bluuebunny/crossref_metadata_2025 huggingface dataset:
Blocking Store‐Operated Ca2+ Entry to Protect Cardiomyocytes from Epirubicin‐Induced Toxicity
Authors: Liu Xian , Chang Yan , Choi Sangyong , Pan Zui
Published: April 2020

Epirubicin (EPI) is one of widely used anthracycline chemotherapy drugs, yet its cardiotoxicity severely limits its clinical application. Altered intracellular Ca2+ homeostasis has been linked to epirubicin‐induced cell death and hypertrophy. While store‐operated Ca2+ entry (SOCE) recently has been linked with cardiac hypertrophy and heart failure, its role in epirubicin‐induced cardiotoxicity remains unknown.

METHOD

HL‐1, a cardiomyocyte cell line derived from adult mouse atria, was used in this study. Intracellular ROS was measured by
dihydroethidium(DHE) fluorescence and intracellular Ca2+ was monitored by ratiometric dye Fura‐2 on a spectrofluorometer (excitation λ = 350/385nm and emission λ = 510nm; Photon Technology International, NJ). Upon depletion of ER Ca2+ stores by 10μM thapsigargin (TG) in 0mM Ca2+ extracellular solution, SOCE was activated when extracellular solution was rapidly exchanged to 2mM Ca2+. Apoptosis assay was conducted by nuclei staining, F‐actin phalloidin staining and Western Blotting of caspase‐3. While cell size was compared in HL‐1 cells with different treatments using Image J, the mRNA of Orai1, Orai3, STIM1 and B‐type natriuretic peptide (BNP) were also compared using real time qPCR.

RESULTS

Incubation of 1uM EPI for 30min induced significant ROS production in cultured HL‐1 cells compared with vehicle control (10410±1492 vs. 2762±939, p<0.0001). EPI induced an enhanced SOCE (0.1214±0.0104 vs. 0.0682±0.0062, n=32, p=0.0008), likely through increased expression of SOCE components Orai1, Orai3, and STIM1 compared with control cells. Apoptosis was observed upon EPI treatment, indicated by the condensed and fragmented nuclei, degradation of F‐actin and increased cleavage of caspase‐3 protein. EPI treatment also resulted in larger cell size (3894±120 μm2) compared with non‐treated control cells (2452±57 μm2, n=581, p<0.0001). The hypertrophy marker BNP was up‐regulated upon EPI treatment as well. BTP‐2, a known SOCE blocker, could block this EPI‐induced SOCE and rescue HL‐1 cells from EPI‐induced apoptosis. BTP‐2 also prevented HL‐1 cells from EPI‐induced hypertrophy in terms of cell size (see Figure
, 2548±69 μm2) and also reduction of BNP expression.

CONCLUSION

Epirubicin upregulated SOCE, induced apoptosis and hypertrophy in HL‐1 cardiomyocytes. Blocking SOCE by BTP‐2 could at least partially rescue HL‐1 cells from epirubicin‐induced apoptosis and hypertrophy.

Support or Funding Information

(1) NIH S10 OD025230 to Dr. Zui Pan(2) University of Texas at Arlington Center for Research and Scholarship Pilot Grant for Trainee to Xian Liu

Figure 1
Regulation of cranial neural crest cell fate by Irf6 and Twist1 interaction
Authors: Fakhouri Walid D. , Bertol Jessica Wildgrube , Xie Victoria K. , Johnston Shelby , Hubka Kelsea , Keuls Rachel , Parchem Ronald J. , Farach-Carson Mary C.
Published: April 2020

A wide variety of common craniofacial birth defects and pediatric cancers arise from errors in the development of cranial neural crest cells (CNCC) that give rise to craniofacial skeletal and peripheral nervous systems. Identification of the genetic and environmental factors that regulate cell fate of CNCCs is crucial for uncovering the causes behind craniofacial disorders. Our lab has identified a dual‐transcription factor pathway that regulates CNCCs during EMT and migration. Initially, we identified a causative mutation in a TWIST1 binding site within an Interferon Regulatory Factor 6 (IRF6) enhancer in a multi‐generational family affected with syndromic cleft lip and palate called Van der Woude syndrome. Our subsequent animal work has shown that Twist1 and Irf6 genetically interact during early craniofacial development, and that the compound heterozygotes exhibit craniofacial abnormalities. We recently demonstrated that Irf6 is required for neural tube and CNCC development and that it interacts with Twist1 during EMT and migration of CNCCs. We also showed that TWIST1 is highly phosphorylated in CNCCs and its phosphorylation is crucial for regulating Irf6 and potentially miR10 family members in CNCC‐derived craniofacial tissues. Our recent in‐vivo and neural tube explants using dual fluorescent cell tracing system showed that Twist1 conditional knockout (CKO) in CNCCs significantly reduced cell delamination and disrupted EMT. The detached Twist1 CKO in CNCCs retained their epithelial signatures and migrated as clusters of epithelial‐like cells over significantly shorter distances. Finally, Twist1 phospho‐incompetent mice for two serine residues were recently generated to determine their impact on TWIST1 activity. Our preliminary results showed that Twist1S68A/S68A phospho‐mutant mice have craniofacial bone defects and forebrain hemorrhage.

Support or Funding Information

UTHealth start‐up funds and a small grant from theRolanette and Berdon Lawrence Bone Disease Program of Texas
DNA Methylation Markers in the Diagnosis and Prognosis of Common Leukemias
Authors: Li Oulan , Yu Meixing , Zheng Lianghong , Luo Huiyan , Wei Wei , Li Zhihuan , Jiang Hua , Li Gen
Published: April 2020

An effective and accurate diagnostic method for leukemia has not yet been developed. Using genome‐wide methylation profiling and machine learning methods, we evaluated the utility of CpG methylation status to differentiate blood from patients with acute lymphocytic leukemia (ALL) or acute myelogenous leukemia (AML) from normal blood. We constructed a diagnostic prediction model that can differentiate ALL and AML blood from normal blood as well as ALL blood from AML blood with high diagnostic specificity and sensitivity by utilizing a CpG methylation panel. We then developed a methylation‐based survival classifier with 23 CpGs for ALL and 20 CpGs for AML that could successfully divide patients into high‐risk and low‐risk groups, with significant differences in clinical outcome in each leukemia type. These methylation markers have outperformed existing methods in their high sensitivity and specificity for diagnosis of ALL and AML, and have implications for the prediction of prognosis and treatment selection.

Support or Funding Information

Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China

Using 11 markers, the methylation profile can differentiate subtype of leukemia and normal blood. Unsupervised hierarchical clustering and heatmap associated with ALL, AML and normal blood.

Figure 1

Methylation markers can predict five‐year overall survival of patients. A. AML training set (n=125); B. AML validation set (n=55); C. ALL training set (n=55); and D. ALL validation set (n=34).

Figure 2
EVIDENCE‐BASED EXERCISE PROGRESSION ON THE DIABETIC PATIENT
Authors: Leon-Ariza Henry Humberto , Garcia-Ramos Andres Felipe , Padron-Ayala Antonietta , Rozo-Cespedes Laura , Reyes-Cruz Dario , Botero-Rosas Daniel Alfonso
Published: April 2020

It is estimated that the worldwide prevalence of Type 2 Diabetes Mellitus by 2030 will be 522 million people, which generates a negative impact on the well‐being of the individual and population health. Within the fundamental pillars of the treatment are the changes in the lifestyle that includes physical exercise. Organizations such as the ADA (American Diabetes Association) and the ACSM (American College of Sports Medicine) suggest strength training 2 to 3 times per week, using weights, bands or machines at moderate to vigorous intensity and aerobic training 3 to 7 days, minimum 150 minutes a week with the same intensity. However, these recommendations are widespread and do not take into account the progression of the load.

This work summarizes the progression of training that diabetic patients should have in order to optimize the results. It is suggested to combine the work of strength with resistance, which is related to better body composition. Training intensity should be progressively increased whenever possible, which is related to increased muscle sensitivity to insulin. The training volume should be progressively increased as well, which allows for a higher concentration of GLUT4 transporters, improving intracellular insulin signaling, and generating a reduction in plasma and intramyocellular free fatty acids that lead to better insulin sensitivity.

Based on the preceding, the physiological proposal of progression includes: Performing resistance work during the first weeks of training and subsequently including endurance training until a concurrent type of training is achieved. Also, there should be an increase the training volume (total weight lifted and total covered distance ), and then increased the intensity, High‐Intensity Interval training can only be done until several weeks of adaptation are completed. Finally, the training frequency should also be increased progressively until ideally reaching seven days a week.

Given the rapid physiological adaptation, the loads must be undulated, alternating the training variables, intensity, volume, time, and type of exercise, until reaching the objective. Therefore, based on the evidence, we propose in this article a dynamic training model for diabetic patients that could be implemented by physicians and corresponding health personnel.

Dynamic training model for diabetic patients

Figure 1
A Novel Plug and Play Robotic Dynamometer to Assess Skeletal Muscle Contractile Function and Perform Plyometric Exercise in Live Mice
Authors: Narayan Neha , Charara Rhonda , Humbach Timothy , Schramm Dara , Teal Brittany , Winczner Kenneth J. , Pepin Marie E. , Roche Joseph A.
Published: April 2020

OBJECTIVE

Our goal was to develop a user‐friendly, all in one instrument, which can be used in longitudinal studies of mice, to assess contractile torque produced by the ankle dorsiflexor muscles and perform forced plyometric exercise on this muscle group.

METHODS

We repurposed a commercial, STEM Education robotics kit, which contains a microcontroller, stepper motors and modular parts, to build a robotic dynamometer. We connected two stepper motors in parallel for optimal driving torque. The axle that connected the motors was linked in series to a torque cell and footplate. Through a commercial plug and play data acquisition device connected to a PC through a USB port, we were able to visualize real‐time data from the torque cell, and record data as needed. We wrote custom routines in the programming language of the robotics kit to perform four sets of ten stretch‐shortening plyometric contractions of the ankle dorsiflexors, at an angular velocity of 300 degrees/s, through a range of 90–160 degrees of plantar flexion and dorsiflexion. During ankle movement produced by the robotic dynamometer, the dorsiflexor muscles were tetanized with subcutaneous needle electrodes connected to an electrical stimulator. To test our rig, we studied four, healthy, 1‐yr old, male, C57BL/6J mice. We performed all testing and training of live animals under general anesthesia induced and maintained by inhaled isoflurane (2–5% to effect).

RESULTS

We found that plyometric exercise performed on our dynamometer induced a significant loss of contractile torque immediately after exercise (2816 ± 222 mNmm before exercise versus 2046 ± 87 mNmm after exercise; *, p < 0.001). At 3 days post‐exercise, contractile torque was still lower than pre‐exercise levels (2322 ± 143 mNmm at Day 3; *, p = 0.002), but was significantly greater than immediate post‐exercise levels (#, p = 0.038). Histological studies (hematoxylin and eosin staining) of cross sections of the injured tibialis anterior muscle revealed that 9.6 ± 4 % of the cross sectional area was damaged (pale and disrupted cytoplasmic staining of muscle fibers).

CONCLUSION

Our novel robotic dynamometer is suitable for assessing contractile function and performing forced plyometric exercise on living mice. Since our rig is made from a commercial STEM Education robotics kit, a plug and play data acquisition system, and other standard parts, it is not only user‐friendly, but is also modular in nature and therefore helps reduce machine to machine variability.

Support or Funding Information

NIH R03HD091648 from NICHD and a FRAP award from EACPHS Wayne State University to JAR

Contractile Torque and Histological Data

Figure 1
Therapeutic Nrf2 Activation improves LV function in the cardiomyocyte‐specific GPER knockdown mouse
Authors: Groban Leanne , Sun Xuming , Hodge Hunter S. , Ferrario Carlos M. , Wang Hao
Published: April 2020

Background

The G protein‐coupled estrogen receptor (GPER) plays an important role in the maintenance of cardiac health partly via its link to anti‐oxidant and anti‐inflammatory pathways. The NLRP3 inflammasome is upregulated in hearts of mice with cardiomyocyte GPER gene deletion, and NLRP3 inhibition limits left ventricle (LV) dysfunction from cardiac GPER deficiency. Studies from others show that GPER mediates the inductive effect of estrogen on the transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2), the master regulator of detoxification and antioxidant systems. This in vivo animal study was designed to further confirm that lack of GPER signaling (from gene deletion or menopause) impedes Nrf2 activation, and in so doing contributes to ROS accumulation and inflammation in the cardiomyocyte. We hypothesize that chronic Nrf2 activation counteracts the adverse effects of cardiac GPER knockdown on LV function, irrespective of estrogen.

Methods

Male GPER KO and WT littermates (7 months of age) were randomized to receive, via drinking water, either 8 weeks of oral treatment with the Nrf2 activator, dimethyl fumarate (KO‐DMF: n=5; WT‐DMF: n=5) at 30mg/kg/day, or its vehicle 0.08% methyl cellulose (KO‐VEH: n=5; WT‐VEH: n=5). At 9 months of age, echocardiographic indices of LV function (isoflurane anesthesia) were obtained prior to sacrifice. Data were analyzed by two‐way ANOVA for gene (GPER), treatment (DMF) and gene x treatment. P<0.05 was considered significant.

Results

Somatic characteristics (e.g. body weight, hair coat appearance) were not overtly affected by GPER knockdown nor DMF treatment. As reported previously, GPER gene deletion led to significant reductions in systolic function (% fractional shortening (FS)), myocardial relaxation (e′) and increases in filling pressure (E/e′) (gene effect: P<0.05). Chronic treatment with the Nrf2 activator significantly attenuated LV systolic dysfunction (treatment effect: P<0.05) and nearly normalized filling pressures (E/e′) in GPER KO without modifying the normal functioning heart of the WT (gene x treatment: P<0.05) (Figure
).

Conclusions

These data suggest that targeting the transcription factor Nrf2 may be a promising strategy to limit LV dysfunction as a result of cardiac oxidative stress and low‐grade inflammation from GPER deactivation (e.g., estrogen loss from ovarian extirpation or menopause).

Support or Funding Information

HL051952 (CMF, LG) and AG033727 (LG)

Figure 1
Differential Mesenteric Venous and Arterial Vascular Reactivity to Adenosine between Rats, Dogs, Mini‐pigs, and Human
Authors: Teng Bunyen , Mustafa S. Jamal , Teng Olivia , Muir William W. , Hamlin Robert L.
Published: April 2020

It is well established that adenosine induces arterial vasodilation in various vascular beds. However, its effect on the venous circulation is still largely unknown. The splanchnic system receives approximately 25% of cardiac output (CO) and contains approximately 20% of total blood volume. Mesenteric (part of splanchnic system, o. d. 150–250 μm) arteries (MA) and their adjacent veins (MV) from rats, dogs, mini‐pigs and humans were isolated and mounted on a myograph (DMT Technology, USA). Vessels were preconstricted with 1 μM phenylephrine (PE) for arteries and prostaglandin F2α (PGF2α) for veins. Cumulative concentrations of 5’‐N‐Ethylcarboxamidoadenosine (NECA, 10−11 – 10−5 M), a non‐specific adenosine agonist, were applied and evaluated. Tension development was normalized to the tension induced by PE/PGF2α as %. NECA induced a concentration dependent arterial vasodilation in all 3 animals and human MA (Fig.
1). The effects were very similar in all 3 animals (maximum of 91.09±10.94% to 93.88±1.93%), however human responses were less pronounced (maximum of 59.14±4.61%). Interestingly, veins from all species responded to NECA very differently (Fig.
2). MVs from rats were the only vessels that constricted strongly in response to NECA (182.94±17.52% of pre‐constriction), which has not been previously reported (Figs.
2–
3). NECA induced vasodilation in MV from the other species varied. NECA induced vasodilation in MV from dogs were similar to MA at high concentrations (Fig.
6, 10−8 M and above). However, MV from mini‐pig (Fig.
5) and human (Fig.
6) responses were minimal (Fig.
2, maximum of 24.56±14.67% in mini‐pig and 33.54±9.61% relaxation in human) compared to 92.93±2.26% relaxation in dogs. In conclusion, although mesenteric arterial vascular reactivity responds similarly to adenosine among species, mesenteric venous vascular reactivity responses varied greatly to adenosine among species. MVs from rats were the only vessel constricted strongly in response to NECA. Caution is advised when choosing animal models for studying vascular reactivity.

Figure 1Figure 2Figure 3Figure 4Figure 5Figure 6
Hepatoprotective Effect of Amygdalin (Vit B17) Against Phenolphthalein Induced liver injury; involvement of Glial fibrillary acidic protein (GFAP)
Authors: Elased Wael , Elbastawisy Yasser , Mohamed Hazem
Published: April 2020

Background

Phenolphthalein (PTH) is an odorless and colorless chemical of laxative action and multiple side effects referred mostly to the production of free . It is primarily metabolized in the liver, hence its main adverse effects occur. Amygdalin (Vit B17) have antifibrotic, antiinflammatory and antitumor activities. The histopathological and functional changes in the liver together with the postulated protective hepatoprotective effect of Amygdalin were investigated in this study. Glial fibrillary acidic protein (GFAP) was considered as a marker of liver pathological changes.

Material and methods

30 adult male albino rats were divided into 3 groups. Group I was the control, group II received PTH alone and group III received both PTH and Amygdalin. At day 21, the levels of serum GFAP, total protein, total bilirubin and the activities of AST and ALT and liver hydroxyproline were estimated. The liver tissue samples were examined H&E, Masson’s trichrome and anti‐GFAP immunoreactive stains, and electron microscopic examination.

Results

The liver enzymes, total bilirubin, hydroxyproline, and serum GFAP were significantly increased in group II compared with the control and in group III compared to group II. The total proteins were significantly decreased in group II in comparison to the controls and highly significantly increased in group III compared to group II. Group II showed disturbed hepatic architecture with extensive congestion, degeneration with inflammatory cell infiltration and marked collagen deposition. Group III showed preserved hepatic parenchyma and scanty inflammatory cells infiltration with decreased collagen. Group II had strong and diffuse immunoexpression and group III liver tissues were similar to the controls. The mean area percentage of GFAP immune staining showed a highly significant increased immunopositivity in group II when compared to the group I and a significant decsrease in group III compared to group II. The ultrastructure of hepatic stellate cells of group II showed dilated rough endoplasmic reticulum and loss of lipid droplets. Group III were similar to the controls.

Conclusion

Amygdalin treatment had a hepatoprotective effect against PTH induced liver injury and fibrosis and GFAP level could be a predictor for HSCs activation.

Graphical Abstract

Figure 1

GFAP immune staining of the liver section of the control group (A) showing positive staining of the stellate cell and the endothelium of the sinusoids. The endothelium of the central veins is negatively stained. B: the PTH group showing strong and diffuse immunoexpression mostly perisinusoidal. C: The PTH‐Amg. group showed less marked dye expression. D: Diagram of the mean GFAP stained area percentage of the 3 animal groups

Figure 2
α‐Hederin induce gastric cancer cell death by blocking autophagic flux and triggering ER stress
Authors: Shen Weixing , Chen Haibo
Published: April 2020

Background

Gastric cancer (GC) is a prevalent refractory disease worldwide, especially in developing countries. α‐Hederin (α‐Hed) is a major active component of triterpenoid saponin isolated from Fructus Akebia, we found it showed significant anti‐proliferative and pro‐apoptotic activity against GC cells in a dose‐dependent manner.

Purpose

This study aims to uncover the potential mechanism of α‐Hedin relation to anti‐GC activity.

Study design

Cytotoxicity of a‐Hed to BGC‐823 and MGC‐803 cells was monitored by CCK8 and Annexin V‐FITC/PI apoptosis assay. Autophagic flux was examined by western blot analysis and the number of green fluorescent protein (GFP)‐LC3B puncta. ER Stress was also probed by western blot analysis. Cellular Reactive Oxygen Species (ROS) Detection Assay Kit was used to detect ROS level.

Results

GC cells growth was significantly inhibited and cell death was induced by α‐Hed in BGC‐823 and MGC‐803 cells. We subsequently discovered that α‐Hed promoted autophagosome formation by upregulatingthe expression of LC3‐II, Beclin‐1 and increasing GFP‐LC3B puncta formation. However, p62 was also upregulated, which was indicative of autophagic flux blockage. Comparing to α‐Hed treatment alone, the combinatorial treatment of α‐Hed and Bafilomycin A1 (Baf A1) did not obviously alter the expression of LC3‐II, suggest that α‐Hed blocked autophagic flux in GC cells. Nevertheless it was later discovered that expression of ATF6, IRE1α, and PERK were elevated after a‐Hed treatment in GC cells, which represents activation of three signaling arms of the Unfolded Protein Response. Besides, α‐Hed obviously increased cellular ROS levels in GC cells, and the ER stress‐regulated apoptosis related proteins such as CHOP, caspase‐12, and JNK also increased.

Conclusion

Our results suggest that α‐Hed induce GC cell death by influencing crosstalk between autophagy and ER Stress pathways.

Support or Funding Information

National Natural Science Foundation of China General Program (81973523)

graphical abstract

Figure 1
Molecular Basis for Acetyl‐CoA Production by ATP‐Citrate Lyase
Authors: Wei Xuepeng , Schultz Kollin , Bazilevsky Gleb , Vogt Austin , Marmorstein Ronen
Published: April 2020

ATP‐citrate lyase (ACLY) synthesizes cytosolic acetyl‐CoA, a fundamental cellular building block. Accordingly, aberrant ACLY activity is observed in many diseases. Here we report cryo‐EM structures of human ACLY alone or bound to substrates or products. ACLY forms a homotetramer with a rigid citrate synthase homology (CSH) module, flanked by four flexible actyl‐CoA synthetase homology (ASH) domains; CoA is bound at the CSH‐ASH interface in mutually exclusive productive or unproductive conformations. The structure of a catalytic mutant of ACLY in the presence of ATP, citrate and CoA substrates reveals a phospho‐citryl‐CoA intermediate in the ASH domain. ACLY with acetyl‐CoA and oxaloacetate (OAA) products shows the products bound in the ASH domain, with an additional OAA in the CSH domain, which could function in ACLY autoinhibition. These structures, which are supported by biochemical and biophysical data, challenge previous proposals of the ACLY catalytic mechanism and suggest additional therapeutic possibilities for ACLY‐associated metabolic disorders.

Support or Funding Information

U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER) ‐ R35 GM118090 [Marmorstein] U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER) ‐ P01 AG031862 [Marmorstein]

a, Two views of the ACLY structure with citrate and CoA. b, Enlarged view of CoA bound at the ASH–CSH interface, highlighting the corresponding cryo‐EM density. b and c, Close‐up view of CoA–protein interactions.

d,Superimposition of ACLY bound with the extended CoA and bent CoA conformations. e, Relative enzyme activity of ACLY mutant constructs.

Figure 1

ACLY‐apo is suboptimal for productive CoA binding and that CoA can bind in an non‐productive conformation, but CoA cannot be converted to acetyl‐CoA until ATP and citrate substrates bind. The ACLY‐E599Q mutant in the presence of CoA, citrate and ATP reveals that a phospho‐citrate‐CoA intermediate forms prior to formation of acetyl‐CoA and OAA. Following cleavage of the phospho‐citrate‐CoA, the ACLY–OAA–acetyl‐CoA structure reveals that acetyl‐ CoA and OAA products are formed in the ASH domain.

Figure 2
‘Multi‐∑QEME of Human Biodynamic Molecular Cell Sustainability in Psycho‐Neuro‐ Endo Processes’
Authors: Einstein George P. , Rahman Michael S. , Tulp Orien P. , Koynk Carla
Published: April 2020

A healthy biological system, whether human or animal, is biodynamic aand must remain in a state of fine tuning with natural bio‐electromagnetic frequencies. A well‐tuned human body is capable of continuous adaptation. The application a controlled dose of modulated coherence quantum bio‐electromagnetic energy was investigated to determine subtle alterations within the properties of the tissue and internal organs, and bring their characteristic frequencies to corresponding levels of healthy tissues.

The Quantum of Electromagnetic wave emitted by modulated wave object and a bsorbed by a human body serves as the “messenger” so that any detrimental changes in the biological state of the body can be swiftly corrected by a natural repair of the degree of tuning‐in.

Neuro‐Immune Stimulation Therapy involves the process of reversing the destructive effects of negative quantum energy within the body by the intentional transference of natural high frequency bio‐electromagnetic field resonance or positive quantum energy transference.

In this research ∑ Bio‐Psycho‐Neuro Quantum Energy model for naturally occurring heart‐brain phenomenon transfer represented in the third step of G. P. Einstein’s mathematical function for:

(3∑) Integrated Quantum Bio‐Energy Therapy (∑ IQBET) =

= ∑BEM‐Phy.QE × ∑BEM‐CHQE ×
∑BEM‐Psy.NQE

Our body serves as a receiver and can absorbed the specific

Bioelectromagnetic Energy for Dynamic Health.

Our Neuro ‐ Immune System has ability to accept and correctly interpret the subsequent sets of incoming signals. It can be carefully monitored and repaired when necessary through the Modulated Quantum Bio‐Electromagnetic Waves. At peak performance, the immune system is the primary defense against any disease.

Dynamic Coherence of ∑ Quantum BEME Human Physiological System

Figure 1

Dynamic influences of biophotonic influences of food,nutrient, and water on the organisms master systems.

Figure 2
The Binuclear Transport Center of ZupT: A Zinc Transporter from E. coli
Authors: Roberts Cameron , Mitra Bharati
Published: April 2020

ZupT is a member of the ZIP family of transporters which are responsible for increasing the intracellular concentration of zinc from E. coli to humans. Defects in these transporters are linked to zinc deficiency, cancer, and cardiovascular disease. The mechanism of transport in this family is still not well‐understood, partly due to the bottleneck in the expression and purification of these integral membrane proteins. Recently a structure was solved of a ZIP transporter from B. bronchiseptica. The structure revealed a cadmium binuclear metal transport site, which is relatively uncommon for metal transporters. Using the crystal structure, a homology model was built for ZupT which shares 32% identity and a conserved binuclear center. In the ZupT model the metal ions are separated by roughly 4.2 A and coordinated by a bidentate Glu123 (orange). His148 and Glu152 round out site 1 (red) and Asn120, Asn149, and Glu181 site 2 (yellow). In this work, solution studies including competitive metal titrations were carried out with purified ZupT. Our results show that ZupT binds one equivalent of zinc, its primary substrate, at physiological concentrations. In contrast, it binds two equivalents of iron, a secondary substrate. Site directed mutagenesis was carried out to determine which residues are important in coordinating zinc and iron. Zinc and iron both bind to a ‘primary’ transport site (site 1‐red), while iron also binds to a secondary site (site 2‐yellow). Activity assays were used to determine the relationship between binding and function. ZupT showed transport activity with both iron and zinc; additionally, it was observed that iron positively regulated zinc activity. Our results also indicated that the highly conserved residue His119 (blue) is not essential for binding of either zinc or iron, but is important for overall transport activity, probably by facilitating metal release. Overall these results show that ZIP transporters have a single zinc transport site which can be regulated by iron binding to an adjacent secondary site.

Binuclear metal center of ZupT.

Utilizing the crystal structure of ZIPB from B. bronchiseptica a homology model was made with the SWISS‐MODEL server. Visualization of the binculear center was carried out with UCSF CHIMERA.

Figure 1
Hepatic Tumour Cell Reduction with Quanta Energy – a Technological Exploration and Expanded Mathematical Model.
Authors: Rahman Michael S. , Einstein George P. , Tulp Orien P. , Koynk Carla
Published: April 2020

Manley (2014) developed several mathematical models based on the CSC concept that not only explain the growth of a tumour, but also its demise based on the applied radiation energy. If a population A of CSCs divide asymmetrically, they will yield one daughter cell of type A and one cancer cell of type B. The speed with which new type B cells emerge depends on the number of A cells – if there are 100 A cells, 100 B cells will emerge in a given unit of time; if the number of A cells is 200, 200 B cells will emerge in the same time window, twice as many as before. Therefore, one can model the growth or increase in numbers of B cells. which allows us to model the growth of B as differential equation. The basic form of this model has the number of CSCs (type A) constant, while the increase in differentiated tumor cells (type B) grows.

In other words, the population of cancer cells grows linearly. One can introduce further parameters into this simple equation and distinguish between cancer stem cells A, differentiated tumour cells B and healthy cells H.

If we further irradiate cells with energy from X‐rays, proton beams, or light of visible spectrum, photodynamic therapy (PDT) or invisible UV; there will have likely different effects on each cell type A, B and H. Manley (2014) established the following formulas with r1, r2 and r3 as specific effects of radiation or PDT on each of the cell types, the equation in diagram 1 is established.

Where S is the desired number of stem cells, and M1 and M2 are the carrying capacity of B and H cells, respectively (Manley, 2014).

If we use different assumptions for the parameters in these equations, we can come up with different long term behaviors of the cell lines. The most desirable situation is one in which the number of healthy cells remains constant, while the CSCs and tumor cells are reaching a number near zero. This would mean shrinkage of the tumor without affecting healthy tissue.

The different ri values are effects the radiation energy will have on each cell type; one should be able to derive the effect from the wavelength or frequency of the used radiation, but the relationship is not entirely clear. The energy of one quantum of energy can be described using the classic equation of light and quanta.

with c as the speed of light (c = 2.998 × 108 m/s) and h as Planck constant (h = 6.626 × 10−34 m2 kg/s. Since the above equations for dA/dt, dB/dt and dH/dt are all describing the total change in cell numbers as influenced or determined by time, r1, r2 and r3 must represent the number of cells that die off by application of energy with radiation of a certain frequency or wavelength in the visible or invisible spectrum of light. Importantly, cells may not be damaged if the radiation that we use to illuminate them with has a frequency that is too low.

Simple model of linear tumour growth

Figure 1

GP Einstein Sigma Quanta tumor growth and development model

Figure 2
Fumarate Reduced Mean Arterial Blood Pressure and Improved Renal Outcomes in DOCA/salt Hypertension
Authors: Edosuyi Osaze , Igbe Ighodaro , Choi Myung , Oyekan Adebayo
Published: April 2020

The mitochondria, through the tricarboxylic (TCA) acid cycle, converts organic molecules into energy that drives intricate renal blood‐pressure regulatory functions. The TCA cycle intermediaries regulate the metabolic state of the mitochondria and by extension, the redox status of the cell. Recently, fumarase, a major TCA cycle enzyme that converts fumarate to malate, has been linked to L‐arginine metabolism and implicated in the pathophysiology of Dahl‐salt sensitive hypertension. This study aimed to investigate the role of fumarase and L‐arginine in deoxycorticosterone (DOCA)/salt hypertension, a non‐genetic model of hypertension. Hypertension was induced in uninephrectomised rats with DOCA (25 mg/kg) + 1 % NaCL. Mean arterial blood pressure was measured in conscious rats via carotid cannulation. Biochemical and western blot analyses were carried out on homogenized kidney fractions. Fumarate reduced arterial blood pressure (198±5 vs 167±7 mmHg, P<0.01). There were no changes in urinary output and sodium excretion in fumarate‐treated DOCA rats (P>0.05). Superoxide dismutase and catalase activities were higher in the cortex, but not the medulla of DOCA‐hypertensive rats and were exacerbated by fumarate (P<0.01). There was a selective increase in catalase activity in the medulla of fumarate‐treated DOCA‐hypertensive rats (P<0.01). Fumarate also reduced urinary protein excretion in DOCA‐hypertensive rats (23.6 %, P<0.05). Fumarate evoked a selective increase in nitric oxide in the medulla (34.1±2.9 vs 47.3±2.8 nM/μg, P<0.05) of DOCA‐hypertensive rats. Consistent with this, Fumarate also tended to increase arginase activity in the cortex but not the medulla of DOCA‐hypertensive rats. However, there was an increase in expression TGF‐β, an index of fibrosis, in DOCA‐hypertensive rats, which was paradoxically increased in fumarate‐treated rats (P>0.05). In conclusion, fumarate attenuated the hypertension and renal injury but not the fibrosis in DOCA/salt hypertension by mechanisms involving selective reduction of L‐arginine metabolism in the medulla and amelioration of renal oxidative stress.

Support or Funding Information

National Institute of Health grant HL03674 and G12 MD0076056

Mean arterial blood changes after 21‐day administration of fumarate to DOCA/salt induced hypertensive rats. Control (n=8), DOCA (n=8), fumarate (n=8). a=P<0.001 when compared to control; b=P<0.01 when compared to DOCA group.

Figure 1

Nitric oxide produced in homogenized kidneys (cortex and medulla) of DOCA salt induced hypertensive rats after 21‐day fumarate (1 mg/kg) administrationa=P<0.05 when compared to control.

Figure 2
Prolotherapy upregulates Fibroblast Growth Factor‐2 (FGF‐2) and Insulin‐like Growth Factor‐1 (IGF‐1) mRNA which may increase chondrocyte proliferation and mediates osteoarthritic inflammation
Authors: Johnston Elisha Daniel , Emani Chandrakanth
Published: April 2020

Osteoarthritis is a highly prevalent disease that is progressively generated and has no known cure. Current treatments, such as opioids, have highly adverse effects. A more effective treatment can be the form of proliferative therapy (prolotherapy), a complementary medical intervention with promising clinical evidence. The purpose of the present study is to investigate the molecular basis of prolotherapy as a treatment option for osteoarthritis. Specifically, the study investigates whether prolotherapy upregulates proliferation‐enhancing cytokines (FGF‐2 and IGF‐1) in chondroprogenitor cells. In vitro stimulation of chondroprogenitor cells was carried out with prolotherapy treatment followed by qRT‐PCR quantification to determine the mRNA expression of the genes FGF‐2, IGF‐1, CCND‐1, TGF‐β1, AKT, STAT1, and BMP2. Results indicated a likely upregulation of cytokines that enhanced cell proliferation in chondroprogenitor cells with statistically higher levels of expression for FGF‐2 (p<0.001, p<0.05, p<0.01), IGF‐1 (p<0.001), and CCND‐1 (p<0.05) relative to controls. Results in conjunction with prolotherapy and molecular‐focused inflammation theory suggest that prolotherapy has the potential to transform chondroprogenitor cells that are dysregulated by osteoarthritic inflammation. This would contribute to cartilage degradation back into chondroprogenitor cells that proliferate and balance catabolic/anabolic roles to repair and maintain cartilage.

P2G (1.5%) upregulates FGF‐2 mRNA expression in chondroprogenitor cells. A Exploratory Trial 1 suggests P2G effects FGF‐2 gene expression (Welch’s one‐way ANOVA, p<0.01). B Confirmatory Trial 2 indicates that relative to time‐specific controls, chondrocytes treated with P2G exhibit increased levels of FGF‐2 at hours 24, 30, and 38 (Welch’s t‐tests yield p<0.001, p<0.05, and p<0.01). qRT‐PCR quantifies mRNA expression. NS p>0.05, * p<0.05, ** p<0.01, *** p<0.001

Figure 1

P2G (1.5%) upregulates CCND‐1 (Cyclin D) mRNA expression at hour 30 in chondroprogenitor cells in the confirmatory Trial 2 (directional Welch’s t‐test yields p<0.05). CCND‐1 mRNA upregulation at hour 30 suggests subsequent entry chondroprogenitor cell proliferation. qRT‐PCR quantifies mRNA expression. NS p>0.05, * p<0.05, ** p<0.01, *** p<0.001

Figure 2
Oligomerization of VDAC1 promotes mtDNA release and lupus‐like disease
Authors: Kim Jeonghan
Published: April 2020

Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, triggering immunostimulatory pathways such as the type‐Ι interferon response. Pores formed in the outer membrane of mitochondria (OMM) can promote mtDNA release; however, the identity of such a pore in living cells is not well characterized. Here, we provide genetic and biochemical evidence demonstrating that the oligomerization of voltage‐dependent anion channel 1 (VDAC1) in the OMM promotes mtDNA release and triggers the type‐Ι interferon response in living cells. In addition to forming OMM pores, VDAC1 interacts with mtDNA via its positively charged residues in the N‐terminal domain and increases both VDAC1 oligomerization and type‐Ι interferon response. VBIT‐4, which inhibits VDAC1 oligomerization, decreases mtDNA release, type‐Ι interferon signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus. These findings suggest that VDAC1 oligomerization is a potential therapeutic target for lupus.

Support or Funding Information

Supported by the Intramural Research Program of the National Heart Lung and Blood Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases and by a grant from the National Institute for Biotechnology in the Negev (V.S.‐B.) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number HI14C1176) and a grant from the KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea.

VDAC oligomers form mitochondrial pores to release mtDNA fragments.

Figure 1
Discovery and Quantitative Analysis of Nuclear Factor Erythroid 2‐Related Factor (Nrf2) Activators in Maca (Lepidium meyenii) Using the Synthetic Macamides
Authors: Hahn Dongyup , Lee Mijeong , Jeong Hyeyoon , Kim Jaewon , Kim Minyoul
Published: April 2020

Maca (Lepidium meyenii) is a biennial herbaceous plant of family Brassicaceae with various bioactivities such as reproductive health enhancement, antifatigue, antioxidation, neuroprotection, anticancer, hepatoprotection, and immunomodulation. But studies on molecular mechanisms beyond the phenomenal physiology are rare because the putative bioactive chemical constituents, macamides, a series of unique N‐benzylamides with long‐chain fatty acids are difficult to isolate from the natural maca specimen. In this study, ten macamides were chemically synthesized to investigate biological mechanisms underlying the various bioactivities. Three of macamides exhibited moderate nuclear factor erythroid 2‐related factor 2 (Nrf2) activation was observed from cell‐based assay (EC50 7.3–16.5 μM), which might account for some of the known bioactivities of maca. Quantitative analysis of macamide compositions in maca specimen using LC‐MS/MS was followed, which revealed the macamides with Nrf2 activation activity consist the majority among macamides contained in maca. The difference in composition of macamides among three cultivars, yellow, red and black macas was also examined.

Support or Funding Information

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (2019R1F1A1051041).

Chemical synthesis of macamides

Figure 1
Withdrawn: Invisible State of MdmX and Design of its Inhibitors
Authors: Cheng Xiyao , Huang Yongqi , Su Zhengding
Published: April 2020

Withdrawal: Xiyao Cheng, Yongqi Huang, and Zhengding Su. Invisible State of MdmX and Design of its Inhibitors. The FASEB Journal. 34:s1. doi: 10.1096/fasebj.2020.34.s1.09193.

The above abstract, published online on April 20, 2020, in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the authors, FASEB, and Wiley Periodicals, Inc. The abstract has been withdrawn at the request of the authors.
Cyp2j5‐gene Deletion Affects on Acetylcholine and Adenosine‐induced Relaxation in Mice: Role of Angiotensin‐II, CYP‐epoxygenase and Omega‐hydroxylase inhibitors
Authors: Agba Stephanie O. , Hanif Ahmed , Edin Matthew L. , Zeldin Darryl C. , Mohammed Nayeem A.
Published: April 2020

Previously, we showed vascular endothelial overexpression of human‐CYP2J2 enhances coronary reactive hyperemia in Tie2‐CYP2J2 Tr mice, but we did not see the response in CYP2J‐epoxygenase knockout mice. Therefore, we hypothesized that Cyp2j5‐gene deletion affects acetylcholine‐, NECA (adenosine)‐and CGS 21680 (adenosine A2A receptor)‐induced relaxation and their response is partially inhibited by angiotensin‐II (Ang‐II) and ω‐hydroxylase inhibitor in mice. ACh‐induced response was tested with N‐(methylsulfonyl)‐2‐(2‐propynyloxy)‐benzenehexanamide (MS‐PPOH, CYP‐epoxygenase inhibitor; 10–5M) and Ang‐II (10‐6M). In Cyp2j5−/− mice, ACh‐induced relaxation was different from C57Bl/6 mice, at 10‐5 M (76.1 ± 3.3 vs. 58.3 ± 5.2, P<0.05). However, ACh‐induced relaxation was not blocked by MS‐PPOH in Cyp2j5−/−: 58.5 ± 5.0%, P>0.05, but blocked in C57Bl/6: 52.3 ± 7.5%, P<0.05, and Ang‐II reduces ACh‐induced relaxation in both Cyp2j5−/− and C57Bl/6 mice (38.8 ± 3.9% and 45.9 ± 7.8, P <0.05). In addition, NECA‐induced response tested with Ang‐II and 20‐HETE inhibitor, dibromo‐dodecenyl‐methylsulfimide (DDMS, 10‐5M). In Cyp2j5−/− mice, NECA‐induced response was not different from C57Bl/6 mice at 10‐5M (23.1 ± 2.1 vs. 21.1 ± 3.8, P>0.05). However, NECA‐induced response was reduced by Ang‐II in both Cyp2j5−/− and C57Bl/6 mice (−10.8 ± 2.3% and 3.2 ± 2.7, P <0.05), and the reduced response due to Ang‐II was partially rescued by DDMS in both Cyp2j5−/− and C57Bl/6 mice (at 10‐5M, A2AAR‐agonist, CGS‐21680, 15.8 ± 3.4% and 13.0 ± 2.3, P <0.05). Data suggest that ACh‐induced relaxation in Cyp2j5−/− mice depends on nitric oxide (NO) but not CYP‐epoxygenases, and the NECA‐induced different response in male vs. female Cyp2j5−/− mice when Ang‐II treated.

Support or Funding Information

National Institutes of Health (HL‐114559) to M. A. Nayeem and the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01 ES025034) to D. C. Zeldin supported this work.

Flow diagram: Comparison between Cyp2j5−/− vs. C57Bl/6 mice treated with Acetylcholine, Acetylcholine + MS‐PPOH, Acetylcholine + Ang‐II, NECA, NECA + Ang‐II and CGS 21680 + DDMS + Ang‐II.

Figure 1
Effects of Jwagwieum on Renal Dysfunction in Ischemia/Reperfusion‐induced Acute Renal Failure in Rats
Authors: Na Se Won , Kim Hye Yoom , Ahn You Mee , Hong Mi Hyeon , Jang Youn Jae , Lee Ho Sub , Kang Dae Gill
Published: April 2020

Jwagwieum (
, JGE), a Korean traditional medicine, has been used for treatment of kidney‐yin deficient (
) syndrome. However, there is no pharmacological study of JGE on ischemia/reperfusion‐induced acute renal failure (ARF). Therefore, the objective of this study was to evaluate whether JGE ameliorates renal function and its related mechanism in acute kidney injury‐induced by ischemia/reperfusion in rats. In this experiment, 5‐week‐old male Sprague Dawley (SD) rats were used under 12 h light and dark cycle. After a week of adaptation, they were randomly divided into following groups. 1) Cont. (Control), 2) ischemia/reperfusion injury (ARF), 3) ARF + JGE100 (100 mg/kg/day), 4) ARF + JGE200 (200 mg/kg/day). The ARF group was subjected to reperfusion after inserting a clip into the renal artery for 45 min. ARF + JGE100 group was orally administered with JGE 100 mg/kg/day after ischemia/reperfusion surgery, and ARF + JGE200 group was orally administered with JGE 200 mg/kg/day for 4 days, respectively. As a result, JGE suppressed the increase of kidney size in the acute renal failure animal model and alleviated polyuria symptoms. In addition, solute‐free water reabsorption (TcH2O) and creatinine clearance (Ccr), indicators of glomerular filtration rate, were significantly increased in JGE group compared with those of ARF rats. In ARF group, blood urea nitrogen (BUN)/creatinine (Cr) and lactate dehydrogenase (LDH) were significantly increased compared to the control group, respectively, while they were significantly decreased in JGE group. The present results also showed that JGE improved the morphological aspects of renal tissue and ameliorated fibrosis in ARF group. Inflammation is one of the main causes of ischemic acute kidney injury and was inhibited by JGE, which was confirmed by the NLRP3 inflammasome decline.

The present results showed that JGE has protective effects against inflammatory process via inhibition of NLRP3 signal pathway, which is associated with improvement of renal function in rats with ARF. These results suggest that JGE has a therapeutic effect on acute kidney injury‐induced by ischemia/reperfusion in rats.

Support or Funding Information

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2017R1A5A2015805)(2015M3A9A5030620)(2017R1A2B4009884).