bluuebunny/crossref_metadata_2025_split huggingface dataset:
Manipulation of Curcumin Degradation to Enhance its Stability and Biological Activity
Authors: Sanidad Katherine Zabala , Wang Weicang , Zhu Julia , Nimiya Yoshiki , Du Zheyuan , Sukamtoh Elvira , Zhang Guodong 
Published: June 2021

Curcumin, a dietary compound from turmeric, is one of the most promising dietary compounds for cancer prevention and inflammation. However, curcumin rapidly degrades at physiological pH with a half‐life of several minutes, making it difficult to discern whether the cancer preventing and inflammation reducing effects are due to curcumin itself or its degradation products. In order to determine which compounds were most responsible for the observed anti‐cancer and anti‐inflammatory effects, we compared the biological activities of curcumin with a mixture of its stable total degradation products (TDP) and the most abundant stable degradation product, bicyclopentadione (BCP). We compared the effects of these compounds on cell proliferation, cell cycle progression, and apoptosis in MC38 colon cancer cells and lipopolysaccharide (LPS)‐induced inflammatory responses and NF‐kB signaling in RAW 264.7 macrophages. Our results showed that compared with curcumin, both TDP and BCP have dramatically reduced effects on cell proliferation, cell cycle progression and apoptosis in MC38 cells, and reduced effects on inhibition of inflammatory responses and NF‐kB signaling in RAW264.7 cells. These results suggest that the observed effects of curcumin are mainly mediated by curcumin itself, rather than its degradation products. We further showed that co‐addition of redox active antioxidants, which stabilizes curcumin in aqueous buffer, significantly enhanced the biological effects of curcumin in MC38 cells. Together, these results suggest that manipulation of curcumin degradation is a promising strategy to enhance its anti‐cancer and anti‐inflammatory effects.Support or Funding InformationArmstrong Fund of Science Award from University of Massachusetts Amherst and USDA NIFA 2016‐67017‐24423
ARSENIC EXPOSURE PROMOTES AGGRESSIVE BREAST CANCER PHENOTYPE
Authors: Luelsdorf Andre 
Published: June 2021

Environmental arsenic (AS) is a class I human carcinogen with established roles in promoting skin, colon, bladder and kidney cancers. The role of AS as a breast carcinogen is less established although numerous studies have indicated that that in cell culture AS promotes the specification of breast cancer towards phenotypes that are estrogen receptor negative (ERα(−)) which are more lethal as well as more challenging to treat. The molecular mechanism involved remain unknown. Our laboratory found that AS promotes alterations in the metabolism of mitochondria reactive oxygen species (ROS) via inhibiting the tumor suppressor Sirtuin 3 which leads to the accumulation of manganese superoxide dismutase (MnSOD) in an acetylated form (MnSOD‐K68Ac) which activates hypoxia induced factor 2α (HIF2α). The activation of HIF2α is a well‐stablished mechanism os stem cell reprogramming that has also been implicated in metastatic recurrence as well as treatment failure in women with breast cancer. Hence, we propose that chrnic AS exposure is a risk factor for the development of ER(−) breast cancer via a mechanism that involves MnSOD acetylation and mitochondria ROS. In support of this idea, we found that exposure of MCF‐7 (normally ERα+), leads to the accumulation of MnSOD‐K68Ac and ER(−) phenotype. Our results indicate that exposure to AS may be a risk factor for the development of ER(−) tumors which are more aggressive and prone to metastasize.Support or Funding InformationDOD
Streptomyces wadayamensis MppP: A Novel PLP‐Dependent L‐Arginine Hydroxylase in L‐Enduracididine Biosynthesis
Authors: Han Lanlan , Silvaggi Nicholas 
Published: June 2021

The nonproteinogenic amino acid L‐enduracididine (L‐End) is a critical component of the mannopeptimycins, a family of cyclic glycopeptide antibiotics with potent activities against drug‐resistant pathogens like MRSA. Creating derivatives of mannopeptimycin and other L‐End‐containing natural products is hampered by the limited availability of L‐End. We are investigating the L‐End biosynthetic pathway in order to develop an efficient enzymatic or chemo‐enzymatic route to produce this unusual amino acid. Recently, we found that MppP is a PLP‐dependent L‐Arg hydroxylase in L‐End biosynthesis in Streptomyces wadayamensis. It reacts with L‐Arg and dioxygen to yield two products, 2‐ketoarginine and 4‐hydroxy‐2‐ketoarginine in a ratio of ~1.7:1. Surprisingly, 1 equivalent of H2O2 is produced for each equivalent of O2 consumed. In addition, the ratio of O2 consumption to L‐Arg consumption was ~1.4:1, suggesting that one product requires 2 equivalents of O2, and the other only 1 equivalent. We have determined the structures of MppP in four states: the internal aldimine, the external aldimine with the substrate, L‐Arg, the product complex with 4‐hydroxy‐2‐ketoarginine, and the product complex with 2‐ketoarginine. According to the structures, the N‐terminal helix is disordered in the internal aldimine and covers the active site only when the substrate is bound. A glutamate residue in the N‐terminal helix, E15, makes a hydrogen bonding interaction with the carboxylate of the substrate, L‐Arg. This observation prompted us to make three N‐terminal variants of SwMppP: E15A, E15Q, and the truncation mutant, SwMppP23‐276. Steady state kinetics showed that the two point mutants had no effect on kcat or KM,L‐Arg. The truncation mutant, however, showed an approximately 10‐fold increase in KM and a 3‐fold decrease in kcat, which reduced the pseudo‐second order rate constant by almost 25‐fold. Interestingly, although the steady state kinetics (as measured by dioxygen consumption) are indistinguishable for the E15A and E15Q variants, the E15A variant does not produce 4‐hydroxy‐2‐ketoarginine, only the abortive product 2‐ketoarginine. Likewise, the truncation mutant also produced only 2‐ketoarginine. Our structural and kinetic characterization of the wild‐type and variant forms of SwMppP have allowed us to propose a revised model where the oxygen incorporated in the hydroxy‐arginine product is derived from water rather than from dioxygen.Support or Funding InformationNational Science Foundation CHE‐1606842
Cardiovascular disease prevention in individuals with underlying chronic inflammatory disease
Authors: Weber Brittany , Liao Katherine P. , DiCarli Marcelo , Blankstein Ron 
Published: June 2021

Purpose of review
Patients with chronic inflammatory disease have an increased risk of cardiovascular disease. This article reviews the current evidence of cardiovascular prevention in three common systemic inflammatory disorders (SIDs): psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.

Recent findings
General population cardiovascular risk assessment tools currently underestimate cardiovascular risk and disease-specific risk assessment tools are an area of active investigation. A disease-specific cardiovascular risk estimator has not been shown to more accurately predict risk compared with the current guidelines. Rheumatoid arthritis-specific risk estimators have been shown to better predict cardiovascular risk in some cohorts and not others. Systemic lupus erythematosus-specific scores have also been proposed and require further validation, whereas psoriasis is an open area of active investigation. The current role of universal prevention treatment with statin therapy in patients with SID remains unclear. Aggressive risk factor modification and control of disease activity are important interventions to reduce cardiovascular risk.

Summary
A comprehensive approach that includes cardiovascular risk factor modification, control of systemic inflammation, and increased patient and physician awareness is needed in cardiovascular prevention of chronic inflammation. Clinical trials are currently underway to test whether disease-specific anti-inflammatory therapies will reduce cardiovascular risk.
Long Anterior Zonules and Angle Closure Disease
Authors: Khurana Mona , Ganesh Nagalekshmi , Jaiswal Ashutosh G. , Vijaya Lingam , George Ronnie J. , Balekudaru Shantha 
Published: June 2021

Précis:
Angle closure disease was present in 59.3% of eyes with long anterior zonules (LAZ). The cause is multifactorial including a thick anteriorly positioned crystalline lens, shorter axial length, and increased lens thickness to axial length factor.

Purpose:
To study the profile of eyes with LAZ presenting in a glaucoma clinic in a tertiary eye care centre and understand the pathogenesis of angle closure disease in these eyes.

Methods:
This was a retrospective cross-sectional study.
All patients with LAZ seen from January 2014 to December 2018 were included. Demographic and clinical characteristics were noted. LAZ eyes (177 eyes of 177 patients) were compared with an equal number of age and sex-matched controls. LAZ was defined as radially oriented zonular fibers (both pigmented and nonpigmented), extending central to the normal zonular termination zone on the anterior lens surface >1 mm beyond their usual insertion of 1.42±0.24 mm from the lens equator onto the mid peripheral zone or central to it, as seen on slit-lamp examination, following pupillary dilation by a single examiner. Glaucoma was defined according to the International Society for Geographical and Epidemiological Ophthalmology classification. The following biometric parameters were compared: anterior chamber depth (ACD), axial length (AXL), lens thickness (LT), lens position (LP=ACD+0.5×LT), relative lens position (RLP=LP/AXL); lens thickness to axial length factor (LAF=(LT/AXL)×10). LAZ eyes without angle closure disease were also compared with controls.

Results:
Mean age of patients with LAZ was 64.8±8.1 years. Of these, 63.3% were females. Angle closure disease was present in 59.3% (105/177) patients. Majority of these eyes were primary angle closure suspects (PACS) (53.3%, n=56). Significant differences were found between LAZ eyes and controls for LT (4.8±0.38 mm vs. 4.49±0.40 mm, P<0.0001), ACD (2.68±0.39 mm vs. 3.0±0.32 mm, P<0.0001), AXL (22.37±0.79 mm vs. 22.94±1.1, P<0.0001), LAF (2.14±0.19 vs. 1.96±0.21, P<0.0001), and LP (5.07±0.37 vs. 5.3±0.25, P<0.0001).

Conclusions:
Angle closure was present in more than half the eyes with LAZ. Majority of these eyes were PACS or had primary angle closure. LAZ eyes had a thicker lens, shallow AC, a shorter axial length and an increased LAF as compared with age and sex matched normal controls. The presence of LAZ may be an indicator of increased risk for angle closure.
Short and long-term effectiveness and safety of vedolizumab in treatment-refractory patients with ulcerative colitis and Crohn’s disease – a real-world two-center cohort study
Authors: Attauabi Mohamed , Vind Ida , Pedersen Gitte , Bendtsen Flemming , Seidelin Jakob Benedict , Burisch Johan 
Published: June 2021

Objectives
Real-world data about sustained clinical remission (SCR) and treatment optimization with vedolizumab for ulcerative colitis (UC) and Crohn’s disease (CD) are scarce. We aimed to investigate the short and long-term effectiveness and safety of vedolizumab in a real-world cohort in Denmark.

Methods
A retrospective two-center cohort study was conducted between November 2014 and November 2019 with the primary outcomes of clinical remission (CR) at weeks 14, 30, 52 and 104 and SCR defined as CR at week 14 through week 52.

Results
The study included 182 patients (UC: 97, CD: 85), all previously exposed to at least one biological therapy. Rates of CR at weeks 14, 30, 52 and 104 were 36.6, 35.1, 34.0 and 27.8%, respectively, in UC, and 31.7, 30.1, 26.5 and 22.4% in CD. SCR was achieved in 19.6 and 20.0%, respectively. In UC and CD, optional dosing of vedolizumab at week 10 (odds ratio [OR] = 0.23 (95% confidence interval [CI], 0.03–1.17), and OR = 0.68 (95% CI, 0.22–2.04)), as well as increase of frequency (OR = .26 (95% CI, 0.01–2.86), and OR = 0.19 (95% CI, 0.01–1.45)), were not associated with CR at week 52. Furthermore, combination treatment with azathioprine was not associated with long-term outcomes. However, dose intensification of vedolizumab successfully restored CR in 65.2 and 57.1% of patients with UC and CD experiencing loss of response.

Conclusions
Vedolizumab is effective in achieving and restoring short and long-term CR and SCR in patients with treatment-refractory UC and CD. This study emphasizes that supplementary dosing at week 10, and simultaneous treatment with azathioprine, did not improve long-term outcomes.
Safety and efficacy of antiviral therapy alone or in combination in COVID-19 - a randomized controlled trial (SEV COVID Trial)
Authors:   SEV COVID trial group, Singh Budha O , Moirangthem Bikram , Panda Prasan Kumar , Bahurupi Yogesh Arvind , Saha Sarama , Saini Girraj , Dhar Minakshi , Bairwa Mukesh , Pai Venkatesh Srinivasa , Agarwal Ankit , Sindhwani Girish , Handu Shailendra , Ravikant  
Published: June 2021

ABSTRACTBackgroundDefinitive antiviral treatment is not available for COVID-19 infection except remdesivir that even with many doubts. Various combination antivirals have been tried.MethodsA single-center, open-label, parallel-arm, stratified randomized controlled trial evaluated the therapeutic potential of hydroxychloroquine and lopinavir-ritonavir in combination with ribavirin in COVID-19. Enrolled patients in severe category were randomized into three groups: A: standard treatment, B: hydroxychloroquine+ribavirin+standard treatment, or C: lopinavir+ritonavir+ribavirin+standard treatment; while non-severe category into two groups: A: standard treatment or B: hydroxychloroquine+ribavirin. Combination antivirals was given for 10 days and followed for 28 days. The primary endpoints were safety, symptomatic and laboratory recovery of organ dysfunctions, and time to SARS-CoV-2 RT-PCR negative report.ResultsTotal 111 patients randomized: 24, 23, and 24 in severe category A, B, and C respectively, and 20 in each non-severe group. Two patients receiving ribavirin experienced drug induced liver injury and another developed QT prolongation after hydroxychloroquine. In the severe category, 47.6%, 55%, and 30.09% in A, B, and C groups respectively showed symptomatic recovery compared to 93.3% and 86.7% in A and B groups respectively in the non-severe category at 72hrs (P>0.05).ConclusionsThe results failed to show statistical superiority of the antiviral combination therapies to that of the standard therapy in both the severe and non-severe categories in symptomatic adult patients of COVID-19. However, results do indicate the benefit of non-standard interventional combination therapy in severe disease. Furthermore, the dose of ribavirin needs to be reconsidered in the Indian population.
Salt-inducible kinase (SIK) inhibition is protective in a mouse model of asthma
Authors: van Gijsel-Bonnello Manuel , Darling Nicola J. , McDonald Laura , Sime Mairi , Clark Jonathan , Mezna Mokdad , Schuettelkopf Alexander , Mackay Craig , Bower Justin , McKinnon Heather , Cohen Philip , Arthur J. Simon C. 
Published: June 2021

AbstractInterleukin-13 (IL-13) and other Th2 cytokines are important regulators of airway hyper-responsiveness, immune cell infiltration and inflammation in allergic asthma, and are produced when immune cells, such as type 2 innate lymphoid cells (ILC2s) and mast cells, are stimulated with IL-33. Here, we report that the IL-33-dependent secretion of IL-13 from ILC2s is prevented by inhibition of the salt-inducible kinases (SIKs), as we have shown previously in mast cells (Darling NJet al., 2021, J. Biol. Chem. doi: 10.1016/j.jbc.2021.100428). We also report that a new SIK inhibitor with improved pharmacokinetic properties suppresses the recruitment of eosinophils to the lungs and serum immunoglobulin E (IgE) levels in theAlternaria alternata-inducedmodel of allergic asthma. Our results suggest that drugs targeting SIK isoforms may have therapeutic potential for the treatment of asthma.
Treadmill exercise promotes retinal astrocyte plasticity and protects against retinal degeneration
Authors: Bales Katie L. , Chacko Alicia S. , Nickerson John M. , Pardue Machelle T. , Boatright Jeffrey H. 
Published: June 2021

AbstractExercise has been shown to be an effective neuroprotective intervention that preserves retinal function and structure in several animal models of retinal degeneration. However, retinal cell morphology and cell types governing exercise-induced retinal neuroprotection remain elusive. Previously, we found that the protective effects of exercise in animal models of retinal disease were accompanied by increased levels of circulating and retinal brain derived neurotrophic factor (BDNF) and required intact signal transduction with its high-affinity receptor, tropomyosin kinase B (TrkB). Studies of neurodegenerative diseases in the brain demonstrate that neurons and astrocytes express BDNF and TrkB. Additionally, astrocytes have been shown to alter their morphology in response to exercise. Here, we have investigated the role of retinal astrocytes as mediators of exercise-induced retinal neuroprotection in a light-induced retinal degeneration mouse model (LIRD). We found that treadmill exercise in both our dim (control maintenance light levels) and LIRD groups promote increased retinal astrocytic population, GFAP expression, branching and endpoints, dendritic complexity, and promotes BDNF-astrocyte interaction. In contrast, LIRD animals that were inactive had significant reductions in all measured parameters. Our findings indicate that exercise is sufficient to rescue retinal astrocyte morphology in a LIRD model maintaining branching and dendritic arborization similar to retinal astrocytes that are not undergoing degeneration. These studies provide essential information to current knowledge gaps in regards to exercise-induced neuroprotection and will additionally provide knowledge in exercise intervention optimization as a rehabilitative method.Significance statementThis study represents an essential step in determining the cell-types governing and morphological alterations elicited from exercise which may provide neural repair and protection. Similar to astrocytes in the brain, retinal astrocytes alter their morphology in response to exercise. Our studies demonstrate exercise promotes increased interactions between retinal astrocytes and neural growth factors in healthy retinas as well as in retinas undergoing degeneration, which may ultimately protect dying retinal neurons. These studies provide insight into the potential neuroprotective role astrocytes play in neurodegenerative diseases.
Altered neutrophil phenotype and function in non-ICU hospitalised COVID-19 patients correlated with disease severity
Authors: Belchamber KBR , Thein OS , Hazeldine J , Grudzinska FS , Hughes MJ , Jasper AE , Yip KP , Sapey E , Parekh D , Thickett DR , Scott A 
Published: June 2021

AbstractRationalInfection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based predominantly on transcriptomics or single functional assays. Cell functions are interwoven pathways, and so understanding the effect of COVID-19 across the spectrum of neutrophil function may identify tractable therapeutic targets.ObjectivesExamine neutrophil phenotype and functional capacity in COVID-19 patients versus age-matched controls (AMC)MethodsIsolated neutrophils from 41 hospitalised, non-ICU COVID-19 patients and 23 AMC underwentex vivoanalyses for migration, bacterial phagocytosis, ROS generation, NET formation (NETosis) and cell surface receptor expression. DNAse 1 activity was measured, alongside circulating levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI. All measurements were correlated to clinical outcome. Serial sampling on day 3-5 post hospitalisation were also measured.ResultsCompared to AMC, COVID-19 neutrophils demonstrated elevated transmigration (p=0.0397) and NETosis (p=0.0366), but impaired phagocytosis (p=0.0236) associated with impaired ROS generation (p<0.0001). Surface expression of CD54 (p<0.0001) and CD11c (p=0.0008) was significantly increased and CD11b significantly decreased (p=0.0229) on COVID-19 patient neutrophils. COVID-19 patients showed increased systemic markers of NETosis including increased cfDNA (p=0.0153) and impaired DNAse activity (p<0.0.001). MPO (p<0.0001), VEGF (p<0.0001), TNFRI (p<0.0001) and IL-6 (p=0.009) were elevated in COVID-19, which positively correlated with disease severity by 4C score.ConclusionCOVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration, impaired antimicrobial responses and elevated NETosis. These changes represent a clear mechanism for tissue damage and highlight that targeting neutrophil function may help modulate COVID-19 severity.
The NF-κB pathway controls H3K9me3 levels at intronic LINE-1 elements and hematopoietic stem cell gene expression in cis
Authors: Pelinski Yanis , Hidaoui Donia , Stolz Anne , Hermetet François , Chelbi Rabie , Diop M’boyba Khadija , Chioukh Amir M. , Porteu Françoise , Elvira-Matelot Emilie 
Published: June 2021

SUMMARYIonizing radiations (IR) alter hematopoietic stem cell (HSC) function on the long-term, but the mechanisms underlying these effects are still poorly understood. We recently showed that IR induces the derepression of L1Md, the mouse young subfamilies of LINE-1/L1 retroelements. L1 contribute to gene regulatory networks. However, how L1Md are derepressed and impact HSC gene expression are not known. Here we show that IR triggers genome-wide H3K9me3 decrease that occurs mainly at L1Md. Loss of H3K9me3 at intronic L1Md harboring NF-κB binding sites motifs but not at promoters is associated with the repression of HSC specific genes. This is correlated with reduced NFKB1 repressor expression. TNF-α-treatment before IR rescued all these effects and prevented IR-induced HSC loss of function in vivo. This TNF-α/NF-κB/H3K9me3/L1Md axis might be important to maintain of HSCs while allowing expression of immune genes during myeloid regeneration or damage-induced bone marrow ablation.