Pancreatic ductal adenocarcinoma (PDA), with its highly metastatic propensity, is one of the most lethal subtypes of pancreatic cancer. Although recent large-scale transcriptomic studies have ...demonstrated that heterogeneous gene expressions play an essential role in determining molecular phenotypes of PDA, biological cues for and consequences of distinct transcriptional programs remain unclear.
We developed an experimental model that enforces the transition of PDA cells toward a basal-like subtype. We combined epigenome and transcriptome analyses with extensive in vitro and in vivo evaluations of tumorigenicity to demonstrate the validity of basal-like subtype differentiation in association with endothelial-like enhancer landscapes via TEA domain transcription factor 2 (TEAD2). Finally, we used loss-of-function experiments to investigate the importance of TEAD2 in regulating reprogrammed enhancer landscape and metastasis in basal-like PDA cells.
Aggressive characteristics of the basal-like subtype are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of our model. Further, we showed that basal-like subtype PDA cells acquire a TEAD2-dependent proangiogenic enhancer landscape. Genetic and pharmacologic inhibitions of TEAD2 in basal-like subtype PDA cells impair their proangiogenic phenotypes in vitro and cancer progression in vivo. Last, we identify CD109 as a critical TEAD2 downstream mediator that maintains constitutively activated JAK-STAT signaling in basal-like PDA cells and tumors.
Our findings implicate a TEAD2-CD109-JAK/STAT axis in the basal-like differentiated pancreatic cancer cells and as a potential therapeutic vulnerability.
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TEAD2 expression is increased in basal-like pancreatic cancer cells and activates endothelial-like enhancers. Hence, inhibition of TEAD2 activity is sufficient to repress basal-like subtype differentiation and its associated phenotypes.
Cancer cells utilize epigenetic alterations to acquire autonomous capabilities for tumor maintenance. Here, we show that pancreatic ductal adenocarcinoma (PDA) cells utilize super-enhancers (SEs) to ...activate the transcription factor EVI1 (ecotropic viral integration site 1) gene, resulting in activation of an EVI1-dependent transcription program conferring PDA tumorigenesis. Our data indicate that SE is the vital
-acting element to maintain aberrant EVI1 transcription in PDA cells. Consistent with disease progression and inferior survival outcomes of PDA patients, we further show that EVI1 upregulation is a major cause of aggressive tumor phenotypes. Specifically, EVI1 promotes anchorage-independent growth and motility
and enhances tumor propagation
. Mechanistically, EVI1-dependent activation of tumor-promoting gene expression programs through the stepwise configuration of the active enhancer chromatin attributes to these phenotypes. In sum, our findings support the premise that EVI1 is a crucial driver of oncogenic transcription programs in PDA cells. Further, we emphasize the instructive role of epigenetic aberrancy in establishing PDA tumorigenesis.
The aim of this study was to investigate the protective effects of dendropanoxide (DPx) isolated from Dendropanax morbifera against cis-diamminedichloroplatinum (II) (CDDP)-induced nephrotoxicity in ...NRK-52E cells and in Sprague-Dawley rats. DPx was administered to Sprague-Dawley rats by oral gavage (5 and 10 mg/kg) for 7 consecutive days, 24 h after intraperitoneal injection with CDDP (6 mg/kg). All rats were euthanized 24 h after the last DPx administration, and histopathological damage, acute kidney injury (AKI) biomarkers, inflammatory cytokines, and oxidative damages were evaluated. DPx (5 and 10 μg/mL) was found to protect against CDDP-induced cytotoxicity and apoptotic cell death in NRK-52E cells. CDDP-induced serum blood urea nitrogen (BUN), creatinine (sCr), and pro-inflammatory cytokines levels were significantly ameliorated by DPx in a dose-dependent manner. Furthermore, excretion of kidney injury molecules (KIM-1), selenium binding protein-1 (SBP-1), and neutrophil gelatinase-associated lipocalin (NGAL) in the urine was significantly reduced in response to DPx administration in CDDP-treated rats. Activities of antioxidant enzymes and lipid peroxidation levels were markedly altered in the kidney of CDDP-treated rats in response to DPx administration. Serum pro-inflammatory cytokine levels were dramatically suppressed by DPx in CDDP-treated rats. DPx also restored renal-cell apoptosis via regulation of AMPK/mTOR signaling in CDDP-treated rats. Our results clearly suggest that DPx ameliorates CDDP-induced nephrotoxicity in vitro and in vivo by inhibiting oxidative stress, inflammation, and apoptosis. Overall, our data demonstrates that DPx may serve as a therapeutic agent in patients with solid tumors to prevent CDDP-induced AKI.
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•DPx exhibits anti-oxidative and anti-inflammatory activities in CDDP-treated rats.•DPx protects against oxidative damage in the kidney of CDDP-treated rats.•DPx inhibits renal cell apoptosis in CDDP-treated rats and NRK-52E cells.•DPx suppresses pro-inflammatory cytokine production in CDDP-treated rats.•DPx ameliorates CDDP-induced nephrotoxicity via modulating AKT/mTOR/AMPK pathways.
Spontaneous intracranial hypotension (SIH), which generally presents as orthostatic headache, is increasingly being identified due to improved imaging technologies and heightened awareness. Many ...prior studies have reported the characteristic brain MRI findings of SIH. However, recently, focus has shifted to spinal MRI, as SIH is believed to be caused by leakage of cerebrospinal fluid from the spinal dural sac. Advanced techniques such as ultrafast CT myelography and digital subtraction myelography have emerged as useful technique to identify the site of cerebrospinal fluid leakage. In this review, we discuss the diagnosis, spinal MRI findings, imaging techniques, and treatment of SIH.
자발두개내압저하의 척추 자기공명영상 소견 류혜진; Hye Jin Yoo
Journal of the Korean Society of Radiology,
01/2024, Letnik:
85, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Spontaneous intracranial hypotension (SIH), which generally presents as orthostatic headache, is increasingly being identified due to improved imaging technologies and heightened awareness. Many ...prior studies have reported the characteristic brain MRI findings of SIH. However, recently, focus has shifted to spinal MRI, as SIH is believed to be caused by leakage of cerebrospinal fluid from the spinal dural sac. Advanced techniques such as ultrafast CT myelography and digital subtraction myelography have emerged as useful technique to identify the site of cerebrospinal fluid leakage. In this review, we discuss the diagnosis, spinal MRI findings, imaging techniques, and treatment of SIH. 자발두개내압저하(spontaneous intracranial hypotension)은 기립성 두통을 특징으로 하는 질환이며, 영상기법의 발달과 질환에 대한 인식이 높아짐에 따라 발견 빈도가 점차 증가하고 있는 추세이다. 이전에는 이 질환에서의 특징적인 뇌 자기공명영상 소견들이 많이 알려져 있었다. 그러나 최근에는 척추에서의 뇌척수액 누출이 원인으로 알려짐에 따라 척추 자기공명영상 소견이 주목받고 있다. 또한 뇌척수액 누출 부위를 정확히 확인할 수 있는 초고속 CT 척수조영술(ultrafast CT myelography), 디지털 감산 척수조영술(digital subtraction myelography) 등이 개발되었다. 이 종설에서는 자발두개내압저하의 진단, 척추 자기공명영상 소견, 최신 영상검사법과 치료에 대해 다루고자 한다.
Eurycoma longifolia Jack (known as tongkat ali), a popular traditional herbal medicine, is a flowering plant of the family Simaroubaceae, native to Indonesia, Malaysia, Vietnam and also Cambodia, ...Myanmar, Laos and Thailand. E. longifolia, is one of the well-known folk medicines for aphrodisiac effects as well as intermittent fever (malaria) in Asia. Decoctions of E. longifolia leaves are used for washing itches, while its fruits are used in curing dysentery. Its bark is mostly used as a vermifuge, while the taproots are used to treat high blood pressure, and the root bark is used for the treatment of diarrhea and fever. Mostly, the roots extract of E. longifolia are used as folk medicine for sexual dysfunction, aging, malaria, cancer, diabetes, anxiety, aches, constipation, exercise recovery, fever, increased energy, increased strength, leukemia, osteoporosis, stress, syphilis and glandular swelling. The roots are also used as an aphrodisiac, antibiotic, appetite stimulant and health supplement. The plant is reported to be rich in various classes of bioactive compounds such as quassinoids, canthin-6-one alkaloids, β-carboline alkaloids, triterpene tirucallane type, squalene derivatives and biphenyl neolignan, eurycolactone, laurycolactone, and eurycomalactone, and bioactive steroids. Among these phytoconstituents, quassinoids account for a major portion of the E. longifolia root phytochemicals. An acute toxicity study has found that the oral Lethal Dose 50 (LD50) of the alcoholic extract of E. longifolia in mice is between 1500-2000 mg/kg, while the oral LD50 of the aqueous extract form is more than 3000 mg/kg. Liver and renal function tests showed no adverse changes at normal daily dose and chronic use of E. longifolia. Based on established literature on health benefits of E. longifolia, it is important to focus attention on its more active constituents and the constituents' identification, determination, further development and most importantly, the standardization. Besides the available data, more evidence is required regarding its therapeutic efficacy and safety, so it can be considered a rich herbal source of new drug candidates. It is very important to conserve this valuable medicinal plant for the health benefit of future generations.
Suppressors of cytokine signaling (SOCS) exhibit diverse antiinflammatory effects. Since ROS acts as a critical mediator of inflammation, we have investigated the anti-inflammatory mechanisms of SOCS ...via ROS regulation in monocytic/macrophagic cells. Using PMA-differentiated monocytic cell lines and primary BMDMs transduced with SOCS1 or shSOCS1, the LPS/TLR4- induced inflammatory signaling was investigated by analyzing the levels of intracellular ROS, antioxidant factors, inflammasome activation, and pro-inflammatory cytokines. The levels of LPS-induced ROS and the production of pro-inflammatory cytokines were notably down-regulated by SOCS1 and up-regulated by shSOCS1 in an NAC-sensitive manner. SOCS1 up-regulated an ROS-scavenging protein, thioredoxin, via enhanced expression and binding of NRF-2 to the thioredoxin promoter. SOCS3 exhibited similar effects on NRF-2/thioredoxin induction, and ROS downregulation, resulting in the suppression of inflammatory cytokines. Notably thioredoxin ablation promoted NLRP3 inflammasome activation and restored the SOCS1-mediated inhibition of ROS and cytokine synthesis induced by LPS. The results demonstrate that the anti-inflammatory mechanisms of SOCS1 and SOCS3 in macrophages are mediated via NRF-2-mediated thioredoxin upregulation resulting in the downregulation of ROS signal. Thus, our study supports the anti-oxidant role of SOCS1 and SOCS3 in the exquisite regulation of macrophage activation under oxidative stress. BMB Reports 2020; 53(12): 640-645
Anabolic-androgenic steroids (AAS) are used illegally to enhance muscle development and increase strength and power. In this study, a reliable, and sensitive quantitative method was developed and ...validated using heptafluorobutyric acid anhydride (HFPA) derivatives for the simultaneous detection of prohibited AAS (testosterone TS, boldenone BD, 5α-estrane-3β,17α-diol EAD) using gas chromatography-tandem mass spectrometry (GC-MS/MS). For processing the samples, solid phase extraction, methanolic hydrolysis, and liquid-liquid extraction were used. For detection using mass spectrometry, the multiple reaction monitoring (MRM) mode was used with the electron ionization (EI) positive mode. The method was evaluated for selectivity, linearity, lower limit of quantification, intra- and inter-day precision, accuracy, and stability. The results showed that the method was accurate and reproducible for the quantitation of the three steroids. The developed method was finally applied to the analysis of a suspect gelding urine sample received from the Asian Quality Assurance Program (AQAP).
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