Cardiac Tamponade Due to Pericardial Effusion Following Peripherally Inserted Central Catheter: A Single-Institution Case Series.

INTRODUCTION: Although the use of peripherally inserted central catheters (PICCs) has many advantages, misplacement can lead to serious life-threatening complications such as pericardial effusion (PCE) and cardiac tamponade (CT). This report aims to describe four cases of CT resulting from misplaced PICC, which were successfully managed. METHODS: Retrospective analysis of neonates who required PICC insertion and had PCE leading to CT in the Neonatal Intensive Care Unit (NICU) at The Children's Hospital 2, Ho Chi Minh City, Vietnam, during the year 2022. RESULTS: Four cases involved preterm infants at 28-30 weeks gestational age, weighing between 900-1,500 grams. The PCE/CT developed between 3 and 24 days following PICC insertion. The abrupt onset with clinical manifestations that showed hemodynamic instability included sudden deterioration, lethargy, apnea, bradycardia, pale skin, and cardiovascular collapse. We use cardiac point of care ultrasound (POCUS) to assess the condition of these patients and guide the pericardiocentesis procedure. The analysis of the aspirated fluid used for PCE/CT treatment is consistent with the component of parenteral nutrition. No deaths were encountered. CONCLUSION: Neonates presenting sudden deterioration following PICC insertion should undergo POCUS to prompt identifying PCE/CT. Timely diagnosis via POCUS, prompt pericardiocentesis, and prevention of misplaced PICC-associated serious complications are crucial. Monitoring of the PICC position twice a week is recommended to avoid life-threatening complications. Additionally, incorporating POCUS for identifying the tip of PICC rather than relying solely on X-ray should be considered in the current protocol.

Determination of lutetium density in LYSO crystals: methodology and PET detector applications.

Objective. Lutetium yttrium oxyorthosilicate (LYSO) scintillation crystals are used in positron emission tomography (PET) due to their high gamma attenuation, fair energy resolution, and fast scintillation decay time. The enduring presence of the176Lu isotope, characterized by a half-life of 37.9 billion years, imparts a consistent radiation background (BG) profile that depends on the geometry and composition attributes of the LYSO crystals.Approach. In this work, we proposed a methodology for estimating the composition of LYSO crystals in cases where the exact Lutetium composition remains unknown. The connection between BG spectrum intensity and intrinsic radioactivity enables precise estimation of Lutetium density in LYSO crystal samples. This methodology was initially applied to a well-characterized LYSO crystal sample, yielding results closely aligned with the known composition. The composition estimation approach was extended to several samples of undisclosed LYSO crystals, encompassing single crystal and crystal array configurations. Furthermore, we model the background spectrum observed in the LYSO-based detector and validate the observed spectra via simulations.Main results. The estimated Lutetium composition exhibited adequate consistency across different samples of the same LYSO material, with variations of less than 1%. The result of the proposed approach coupled with the simulation successfully models the background radiation spectra in various LYSO-based detector geometries.Significance. The implications of this work extend to the predictive assessment of system behaviors and the autonomous configuration parameters governing LYSO-based detectors.

The fatigue-inducing effects of cancer and its therapy are characterized by decreased physical activity in the absence of any motivational deficit.

Although cancer and its therapy are well known to be associated with fatigue, the exact nature of cancer-related fatigue remains ill-defined. We previously reported that fatigue-like behavior induced independently by tumor growth and by the chemotherapeutic agent cisplatin is characterized by reduced voluntary wheel running and an intact motivation to expand effort for food rewards. The present set of experiments was initiated to characterize the functional consequences of fatigue induced by chemoradiotherapy in tumor-bearing mice and relate them to changes in the expression of genes coding for inflammation, mitochondria dynamics and metabolism. Two syngeneic murine models of cancer were selected for this purpose, a model of human papilloma virus-related head and neck cancer and a model of lung cancer. In both models, tumor-bearing mice were submitted to chemoradiotherapy to limit tumor progression. Two dimensions of fatigue were assessed, the physical dimension by changes in physical activity in mice trained to run in wheels and the motivational dimension by changes in the performance of mice trained to nose poke to obtain a food reward in a progressive ratio schedule of food reinforcement. Chemoradiotherapy reliably decreased wheel running activity but had no effect on performance in the progressive ratio in both murine models of cancer. These effects were the same for the two murine models of cancer and did not differ according to sex. Livers and brains were collected at the end of the experiments for qRT-PCR analysis of expression of genes coding for inflammation, mitochondria dynamics, and metabolism. The observed changes were mainly apparent in the liver and typical of activation of type I interferon and NF-κB-dependent signaling, with alterations in mitochondrial dynamics and a shift toward glycolysis. Although the importance of these alterations for the pathophysiology of cancer-related fatigue remains to be explored, the present findings indicate that fatigue brought on by cancer therapy in tumor-bearing mice is more physical than motivational.

DFT approach towards accurate prediction of 1H/13C NMR chemical shifts for dipterocarpol oxime.

A computational NMR approach for accurate predicting the 1H/13C chemical shifts of triterpenoid oximes featuring the screening of 144 DFT methods was demonstrated. Efficiently synthesized dipterocarpol oxime was employed as a model compound. The six highest accurate methods from the screening generated root-mean-square-error (RMSE) values in the range of 0.84 ppm (0.55%) to 1.14 ppm (0.75%) for calculated 13C shifts. For 1H results, simple, economical 6-31G basis set unexpectedly outperformed other more expensive basic sets; and the couple of it with selected functionals provided high accuracy shifts (0.0617 ppm (1.49%) ≤ RMSE ≤ 0.0870 ppm (2.04%)). These computational results strongly supported the proton and carbon assignments of the oxime including the difficult ones of diastereotopic methyl groups, the methyl groups attached to an internal olefin, and diastereotopic α-protons.

Impact of the COVID-19 Pandemic on the Severity and Early Postoperative Outcomes of Acute Appendicitis.

Background The coronavirus disease 2019 (COVID-19) pandemic caused changes in surgical practice. For acute appendicitis (AA), measures to control the pandemic might hinder patients from seeking medical care timely, resulting in increasing severity, postoperative complications, and mortality. This study aimed to investigate whether the COVID-19 pandemic had a negative impact on the severity and postoperative outcomes of patients with AA. Methodology We retrospectively reviewed medical records of AA patients treated operatively at Nhan Dan Gia Dinh Hospital hospital from June 1st to September 30th in three consecutive years: pre-pandemic (2019)/Group 1, minor waves (2020)/Group 2, and major wave (2021)/Group 3 (2021). Data were collected focusing on the duration of symptoms, severity of AA, time from admission to operation, postoperative complications, and mortality. Results There were 1,055 patients, including 452 patients in Group 1, 409 in Group 2, and 194 in Group 3. The overall number of patients decreased mainly in non-complicated AA. The percentages of hospital admission after 24 hours gradually increased (20.8%, 27.9%, and 43.8%, p < 0.05). The percentages of complicated AA in Group 2 and Group 3 were statistically higher than in Group 1 (39% and 55% vs. 31%, p < 0.05). Waiting time for operation increased to five hours during the major wave. Laparoscopic appendectomy was performed in 98-99% of AA patients during the pandemic, with an early postoperative complication rate of 5-9% and a mortality rate of 0.2-1%. Conclusions Although the percentages of hospital admission after 24 hours and complicated AA increased, laparoscopic appendectomy was still feasible and effective and should be maintained as the standard management for AA during the COVID-19 pandemic.

GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC), with its hallmark phenotype of high cytosolic lipid content, is considered a metabolic cancer. Despite the implication of this lipid-rich phenotype in ccRCC tumorigenesis, the roles and regulators of de novo lipid synthesis (DNL) in ccRCC remain largely unexplained. METHODS: Our bioinformatic screening focused on ccRCC-lipid phenotypes identified glutathione peroxidase 8 (GPX8), as a clinically relevant upstream regulator of DNL. GPX8 genetic silencing was performed with CRISPR-Cas9 or shRNA in ccRCC cell lines to dissect its roles. Untargeted metabolomics, RNA-seq analyses, and other biochemical assays (e.g., lipid droplets staining, fatty acid uptake, cell proliferation, xenograft, etc.) were carried out to investigate the GPX8's involvement in lipid metabolism and tumorigenesis in ccRCC. The lipid metabolic function of GPX8 and its downstream were also measured by isotope-tracing-based DNL flux measurement. RESULTS: GPX8 knockout or downregulation substantially reduced lipid droplet levels (independent of lipid uptake), fatty acid de novo synthesis, triglyceride esterification in vitro, and tumor growth in vivo. The downstream regulator was identified as nicotinamide N-methyltransferase (NNMT): its knockdown phenocopied, and its expression rescued, GPX8 silencing both in vitro and in vivo. Mechanically, GPX8 regulated NNMT via IL6-STAT3 signaling, and blocking this axis suppressed ccRCC survival by activating AMPK. Notably, neither the GPX8-NNMT axis nor the DNL flux was affected by the von Hippel Lindau (VHL) status, the conventional regulator of ccRCC high lipid content. CONCLUSIONS: Taken together, our findings unravel the roles of the VHL-independent GPX8-NNMT axis in ccRCC lipid metabolism as related to the phenotypes and growth of ccRCC, which may be targeted for therapeutic purposes.

Increased adipose tissue lymphatic vessel density inhibits thermogenesis through elevated neurotensin levels.

During cold exposure, white adipose tissue can remodel to dissipate energy as heat under cold similar to thermogenic brown adipose tissue. This "browning" and the regulation of body temperature is under the control of neural and hormonal signaling. It was recently discovered that neurotensin, a small neuropeptide, not only acts to inhibit thermogenesis, but also that lymphatic vessels may be a surprisingly potent source of neurotensin production. We hypothesized that the induction of adipose tissue lymphangiogenesis would therefore increase tissue neurotensin levels and impair thermogenesis. Methods: We utilized AdipoVD mice that have inducible expression of vascular endothelial growth factor (VEGF)-D, a potent lymphangiogenic stimulator, specifically in adipose tissue. Overexpression of VEGF-D induced significant lymphangiogenesis in both white and brown adipose tissues of AdipoVD mice. Results: Obese Adipo-VD mice demonstrated no differences in adipose morphology or browning under room temperature conditions compared to controls but did express significantly higher levels of neurotensin in their adipose tissues. Upon acute cold exposure, AdipoVD mice were markedly cold intolerant; inhibition of neurotensin signaling ameliorated this cold intolerance as AdipoVD mice were then able to maintain body temperature on cold challenge equivalent to their littermates. Conclusion: In total, these data demonstrate that adipose tissue lymphatic vessels are a potent paracrine source of neurotensin and that lymphangiogenesis therefore impairs the tissues' thermogenic ability.

TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently.

Acute myeloid leukemia (AML) generally has an unsatisfactory prognosis despite the recent introduction of new regimens, including targeted agents and antibodies. To find a new druggable pathway, we performed integrated bioinformatic pathway screening on large OHSU and MILE AML databases, discovered the SUMOylation pathway, and validated it independently with an external data set (totaling 2959 AML and 642 normal sample data). The clinical relevance of SUMOylation in AML was supported by its core gene expression which is correlated with patient survival, European LeukemiaNet 2017 risk classification, and AML-relevant mutations. TAK-981, a first-in-class SUMOylation inhibitor currently under clinical trials for solid tumors, showed antileukemic effects with apoptosis induction, cell-cycle arrest, and induction of differentiation marker expression in leukemic cells. It exhibited potent nanomolar activity, often stronger than that of cytarabine, which is part of the standard of care. TAK-981's utility was further demonstrated in in vivo mouse and human leukemia models as well as patient-derived primary AML cells. Our results also indicate direct and cancer cell-inherent anti-AML effects by TAK-981, different from the type 1 interferon and immune-dependent mechanism in a previous solid tumor study. Overall, we provide a proof-of-concept for SUMOylation as a new targetable pathway in AML and propose TAK-981 as a promising direct anti-AML agent. Our data should prompt studies on optimal combination strategies and transitions to clinical trials in AML.

Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression.

Rationale: Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth. Methods and results: Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression in vivo. Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation. Conclusion: Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.

Organocatalytic synthesis of axially chiral tetrasubstituted allenes.

Asymmetric organocatalysis is a growing method for the synthesis of axially chiral tetrasubstituted allenes, the most challenging one among allene syntheses. In this method, chiral organocatalysts such as phase-transfer catalysts, peptides, disulfonimides, and binaphthyl/bispiro phosphoric acids have displayed remote control of regio- and stereoselectivity. Highly functionalized enantiopure allenes including those with an adjacent tertiary or quaternary stereocenter have been efficiently prepared with high levels of regio-, diastereo-, and enantioselectivity using this method. Several mechanistic pathways, including electrophilic addition to cumulenolate or zwitterionic enolate intermediates, alkynylogous Mukaiyama aldol reaction, nucleophilic addition to quinone methides, and dearomative addition to imino esters, were proposed. The method is necessary for providing access to axially chiral tetrasubstituted allenes, which can be utilized for the preparation of novel ligands, natural products, and organic materials, particularly those having complex structures. This review covers the enantioselective organocatalytic synthesis of these tetrasubstituted allenes and the mechanistic insights into the formation of the chiral axis up to July 2022.

Uniformity calibration for large area XY strip parallel plate ionization chamber.

Demand for large area parallel plate ionization chamber (PPIC) or large area ionization chamber (LAIC) has risen in recent years due to several advantages of the large effective area in monitoring therapeutic radiation beams. PPICs are designed for the measurements of beam profile and dosimetry in radiation therapy quality assurance (QA) procedures.Objective. Heterogeneous responses over the large sensitive area pose an undeniable concern for the straightforward applications of PPICs in clinical dosimetry. Uniformity calibration for the detector response is thus essential for the accurate performance of each PPIC unit.Approach.A large area XY strip PPIC, characterized by a large effective area of 345.44 × 345.44 mm2and 256 readout channels, was investigated in this study. A new systematic uniformity calibration is developed to improve the lateral response of the PPIC over the measurements for both narrow beams and large square field beams. A 2D response map of the PPIC was obtained by a spot-scanning method using a compact x-ray tube (mini x-ray). The mini x-ray, providing stable radiation (uncertainty <0.1%), was moved with a step size of 20 mm in 2 dimensions across the entire PPIC surface to collect a complete spot scan. Different uniformity calibration methods were introduced for the measurement of the PPIC by adopting the information from the detector 2D response map.Main results.Deviation of the detector response, before calibration, was observed to reach about 7% for the testing PPIC unit which is much higher than the recommended uniformity response of 1% (IAEA TRS-398). The uniformity response of the PPIC improved significantly to less than 1% across the detector surface after calibration.Significance.The proposed methods enable the practical application of PPIC in routine clinical dosimetry and can be reliably adopted by any radiation facility to perform daily and monthly QA.

Current Mechanistic Understandings of Lymphedema and Lipedema: Tales of Fluid, Fat, and Fibrosis.

Lymphedema and lipedema are complex diseases. While the external presentation of swollen legs in lower-extremity lymphedema and lipedema appear similar, current mechanistic understandings of these diseases indicate unique aspects of their underlying pathophysiology. They share certain clinical features, such as fluid (edema), fat (adipose expansion), and fibrosis (extracellular matrix remodeling). Yet, these diverge on their time course and known molecular regulators of pathophysiology and genetics. This divergence likely indicates a unique route leading to interstitial fluid accumulation and subsequent inflammation in lymphedema versus lipedema. Identifying disease mechanisms that are causal and which are merely indicative of the condition is far more explored in lymphedema than in lipedema. In primary lymphedema, discoveries of genetic mutations link molecular markers to mechanisms of lymphatic disease. Much work remains in this area towards better risk assessment of secondary lymphedema and the hopeful discovery of validated genetic diagnostics for lipedema. The purpose of this review is to expose the distinct and shared (i) clinical criteria and symptomatology, (ii) molecular regulators and pathophysiology, and (iii) genetic markers of lymphedema and lipedema to help inform future research in this field.

1H/13C chemical shift calculations for biaryls: DFT approaches to geometry optimization.

Twelve common density functional methods and seven basis sets for geometry optimization were evaluated on the accuracy of 1H/13C NMR chemical shift calculations for biaryls. For these functionals, 1H shifts calculations for gas phase optimized geometries were significantly less accurate than those for in-solution optimized structures, while 13C results were not strongly influenced by geometry optimization methods and solvent effects. B3LYP, B3PW91, mPW1PW91 and ωB97XD were the best-performing functionals with lowest errors; among seven basis sets, DGDZVP2 and 6-31G(d,p) outperformed the others. The combination of these functionals and basis sets resulted in high accuracy with CMAEmin = 0.0327 ppm (0.76%) and 0.888 ppm (0.58%) for 1H and 13C, respectively. The selected functionals and basis set were validated when consistently producing optimized structures with high accuracy results for 1H and 13C chemical shift calculations of two other biaryls. This study highly recommends the IEFPCM/B3LYP, B3PW91, mPW1PW91 or ωB97XD/DGDZVP2 or 6-31G(d,p) level of theory for the geometry optimization step, especially the solvent incorporation, which would lead to high accuracy 1H/13C calculation. This work would assist in the fully structural assignments of biaryls and provide insights into in-solution biaryl conformations.

Postpubertal spermatogonial stem cell transplantation restores functional sperm production in rhesus monkeys irradiated before and after puberty.

BACKGROUND: Cancer treatment of prepubertal patients impacts future fertility due to the abolition of spermatogonial stem cells (SSCs). In macaques, spermatogenesis could be regenerated by intratesticular transplantation of SSCs, but no studies have involved cytotoxic treatment before puberty and transplantation after puberty, which would be the most likely clinical scenario. OBJECTIVES: To evaluate donor-derived functional sperm production after SSC transplantation to adult monkeys that had received testicular irradiation during the prepubertal period. MATERIALS AND METHODS: We obtained prepubertal testis tissue by unilaterally castrating six prepubertal monkeys and 2 weeks later irradiated the remaining testes with 6.9 Gy. However, because spermatogenic recovery was observed, we irradiated them again 14 months later with 7 Gy. Three of the monkeys were treated with GnRH-antagonist (GnRH-ant) for 8 weeks. The cryopreserved testis cells from the castrated testes were then allogeneically transplanted into the intact testes of all monkeys. Tissues were harvested 10 months later for analyses. RESULTS: In three of the six monkeys, 61%, 38%, and 11% of the epididymal sperm DNA were of the donor genotype. The ability to recover donor-derived sperm production was not enhanced by the GnRH-ant pretreatment. However, the extent of filling seminiferous tubules during the transplantation procedure was correlated with the eventual production of donor spermatozoa. The donor epididymal spermatozoa from the recipient with 61% donor contribution were capable of fertilizing rhesus eggs and forming embryos. Although the transplantation was done into the rete testis, two GnRH-ant-treated monkeys, which did not produce donor-derived epididymal spermatozoa, displayed irregular tubular cords in the interstitium containing testicular spermatozoa derived from the transplanted donor cells. DISCUSSION AND CONCLUSION: The results further support that sperm production can be restored in non-human primates from tissues cryopreserved prior to prepubertal and post-pubertal gonadotoxic treatment by transplantation of these testicular cells after puberty into seminiferous tubules.

Transcranial alternating current stimulation entrains alpha oscillations by preferential phase synchronization of fast-spiking cortical neurons to stimulation waveform.

Computational modeling and human studies suggest that transcranial alternating current stimulation (tACS) modulates alpha oscillations by entrainment. Yet, a direct examination of how tACS interacts with neuronal spiking activity that gives rise to the alpha oscillation in the thalamo-cortical system has been lacking. Here, we demonstrate how tACS entrains endogenous alpha oscillations in head-fixed awake ferrets. We first show that endogenous alpha oscillations in the posterior parietal cortex drive the primary visual cortex and the higher-order visual thalamus. Spike-field coherence is largest for the alpha frequency band, and presumed fast-spiking inhibitory interneurons exhibit strongest coupling to this oscillation. We then apply alpha-tACS that results in a field strength comparable to what is commonly used in humans (<0.5 mV/mm). Both in these ferret experiments and in a computational model of the thalamo-cortical system, tACS entrains alpha oscillations by following the theoretically predicted Arnold tongue. Intriguingly, the fast-spiking inhibitory interneurons exhibit a stronger entrainment response to tACS in both the ferret experiments and the computational model, likely due to their stronger endogenous coupling to the alpha oscillation. Our findings demonstrate the in vivo mechanism of action for the modulation of the alpha oscillation by tACS.

Energy-Efficient Clustering Multi-Hop Routing Protocol in a UWSN.

Underwater wireless sensor networks are currently seeing broad research in various applications for human benefits. Large numbers of sensor nodes are being deployed in rivers and oceans to monitor the underwater environment. In the paper, we propose an energy-efficient clustering multi-hop routing protocol (EECMR) which can balance the energy consumption of these nodes and increase their network lifetime. The network area is divided into layers with regard to the depth level. The data sensed by the nodes are transmitted to a sink via a multi-hop routing path. The cluster head is selected according to the depth of the node and its residual energy. To transmit data from the node to the sink, the cluster head aggregates the data packet of all cluster members and then forwards them to the upper layer of the sink node. The simulation results show that EECMR is effective in terms of network lifetime and the nodes' energy consumption.

Restoration of functional sperm production in irradiated pubertal rhesus monkeys by spermatogonial stem cell transplantation.

BACKGROUND: In male pre-pubertal cancer patients, radiation and chemotherapy impact future fertility by eradication of spermatogonial stem cells (SSCs). In macaques, spermatogenesis could be regenerated by intratesticular transplantation of SSCs, but only a small percentage of spermatozoa produced were of donor origin. Transient hormone suppression with a GnRH antagonist (GnRH-ant) enhanced spermatogenic recovery from transplanted SSCs. OBJECTIVES: To evaluate donor-derived and endogenous spermatogenic recovery after SSC transplantation into irradiated monkeys and to test whether hormone suppression around the time of transplantation facilitates spermatogenic recovery. MATERIALS AND METHODS: Testes of 15 adult rhesus monkeys were irradiated with 7 Gy and 4 months later transplanted, to one of the testes, with cryopreserved testicular cells containing SSCs from unrelated monkeys. Monkeys were either treated with GnRH-ant for 8 weeks before transplantation, GnRH-ant from 4 weeks before to 4 weeks after transplantation, or with no GnRH-ant. Tissues were harvested 10 months after transplantation. RESULTS: Two of the 15 monkeys, a control and a pre-transplantation GnRH-ant-treated, showed substantially higher levels of testicular spermatogenesis and epididymal sperm output in the transplanted side as compared to the untransplanted. Over 84% of epididymal spermatozoa on the transplanted side had the donor genotype and were capable of fertilizing eggs after intracytoplasmic sperm injection forming morulae of the donor paternal origin. Low levels of donor spermatozoa (~1%) were also identified in the epididymis of three additional monkeys. Transplantation also appeared to enhance endogenous spermatogenesis. DISCUSSION AND CONCLUSION: We confirmed that SSC transplantation can be used for restoration of fertility in male cancer survivors exposed to irradiation as a therapeutic agent. The success rate of this procedure, however, is low. The success of filling the tubules with the cell suspension, but not the GnRH-ant treatment, was related to the level of colonization by transplanted cells.

Igalan from Inula helenium (L.) suppresses the atopic dermatitis-like response in stimulated HaCaT keratinocytes via JAK/STAT3 signaling.

OBJECTIVE: This study aimed to evaluate the protective effect of igalan, a sesquiterpene lactone isolated from Inula helenium (L.), on inhibiting inflammation, regulating the epidermal differentiation gene expression, and reactive oxygen species scavenging in atopic dermatitis (AD)-like inflammatory keratinocytes. METHODS: HaCaT human keratinocytes were treated with igalan at indicated concentrations before being activated by a combination of TNF-α and IFN-γ or IL-4 representative for T-helper 1 and T-helper 2 cell cytokines, which are associated with AD pathogenesis. RESULTS: By inhibiting the NF-κB pathway as well as the STAT activation, igalan could downregulate several marker inflammatory genes in AD, such as TARC/CCL17, MDC/CCL22, and RANTES/CCL5. In contrast, igalan, acting as JAK inhibitor, could promote the mRNA expression levels of the genes FLG, LOR, KRT10, and DSC1, which encode for essential proteins responsible for keratinocyte differentiation, by inhibiting STAT3 signaling. Furthermore, igalan exerts its antioxidant effect through activating the Nrf2 pathway, triggering the expression of some enzymes that contribute to preventing intracellular ROS generation during inflammation. CONCLUSION: These findings indicate that igalan, via suppressing JAK/STAT3 signaling, could impair the production of pro-inflammatory chemokines and enhance expression levels of several genes involved in keratinocyte differentiation in AD-like stimulated keratinocytes.

Functionalization of C-H bonds in acetophenone oximes with arylacetic acids and elemental sulfur.

Fused thieno[3,2-d]thiazoles were synthesized via a coupling of acetophenone ketoximes, arylacetic acids, and elemental sulfur in the presence of Li2CO3 base. Functionalities including chloro, bromo, fluoro, trifluoromethyl, and pyridyl groups were compatible with reaction conditions. High yields and excellent regioselectivities were obtained even if meta-substituted ketoxime acetates were used. Ethyl esters of heteroarylacetic acids were competent substrates, which is very rare in the literature. Our method would offer a convenient protocol to afford polyheterocyclic structures from simple substrates.