and hemin were administered before the surgery, Akt, p-Akt, HO-1, and LC3-II levels were measured 24 h post-surgery. We found that HO-1 overexpression increased the survival rate and inhibited sepsis-induced lung injury. HO-1 overexpression attenuated the levels of proinflammatory cytokines (TNF-α, IL-1β) and increased the anti-inflammatory cytokine (IL-10, HO-1) overexpression. Moreover, HO-1 overexpression was also associated with increased expression of Beclin-1, LC3B-II and LAMP2 protein expression; decreased p62 protein expression; and significantly increased autophagosome formation. The results for HO-1-downregulated mice contrasted with those mentioned above. LY294002 inhibited p-Akt/Akt, HO-1, and LC3B-II protein expression; and hemin reversed the inhibitory effect of LY294002. The protective effect of HO-1 was involved in the mediation of autophagy, which may be regulated by the PI3K/Akt signaling pathway during sepsis-induced lung injury in mice.
Topics: Mice; Animals; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Beclin-1; Hemin; Acute Lung Injury; Cytokines; Autophagy; Sepsis; Anti-Inflammatory Agents; Edema; Heme Oxygenase-1
PubMed: 37857120
DOI: 10.1016/j.intimp.2023.111063 -
Journal of Ethnopharmacology Jan 2024DaiTongXiao (DTX) is a traditional Chinese Dai folk formulation utilized for gouty arthritis treatment, with substantial evidence supporting its anti-inflammatory...
ETHNOPHARMACOLOGICAL RELEVANCE
DaiTongXiao (DTX) is a traditional Chinese Dai folk formulation utilized for gouty arthritis treatment, with substantial evidence supporting its anti-inflammatory properties. The NLRP3 inflammasome disorder is tightly linked to the development of many inflammatory diseases.
AIM OF THE STUDY
To elucidate the therapeutic efficacy of DTX in gouty arthritis and reveal its potential underlying mechanism.
MATERIALS AND METHODS
The primary active constituents in DTX were determined through ultraviolet spectrophotometry and gas chromatography. Rats underwent induction with monosodium urate (MSU), followed by treatment of J774A.1 cells with adenosine triphosphate (ATP) activation and lipopolysaccharide (LPS) induction and the subsequent culture in Dulbecco's modified Eagle's medium. The degree of foot joint swelling in rats was assessed, and ankle joints were evaluated through H&E staining. Enzyme-linked immunosorbent assay was performed to measure the levels of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α in both serum and cells. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to determine the relative mRNA expression levels of NLRP3, ASC, Caspase-1, and NF-κB in J774A.1 macrophages. The expression of NLRP3, ASC, Caspase-1, and NF-κB was examined by western blotting.
RESULTS
DTX could alleviate MSU-induced joint swelling in rats, as evidenced by a reduction in joint inflammation. Moreover, DTX effectively enhanced the survival rate of J774A.1 cells following LPS induction and ATP activation. Furthermore, DTX significantly reduced IL-1β, IL-6, IL-8, and TNF-α levels in both cell culture medium and rat serum. RT-PCR results revealed that DTX notably downregulated the mRNA expression levels of NLRP3, ASC, Caspase-1, and NF-κB in J774A.1 cells. Additionally, DTX downregulated NLRP3, ASC, NF-κB, and Caspase-1 expression in the joint tissue.
CONCLUSIONS
DTX exerts a significant anti-gouty arthritis effect, with its mechanism being tightly linked to the NLRP3 inflammatory signaling pathway. This pathway may be modulated by inhibiting IL-1β differentiation and maturation by downregulating NLRP3, ASC, Caspase-1, and NF-κB protein expression. This, in turn, leads to a reduction in the release of IL-6, IL-8, and TNF-α, ultimately impeding gouty arthritis progression.
Topics: Rats; Animals; Arthritis, Gouty; NLR Family, Pyrin Domain-Containing 3 Protein; NF-kappa B; Tumor Necrosis Factor-alpha; Interleukin-6; Lipopolysaccharides; Interleukin-8; Signal Transduction; Inflammasomes; Uric Acid; Caspase 1; Edema; Adenosine Triphosphate; RNA, Messenger
PubMed: 37924998
DOI: 10.1016/j.jep.2023.117313 -
Clinical Science (London, England :... Sep 2023Resolution of edema remains a significant clinical challenge. Conditions such as traumatic shock, sepsis, or diabetes often involve microvascular hyperpermeability,... (Review)
Review
Resolution of edema remains a significant clinical challenge. Conditions such as traumatic shock, sepsis, or diabetes often involve microvascular hyperpermeability, which leads to tissue and organ dysfunction. Lymphatic insufficiency due to genetic causes, surgical removal of lymph nodes, or infections, leads to varying degrees of tissue swelling that impair mobility and immune defenses. Treatment options are limited to management of edema as there are no specific therapeutics that have demonstrated significant success for ameliorating microvascular leakage or impaired lymphatic function. This review examines current knowledge about the physiological, cellular, and molecular mechanisms that control microvascular permeability and lymphatic clearance, the respective processes for interstitial fluid formation and removal. Clinical conditions featuring edema, along with potential future directions are discussed.
Topics: Humans; Edema; Capillary Permeability; Kinetics; Sepsis
PubMed: 37732545
DOI: 10.1042/CS20220314 -
Gut and Liver Nov 2023Fexuprazan is a novel potassium-competitive acid blocker that could be of benefit to patients with gastric mucosal injury. The aim of this study was to assess the 2-week... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND/AIMS
Fexuprazan is a novel potassium-competitive acid blocker that could be of benefit to patients with gastric mucosal injury. The aim of this study was to assess the 2-week efficacy and safety of fexuprazan in patients with acute or chronic gastritis.
METHODS
In this study, 327 patients with acute or chronic gastritis who had one or more gastric erosions on endoscopy and subjective symptoms were randomized into three groups receiving fexuprazan 20 mg once a day (q.d.), fexuprazan 10 mg twice a day (b.i.d.), or placebo for 2 weeks. The posttreatment assessments were the primary endpoint (erosion improvement rate), secondary endpoints (cure rates of erosion and edema and improvement rates of redness, hemorrhage, and subjective symptoms), and drug-related adverse events.
RESULTS
Among the patients, 57.8% (59/102), 65.7% (67/102), and 40.6% (39/96) showed erosion improvement 2 weeks after receiving fexuprazan 20 mg q.d., fexuprazan 10 mg b.i.d., and placebo, respectively. Both fexuprazan 20 mg q.d. and 10 mg b.i.d. showed superior efficacy to the placebo (p=0.017 and p<0.001, respectively). Likewise, both fexuprazan 20 mg q.d. and 10 mg b.i.d. also showed higher erosion healing rates than the placebo (p=0.033 and p=0.010, respectively). No difference was noted in the edema healing rate and the improvement rates for redness, hemorrhage, and subjective symptoms between the fexuprazan and placebo groups. No significant difference was noted in the incidence of adverse drug reactions.
CONCLUSIONS
Fexuprazan 20 mg q.d. and 10 mg b.i.d. for 2 weeks showed therapeutic efficacy superior to that of placebo in patients with acute or chronic gastritis (ClinicalTrials.gov identifier NCT04341454).
Topics: Humans; Amines; Gastritis; Hemorrhage; Edema; Double-Blind Method; Treatment Outcome
PubMed: 36789577
DOI: 10.5009/gnl220457 -
Journal of Medical Cases Nov 2023TAFRO syndrome, a rapidly progressive and fatal disease, is rare, and its etiology remains unknown. It is characterized by thrombocytopenia, anasarca (edema, pleural...
TAFRO syndrome, a rapidly progressive and fatal disease, is rare, and its etiology remains unknown. It is characterized by thrombocytopenia, anasarca (edema, pleural effusion, and ascites), fever, reticulin fibrosis (or renal insufficiency), and organomegaly with Castleman disease (CD)-like histological features in the lymph nodes. CD is a rare, indolent, lymphoproliferative disorder with no established curative strategies. Most idiopathic multicentric CD cases are controlled with anti-interleukin (IL)-6 therapy (tocilizumab and siltuximab) and/or rituximab. However, it is unclear whether these therapies can be directly applied to treat TAFRO syndrome. Here, we describe stepwise immunotherapy (rituximab induction therapy and cyclosporine maintenance therapy) for two cases of steroid-refractory TAFRO syndrome. A 32-year-old man visited a local hospital with sudden onset of fever and epigastralgia. The diagnosis of TAFRO syndrome was established based on the diagnostic criteria. After rituximab administration, C-reactive protein and IL-6 levels were normalized. However, the ascites persisted, with increased resistance to rituximab. Tocilizumab was also ineffective; therefore, cyclosporine was administered. After the initiation of cyclosporine treatment, the ascites decreased and ultimately disappeared. Twelve months after immunotherapy, the patient remained asymptomatic under cyclosporine maintenance therapy. Similar stepwise immunosuppressive therapy was administered to a 72-year-old man with TAFRO syndrome complicated by renal failure. After rituximab infusion, C-reactive protein was decreased. Although methylprednisolone, rituximab, tocilizumab, and cyclosporine were administered, other laboratory data and clinical symptoms remained unchanged. His level of consciousness subsequently deteriorated due to herpes zoster encephalitis, and he died. We consider the combination of rituximab induction therapy and cyclosporine maintenance therapy to be effective for TAFRO syndrome if initiated at an early stage.
PubMed: 38029058
DOI: 10.14740/jmc4160 -
Indian Journal of Ophthalmology Apr 2024Acute corneal hydrops (ACH) is a rare but sight-threatening complication of corneal ectasias. We aim to review the current literature on etiopathogenesis, histology,... (Review)
Review
Acute corneal hydrops (ACH) is a rare but sight-threatening complication of corneal ectasias. We aim to review the current literature on etiopathogenesis, histology, role of ancillary investigations, management, and outcomes of ACH by classifying the various management strategies based on their site of action and the underlying mechanism. A review of the literature was conducted by searching the following databases: PubMed (United States National Library of Medicine), Embase (Reed Elsevier Properties SA), Web of Science (Thomson Reuters), and Scopus (Elsevier BV) till April 2023. The literature search used various combinations of the following keywords: acute corneal hydrops, keratoconus, ectasia, management, keratoplasty. Nine hundred eighty-three articles were identified based on the above searches. Case reports which did not add any new modality of treatment to the existing literature, articles unrelated to management, those with no full text available, and foreign-language articles with no translation available were excluded. Eventually, 75 relevant articles that pertained to the management of ACH were shortlisted and reviewed. Recent studies have described newer surgical interventions like full-thickness or pre-Descemetic sutures, thermokeratoplasty, and plasma injection that aim to close the posterior stromal break. Posterior lamellar keratoplasties act by replacing the posterior torn Descemet's membrane (DM), and early deep anterior lamellar keratoplasty (DALK) has been attempted to combine the correction of the anatomical defect and visual rehabilitation in a single surgery. These surgical interventions may help by reducing the scarring and increasing the number of patients who can be visually rehabilitated with contact lenses rather than keratoplasty.
Topics: Humans; Corneal Edema; Corneal Transplantation; Cornea; Keratoconus; Edema
PubMed: 38317314
DOI: 10.4103/IJO.IJO_2160_23 -
International Journal of Molecular... Jan 2024Cerebral edema is a life-threatening condition that can cause permanent brain damage or death if left untreated. Existing therapies aim at mitigating the associated...
Cerebral edema is a life-threatening condition that can cause permanent brain damage or death if left untreated. Existing therapies aim at mitigating the associated elevated intracranial pressure, yet they primarily alleviate pressure rather than prevent edema formation. Prophylactic anti-edema therapy necessitates novel drugs targeting edema formation. Aquaporin 4 (AQP4), an abundantly expressed water pore in mammalian glia and ependymal cells, has been proposed to be involved in cerebral edema formation. A series of novel compounds have been tested for their potential inhibitory effects on AQP4. However, selectivity, toxicity, functional inhibition, sustained therapeutic concentration, and delivery into the central nervous system are major challenges. Employing extensive density-functional theory (DFT) calculations, we identified a previously unreported thermodynamically stable tautomer of the recently identified AQP4-specific inhibitor TGN-020 (2-(nicotinamide)-1,3,4-thiadiazol). This novel form, featuring a distinct hydrogen-bonding pattern, served as a template for a COSMOsim-3D-based virtual screen of proprietary compounds from Origenis™. The screening identified ORI-TRN-002, an electronic homologue of TGN-020, demonstrating high solubility and low protein binding. Evaluating ORI-TRN-002 on AQP4-expressing oocytes using a high-resolution volume recording system revealed an IC of 2.9 ± 0.6 µM, establishing it as a novel AQP4 inhibitor. ORI-TRN-002 exhibits superior solubility and overcomes free fraction limitations compared to other reported AQP4 inhibitors, suggesting its potential as a promising anti-edema therapy for treating cerebral edema in the future.
Topics: Animals; Aquaporin 4; Brain Edema; Edema; Niacinamide; Thiadiazoles
PubMed: 38255997
DOI: 10.3390/ijms25020924 -
European Radiology Apr 2024The purpose of this study was to develop and validate a nomogram combined multiparametric MRI and clinical indicators for identifying the WHO grade of meningioma.
OBJECTIVE
The purpose of this study was to develop and validate a nomogram combined multiparametric MRI and clinical indicators for identifying the WHO grade of meningioma.
MATERIALS AND METHODS
Five hundred and sixty-eight patients were included in this study, who were diagnosed pathologically as having meningiomas. Firstly, radiomics features were extracted from CE-T1, T2, and 1-cm-thick tumor-to-brain interface (BTI) images. Then, difference analysis and the least absolute shrinkage and selection operator were orderly used to select the most representative features. Next, the support vector machine algorithm was conducted to predict the WHO grade of meningioma. Furthermore, a nomogram incorporated radiomics features and valuable clinical indicators was constructed by logistic regression. The performance of the nomogram was assessed by calibration and clinical effectiveness, as well as internal validation.
RESULTS
Peritumoral edema volume and gender are independent risk factors for predicting meningioma grade. The multiparametric MRI features incorporating CE-T1, T2, and BTI features showed the higher performance for prediction of meningioma grade with a pooled AUC = 0.885 (95% CI, 0.821-0.946) and 0.860 (95% CI, 0.788-0.923) in the training and test groups, respectively. Then, a nomogram with a pooled AUC = 0.912 (95% CI, 0.876-0.961), combined radiomics score, peritumoral edema volume, and gender improved diagnostic performance compared to radiomics model or clinical model and showed good calibration as the true results. Moreover, decision curve analysis demonstrated satisfactory clinical effectiveness of the proposed nomogram.
CONCLUSIONS
A novel nomogram is simple yet effective in differentiating WHO grades of meningioma and thus can be used in patients with meningiomas.
CLINICAL RELEVANCE STATEMENT
We proposed a nomogram that included clinical indicators and multi-parameter radiomics features, which can accurately, objectively, and non-invasively differentiate WHO grading of meningioma and thus can be used in clinical work.
KEY POINTS
• The study combined radiomics features and clinical indicators for objectively predicting the meningioma grade. • The model with CE-T1 + T2 + brain-to-tumor interface features demonstrated the best predictive performance by investigating seven different radiomics models. • The nomogram potentially has clinical applications in distinguishing high-grade and low-grade meningiomas.
Topics: Humans; Multiparametric Magnetic Resonance Imaging; Meningioma; Retrospective Studies; Nomograms; Brain Neoplasms; Meningeal Neoplasms; Machine Learning; Edema; World Health Organization
PubMed: 37812296
DOI: 10.1007/s00330-023-10252-8