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BACKGROUND: Synthetic mid-urethral sling surgery has long been the standard surgical treatment for stress urinary incontinence (SUI) worldwide. Using an autologous fascial sling is an alternative to reduce adverse events. We evaluated the treatment outcomes of a novel fixation method applied to the autologous transobturator fascial (TOF) sling procedure for female patients with SUI. METHODS: A retrospective study was conducted between 2017 and 2020, including 33 patients with SUI who underwent mid-urethral TOF sling surgery with the novel fixation method. We used a self-locking feature (V-LOC™) that was fixed to each side of skin layer above the obturator foramen, and the tension of the fascia sling was adjusted by manipulating the V-LOC™ suture. We analyzed all data collected through questionnaires, including Urinary Distress Inventory-Short Form (UDI-6), Incontinence Impact Questionnaire-Short Form (IIQ-7), Overactive Bladder Symptom Score (OABSS), and Clinical Global Impressions of Improvement (CGI-I). Adverse events were also recorded. RESULTS: This study included 33 female patients aged 39-79 (mean 59.76 years). Following the procedure, there was a significant reduction in the total scores of UDI-6, IIQ-7, and OABSS (preoperative 9.73±4.35, 10.21±5.79, 6.06±4.03 and postoperative 3.52±3.41, 0.85±3.67, 3.06±2.90, respectively) (p < 0.001). Further analysis of each sub-score of the questionnaires revealed significant improvement in certain symptoms. The mean total score of CGI-I was 2.00 ± 0.80. The maximum flow rate was documented for 18 patients, and no significant reduction was observed after the procedure (p = 0.804). Complications reported included voiding dysfunction in two patients (6.1 %), inguinal pain in one patient (3.0 %), and mild delayed wound healing in one patient (3.0 %). CONCLUSION: This modified TOF sling surgery with a novel fixation method by V-LOC™ suture offers feasibility and adjustability as its main advantages. Our study demonstrated significant improvements in patient outcomes.
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High-grade gliomas, including glioblastoma multiforme (GBM), continue to be a leading aggressive brain tumor in adults, marked by its rapid growth and invasive nature. Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), an enzyme, plays a significant role in tumor progression, yet its function in high-grade gliomas is still poorly investigated. In this study, we evaluated ALDH1A1 levels in clinical samples of GBM. We also assessed the prognostic significance of ALDH1A1 expression in GBM and LGG (low grade glioma) patients using TCGA (The Cancer Genome Atlas) database analysis. The MTT and transwell assays were utilized to examine cell growth and the invasive capability of U87 cells, respectively. We quantitatively examined markers for cell proliferation (Ki-67 and cyclin D1) and invasion (MMP2 and 9). A Western blot test was conducted to determine the downstream signaling of ALDH1A1. We found a notable increase in ALDH1A1 expression in high-grade gliomas compared to their low-grade counterparts. U87 cells that overexpressed ALDH1A1 showed increased cell growth and invasion. We found that ALDH1A1 promotes the phosphorylation of AKT, and inhibiting AKT phosphorylation mitigates the ALDH1A1's effects on tumor growth and migration. In summary, our findings suggest ALDH1A1 as a potential therapeutic target for GBM treatment.
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Cancer-associated fibroblasts (CAFs) play a key role in metabolic reprogramming and are well-established contributors to drug resistance in colorectal cancer (CRC). To exploit this metabolic crosstalk, we integrated a systems biology approach that identified key metabolic targets in a data-driven method and validated them experimentally. This process involved high-throughput computational screening to investigate the effects of enzyme perturbations predicted by a computational model of CRC metabolism to understand system-wide effects efficiently. Our results highlighted hexokinase (HK) as one of the crucial targets, which subsequently became our focus for experimental validation using patient-derived tumor organoids (PDTOs). Through metabolic imaging and viability assays, we found that PDTOs cultured in CAF conditioned media exhibited increased sensitivity to HK inhibition. Our approach emphasizes the critical role of integrating computational and experimental techniques in exploring and exploiting CRC-CAF crosstalk.
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Removing water-soluble chlorides (WSCs) through water extraction is a common pretreatment technology for recycling municipal solid waste incineration (MSWI) fly ash (FA). However, the extracted solution often contains heavy metals, the concentrations of which exceed standards for effluent. This study aims to investigate the adsorption of heavy metals by palygorskite in water-extracted solution and explore the feasibility of stabilizing heavy metals through comilling palygorskite-adsorbed heavy metals (PAHMs) with water-extracted fly ash (WFA). The experimental parameters include: two-stage water extraction with a liquid-to-solid ratio of 5, adding 0, 0.125, 0.25, 0.5, 1, 2 or 3 g of palygorskite to 100 mL of water-extracted solution, and comilling the mixture of PAHMs and WFA for 0, 0.5, 1, 2, 4, 8, 12, 24 or 96 hours. The experimental results revealed that 3 g of palygorskite in 100 mL of extracted solution could absorb Pb, Cd, Cr, Cu and Zn, meeting the effluent standards. The total amount of Pb, Cd, Cr, Cu and Zn removal rate reached 99.7%. Moreover, 98.44% of the WSCs were not adsorbed, the water extraction process for removing WSCs was not compromised. After the comilling of PAHMs and WFA, the distribution of the heavy metals in the milled blended powder was greater than 99.44%; moreover, toxicity characteristic leaching procedure concentrations were determined to conform to regulatory standards, and the sequential extraction procedure revealed that the heavy metals tended to be in stable fractions. This achieves the goal of preventing secondary pollution from heavy metals during the MSWI FA recycling process.
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This paper presents a low-noise bioimpedance (bio-Z) spectroscopy interface for electrical impedance myography (EIM) over the 1 kHz to 2 MHz frequency range. The proposed interface employs a sinusoidal signal generator based on direct-digital-synthesis (DDS) to improve the accuracy of the bio-Z reading, and a quadrature low-intermediate frequency (IF) readout to achieve a good noise-to-power efficiency and the required data throughput to detect muscle contractions. The readout is able to measure baseline and time-varying bio-Z by employing robust and power-efficient low-gain IAs and sixth-order single-bit bandpass (BP) ΔΣ ADCs. The proposed bio-Z spectroscopy interface is implemented in a 180 nm CMOS process, consumes 344.3 - 479.3 µW, and occupies 5.4 mm2 area. Measurement results show 0.7 m Ω/â{Hz} sensitivity at 15.625 kHz, 105.8 dB SNR within 4 Hz bandwidth, and a 146.5 dB figure-of-merit. Additionally, recording of EIM in time and frequency domain during contractions of the bicep brachii muscle demonstrates the potential of the proposed bio-Z interface for wearable EIM systems.
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Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Proteínas Proto-Oncogénicas p21(ras) , Proliferación Celular , Neoplasias Pancreáticas/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Gemcitabina , Proteínas de la Membrana/metabolismo , Proteínas ADAM/metabolismo , Proteínas ADAM/uso terapéuticoRESUMEN
Optic pathway glioma (OPG) is one of the causes of pediatric visual impairment. Unfortunately, there is as yet no cure for such a disease. Understanding the underlying mechanisms and the potential therapeutic strategies may help to delay the progression of OPG and rescue the visual morbidities. Here, we provide an overview of preclinical OPG studies and the regulatory pathways controlling OPG pathophysiology. We next discuss the role of microenvironmental cells (neurons, T cells, and tumor-associated microglia and macrophages) in OPG development. Last, we provide insight into potential therapeutic strategies for treating OPG and promoting axon regeneration.
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Glaucoma is a neurodegenerative eye disease that causes permanent vision impairment. The main pathological characteristics of glaucoma are retinal ganglion cell (RGC) loss and optic nerve degeneration. Glaucoma can be caused by elevated intraocular pressure (IOP), although some cases are congenital or occur in patients with normal IOP. Current glaucoma treatments rely on medicine and surgery to lower IOP, which only delays disease progression. First-line glaucoma medicines are supported by pharmacotherapy advancements such as Rho kinase inhibitors and innovative drug delivery systems. Glaucoma surgery has shifted to safer minimally invasive (or microinvasive) glaucoma surgery, but further trials are needed to validate long-term efficacy. Further, growing evidence shows that adeno-associated virus gene transduction and stem cell-based RGC replacement therapy hold potential to treat optic nerve fiber degeneration and glaucoma. However, better understanding of the regulatory mechanisms of RGC development is needed to provide insight into RGC differentiation from stem cells and help choose target genes for viral therapy. In this review, we overview current progress in RGC development research, optic nerve fiber regeneration, and human stem cell-derived RGC differentiation and transplantation. We also provide an outlook on perspectives and challenges in the field.
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Glaucoma , Enfermedades Neurodegenerativas , Enfermedades del Nervio Óptico , Humanos , Animales , Glaucoma/tratamiento farmacológico , Glaucoma/patología , Células Ganglionares de la Retina/patología , Enfermedades del Nervio Óptico/terapia , Enfermedades del Nervio Óptico/patología , Progresión de la Enfermedad , Enfermedades Neurodegenerativas/patología , Modelos Animales de EnfermedadRESUMEN
The development of "anode-free" lithium-metal batteries with high energy densities is, at present, mainly limited by the poor control of the nucleation of lithium directly on the copper current collector, especially in conventional carbonate electrolytes. It is therefore essential to improve the understanding of the lithium nucleation process and its interactions with the copper substrate. In this study, it is shown that diffusion of lithium into the copper substrate, most likely via the grain boundaries, can significantly influence the nucleation process. Such diffusion makes it more difficult to obtain a great number of homogeneously distributed lithium nuclei on the copper surface and thus leads to inhomogeneous electrodeposition. It is, however, demonstrated that the nucleation of lithium on copper is significantly improved if an initial chemical prelithiation of the copper surface is performed. This prelithiation saturates the copper surface with lithium and hence decreases the influence of lithium diffusion via the grain boundaries. In this way, the lithium nucleation can be made to take place more homogenously, especially when a short potentiostatic nucleation pulse that can generate a large number of nuclei on the surface of the copper substrate is applied.
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This study aimed to investigate the regulatory role of Aldo-keto reductase family 1 member B1 (AKR1B1) in glioma cell proliferation through p38 MAPK activation to control Bcl-2/BAX/caspase-3 apoptosis signaling. AKR1B1 expression was quantified in normal human astrocytes, glioblastoma multiforme (GBM) cell lines, and normal tissues by using quantitative real-time polymerase chain reaction. The effects of AKR1B1 overexpression or knockdown and those of AKR1B1-induced p38 MAPK phosphorylation and a p38 MAPK inhibitor (SB203580) on glioma cell proliferation were determined using an MTT assay and Western blot, respectively. Furthermore, the AKR1B1 effect on BAX and Bcl-2 expression was examined in real-time by Western blot. A luminescence detection reagent was also utilized to identify the effect of AKR1B1 on caspase-3/7 activity. The early and late stages of AKR1B1-induced apoptosis were assessed by performing Annexin V-FITC/PI double-staining assays. AKR1B1 expression was significantly downregulated in glioma tissues and GBM cell lines (T98G and 8401). Glioma cell proliferation was inhibited by AKR1B1 overexpression but was slightly increased by AKR1B1 knockdown. Additionally, AKR1B1-induced p38 MAPK phosphorylation and SB203580 reversed AKR1B1's inhibitory effect on glioma cell proliferation. AKR1B1 overexpression also inhibited Bcl-2 expression but increased BAX expression, whereas treatment with SB203580 reversed this phenomenon. Furthermore, AKR1B1 induced caspase-3/7 activity. The induction of early and late apoptosis by AKR1B1 was confirmed using an Annexin V-FITC/PI double-staining assay. In conclusion, AKR1B1 regulated glioma cell proliferation through the involvement of p38 MAPK-induced BAX/Bcl-2/caspase-3 apoptosis signaling. Therefore, AKR1B1 may serve as a new therapeutic target for glioma therapy development.
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As part of the central nervous system (CNS), retinal ganglion cells (RGCs) and their axons are the only neurons in the retina that transmit visual signals from the eye to the brain via the optic nerve (ON). Unfortunately, they do not regenerate upon injury in mammals. In ON trauma, retinal microglia (RMG) become activated, inducing inflammatory responses and resulting in axon degeneration and RGC loss. Since aldose reductase (AR) is an inflammatory response mediator highly expressed in RMG, we investigated if pharmacological inhibition of AR can attenuate ocular inflammation and thereby promote RGC survival and axon regeneration after ON crush (ONC). In vitro, we discovered that Sorbinil, an AR inhibitor, attenuates BV2 microglia activation and migration in the lipopolysaccharide (LPS) and monocyte chemoattractant protein-1 (MCP-1) treatments. In vivo, Sorbinil suppressed ONC-induced Iba1 + microglia/macrophage infiltration in the retina and ON and promoted RGC survival. Moreover, Sorbinil restored RGC function and delayed axon degeneration one week after ONC. RNA sequencing data revealed that Sorbinil protects the retina from ONC-induced degeneration by suppressing inflammatory signaling. In summary, we report the first study demonstrating that AR inhibition transiently protects RGC and axon from degeneration, providing a potential therapeutic strategy for optic neuropathies.
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Atrofia Óptica , Traumatismos del Nervio Óptico , Animales , Microglía , Axones/fisiología , Aldehído Reductasa , Regeneración Nerviosa , Retina , Traumatismos del Nervio Óptico/patología , Atrofia Óptica/patología , Degeneración Nerviosa/patología , MamíferosRESUMEN
Microglia-associated neuroinflammation is recognized as a critical factor in the pathogenesis of neurodegenerative diseases; however, there is no effective treatment for the blockage of neurodegenerative disease progression. In this study, the effect of nordalbergin, a coumarin isolated from the wood bark of Dalbergia sissoo, on lipopolysaccharide (LPS)-induced inflammatory responses was investigated using murine microglial BV2 cells. Cell viability was assessed using the MTT assay, whereas nitric oxide (NO) production was analyzed using the Griess reagent. Secretion of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) was detected by the ELISA. The expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, mitogen-activated protein kinases (MAPKs) and NLRP3 inflammasome-related proteins was assessed by Western blot. The production of mitochondrial reactive oxygen species (ROS) and intracellular ROS was detected using flow cytometry. Our experimental results indicated that nordalbergin ≤20 µM suppressed NO, IL-6, TNF-α and IL-1ß production; decreased iNOS and COX-2 expression; inhibited MAPKs activation; attenuated NLRP3 inflammasome activation; and reduced both intracellular and mitochondrial ROS production by LPS-stimulated BV2 cells in a dose-dependent manner. These results demonstrate that nordalbergin exhibits anti-inflammatory and anti-oxidative activities through inhibiting MAPK signaling pathway, NLRP3 inflammasome activation and ROS production, suggesting that nordalbergin might have the potential to inhibit neurodegenerative disease progression.
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Lipopolisacáridos , Enfermedades Neurodegenerativas , Ratones , Animales , Lipopolisacáridos/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Microglía/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Enfermedades Neuroinflamatorias , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Transducción de Señal , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismoRESUMEN
BACKGROUND: Barrett's esophagus (BE), which has increased in prevalence worldwide, is a precursor for esophageal adenocarcinoma. Although there is a gap in the detection rates between endoscopic BE and histological BE in current research, we trained our artificial intelligence (AI) system with images of endoscopic BE and tested the system with images of histological BE. AIM: To assess whether an AI system can aid in the detection of BE in our setting. METHODS: Endoscopic narrow-band imaging (NBI) was collected from Chung Shan Medical University Hospital and Changhua Christian Hospital, resulting in 724 cases, with 86 patients having pathological results. Three senior endoscopists, who were instructing physicians of the Digestive Endoscopy Society of Taiwan, independently annotated the images in the development set to determine whether each image was classified as an endoscopic BE. The test set consisted of 160 endoscopic images of 86 cases with histological results. RESULTS: Six pre-trained models were compared, and EfficientNetV2B2 (accuracy [ACC]: 0.8) was selected as the backbone architecture for further evaluation due to better ACC results. In the final test, the AI system correctly identified 66 of 70 cases of BE and 85 of 90 cases without BE, resulting in an ACC of 94.37%. CONCLUSION: Our AI system, which was trained by NBI of endoscopic BE, can adequately predict endoscopic images of histological BE. The ACC, sensitivity, and specificity are 94.37%, 94.29%, and 94.44%, respectively.
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Adenocarcinoma , Esófago de Barrett , Neoplasias Esofágicas , Humanos , Esófago de Barrett/diagnóstico por imagen , Inteligencia Artificial , Neoplasias Esofágicas/diagnóstico por imagen , Adenocarcinoma/diagnóstico por imagen , Hospitales UniversitariosRESUMEN
The occurrence of Alzheimer's disease has been associated with the accumulation of beta-amyloid (ß-amyloid) plaques. These plaques activate microglia to secrete inflammatory molecules, which damage neurons in the brain. Thus, understanding the underlying mechanism of microglia activation can provide a therapeutic strategy for alleviating microglia-induced neuroinflammation. The aldose reductase (AR) enzyme catalyzes the reduction of glucose to sorbitol in the polyol pathway. In addition to mediating diabetic complications in hyperglycemic environments, AR also helps regulate inflammation in microglia. However, little is known about the role of AR in ß-amyloid-induced inflammation in microglia and subsequent neuronal death. In this study, we confirmed that AR inhibition attenuates increased ß-amyloid-induced reactive oxygen species and tumor necrosis factor α secretion by suppressing ERK signaling in BV2 cells. In addition, we are the first to report that AR inhibition reduced the phagocytotic capability and cell migration of BV2 cells in response to ß-amyloid. To further investigate the protective role of the AR inhibitor sorbinil in neurons, we co-cultured ß-amyloid-induced microglia with stem cell-induced neurons. sorbinil ameliorated neuronal damage in both cells in the co-culture system. In summary, our findings reveal AR regulation of microglia activation as a novel therapeutic target for Alzheimer's disease.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Péptidos beta-Amiloides/metabolismo , Aldehído Reductasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Células Cultivadas , Microglía/metabolismo , Placa Amiloide/metabolismo , Inflamación/patologíaRESUMEN
Oxidative stress mediated by reactive oxygen species (ROS) is a key process for adverse aerosol health effects. Secondary organic aerosols (SOA) account for a major fraction of fine particulate matter, and their inhalation and deposition into the respiratory tract causes the formation of ROS by chemical and cellular processes, but their relative contributions are hardly quantified and their link to oxidative stress remains uncertain. Here, we quantified cellular and chemical superoxide generation by 9,10-phenanthrenequinone (PQN) and isoprene SOA using a chemiluminescence assay combined with electron paramagnetic resonance spectroscopy as well as kinetic modeling. We also applied cellular imaging techniques to study the cellular mechanism of superoxide release and oxidative damage on cell membranes. We show that PQN and isoprene SOA activate NADPH oxidase in macrophages to release massive amounts of superoxide, overwhelming the superoxide formation by aqueous chemical reactions in the epithelial lining fluid. The activation dose for PQN is 2 orders of magnitude lower than that of isoprene SOA, suggesting that quinones are more toxic. While higher exposures trigger cellular antioxidant response elements, the released ROS induce oxidative damage to the cell membrane through lipid peroxidation. Such mechanistic and quantitative understandings provide a basis for further elucidation of adverse health effects and oxidative stress by fine particulate matter.
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Contaminantes Atmosféricos , Superóxidos , Especies Reactivas de Oxígeno/metabolismo , Quinonas , NADPH Oxidasas/metabolismo , NADPH Oxidasas/farmacología , Contaminantes Atmosféricos/análisis , Aerosoles , Material Particulado/toxicidad , Material Particulado/análisis , Estrés Oxidativo , MacrófagosRESUMEN
Fluorescence correlation spectroscopy (FCS) is an extremely versatile tool that has been widely used to measure chemical reaction rates, protein binding, nanoparticle-protein interactions, and biomolecular dynamics in vitro and in vivo. As an inherently micro-sized approach, FCS is compatible with high-throughput screening applications, as demanded for drug design, but typically limited to nanomolar concentrations, which restricts possible applications. Here, we show how massively parallel camera-based detection with side illumination can extend the usable concentration range of FCS more than 100-fold to measure low affinity processes. Our line illumination (LIM) approach is robust, fast (1 s acquisition times), and does not require any reference measurements to characterize the observation volume size.
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Iluminación , Microscopía Fluorescente/métodos , Espectrometría de Fluorescencia/métodosRESUMEN
Purpose: Neurodegenerative diseases are associated with neuroinflammation along with activation of microglia and oxidative stress, but currently lack effective treatments. Punicalagin is a natural bio-sourced product that exhibits anti-inflammatory effects on several chronic diseases; however, the anti-inflammatory and anti-oxidative effects on microglia have not been well examined. This study aimed to investigate the effects of punicalagin on LPS-induced inflammatory responses, NLRP3 inflammasome activation, and the production of ROS using murine microglia BV2 cells. Methods: BV2 cells were pre-treated with punicalagin following LPS treatment to induce inflammation. The secretion of NO and PGE2 was analyzed by Griess reagent and ELISA respectively, while the expressions of iNOS, COX-2, STAT3, ERK, JNK, and p38 were analyzed using Western blotting, the production of IL-6 was measured by ELISA, and the activity of NF-κB was detected using promoter reporter assay. To examine whether punicalagin affects NLRP3 inflammasome activation, BV2 cells were stimulated with LPS and then treated with ATP or nigericin. The secretion of IL-1ß was measured by ELISA. The expressions of NLRP3 inflammasome-related proteins and phospho IκBα/IκBα were analyzed using Western blotting. The production of intracellular and mitochondrial ROS was analyzed by flow cytometry. Results: Our results showed that punicalagin attenuated inflammation with reduction of pro-inflammatory mediators and cytokines including iNOS, COX-2, IL-1ß, and reduction of IL-6 led to inhibition of STAT3 phosphorylation by LPS-induced BV2 cells. Punicalagin also suppressed the ERK, JNK, and p38 phosphorylation, attenuated NF-κB activity, inhibited the activation of the NLRP3 inflammasome, and reduced the production of intracellular and mitochondrial ROS by LPS-induced BV2 cells. Conclusion: Our results demonstrated that punicalagin attenuated LPS-induced inflammation through suppressing the expression of iNOS and COX-2, inhibited the activation of MAPK/NF-κB signaling pathway and NLRP3 inflammasome, and reduced the production of ROS in microglia, suggesting that punicalagin might have the potential in treating neurodegenerative diseases.
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Calmodulin kinase-like vesicle-associated (CaMKv), a pseudokinase belonging to the Ca2+/calmodulin-dependent kinase family, is expressed predominantly in brain and neural tissue. It may function in synaptic strengthening during spatial learning by promoting the stabilization and enrichment of dendritic spines. At present, almost nothing is known regarding CaMKv structure and regulation. In this study we confirm prior proteomic analyses demonstrating that CaMKv is palmitoylated on Cys5. Wild-type CaMKv is enriched on the plasma membrane, but this enrichment is lost upon mutation of Cys5 to Ser. We further show that CaMKv interacts with another regulator of synaptic plasticity, Arc/Arg3.1, and that the interaction between these two proteins is weakened by mutation of the palmitoylated cysteine in CamKv.
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There are an estimated 5.4 million snakebite cases every year. People with snakebite envenoming suffer from severe complications, or even death. Although some review articles cover several topics of snakebite envenoming, a review of the cases regarding cerebral complications, especially rare syndromes, is lacking. Here, we overview 35 cases of snakebite by front-fanged snakes, including Bothrops, Daboia, Cerastes, Deinagkistrodon, Trimeresurus, and Crotalus in the Viperidae family; Bungarus and Naja in the Elapidae family, and Homoroselaps (rare cases) in the Lamprophiidae family. We also review three rare cases of snakebite by rear-fanged snakes, including Oxybelis and Leptodeira in the Colubridae family. In the cases of viper bites, most patients (17/24) were diagnosed with ischemic stroke and intracranial hemorrhage, leading to six deaths. We then discuss the potential underlying molecular mechanisms that cause these complications. In cases of elapid bites, neural, cardiac, and ophthalmic disorders are the main complications. Due to the small amount of venom injection and the inability to deep bite, all the rear-fanged snakebites did not develop any severe complications. To date, antivenom (AV) is the most effective therapy for snakebite envenoming. In the six cases of viper and elapid bites that did not receive AV, three cases (two by viper and one by elapid) resulted in death. This indicates that AV treatment is the key to survival after a venomous snakebite. Lastly, we also discuss several studies of therapeutic agents against snakebite-envenoming-induced complications, which could be potential adjuvants along with AV treatment. This article organizes the diagnosis of hemotoxic and neurotoxic envenoming, which may help ER doctors determine the treatment for unidentified snakebite.
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Mordeduras de Serpientes , Viperidae , Animales , Antivenenos/uso terapéutico , Bungarus , Elapidae , Humanos , Mordeduras de Serpientes/tratamiento farmacológicoRESUMEN
Hypoxia and angiogenesis play key roles in the pathogenesis of esophageal squamous cell carcinoma (ESCC), but regulators linking these two pathways to drive tumor progression remain elusive. Here we provide evidence of ADAM9's novel function in ESCC progression. Increasing expression of ADAM9 was correlated with poor clinical outcomes in ESCC patients. Suppression of ADAM9 function diminished ESCC cell migration and in vivo metastasis in ESCC xenograft mouse models. Using cellular fractionation and imaging, we found a fraction of ADAM9 was present in the nucleus and was uniquely associated with gene loci known to be linked to the angiogenesis pathway demonstrated by genome-wide ChIP-seq. Mechanistically, nuclear ADAM9, triggered by hypoxia-induced translocation, functions as a transcriptional repressor by binding to promoters of genes involved in the negative regulation of angiogenesis, and thereby promotes tumor angiogenesis in plasminogen/plasmin pathway. Moreover, ADAM9 suppresses plasminogen activator inhibitor-1 gene transcription by interacting with its transcription factors at the promoter. Our findings uncover a novel regulatory mechanism of ADAM9 as a transcriptional regulator in angiogenesis and highlight ADAM9 as a promising therapeutic target for ESCC treatment.