A Possible Antineoplastic Potential of Selective,Irreversible Proteasome Inhibitor,Carfilzomib on Chemically Induced Hepatocarcinogenesis in Rats

The antineoplastic effect of carfilzomib (CFZ) against chemically induced hepatocarcinogenesis was studied. A total of 60 male Wistar albino rats were divided into six groups with 10 animals in each group. Rats in group 1 (control group) were given dimethylsulphoxide (DMSO) (0.4 mL/kg i.p) twice a week for 3 weeks from week 8 to week 10. Animals in groups 2 and 3 were given CFZ (2 and 4 mg/kg i.p) twice a week from week 8 to week 10, respectively. Rats in group 4 were given diethylnitrosamine (DENA) at a dose of 0.01% in drinking water for 10 weeks and received a DMSO (0.4 mL/kg i.p) twice a week from week 8 to week 10. Animals in groups 5 and 6 were given DENA at a dose of 0.01% in drinking water for 10 weeks and treated with CFZ (2 and 4 mg/kg i.p) twice a week from week 8 to week 10, respectively. CFZ succeeded in suppressing the elevated serum tumor marker α‐fetoprotein and carcinoembryonic antigen. The antineoplastic effect of CFZ was also accompanied by normalization of elevated hepatic tissue growth factors, matrix metalloproteinase‐2 and tissue inhibitor of metalloproteinase‐1, and augmentation of hepatic endostatin and metallothionein. A histopathological examination of liver samples treated with CFZ after DENA intoxication correlated with the biochemical observation. Treatment with CFZ confers an antineoplastic activity against chemically induced hepatocarcinogenesis. These findings suggest that CFZ plays a pivotal role in the treatment of hepatocarcinogenesis.     

The Role of Resting State Networks in Focal Neocortical Seizures

Objective

The role of resting state functional networks in epilepsy is incompletely understood. While some pathologic diagnoses have been shown to have maintained but altered resting state connectivity, others have implicated resting state connectivity in disease progression. However little is known about how these resting state networks influence the behavior of a focal neocortical seizure.

Methods

Using data taken from invasively monitored patients with intractable focal neocortical epilepsy, we evaluated network connectivity (as determined by oscillatory covariance of the slow cortical potential (<0.5 Hz)) as it relates to neocortical seizure foci both in the interictal and ictal states.

Results

Similar to what has been shown in the past for sleep and anesthesia, electophysiologic resting state networks that are defined by this slow cortical potential covariance maintain their topographic correlation structure throughout an ictal event. Moreover, in the context of focal epilepsy in which the seizure has a specific site of onset, seizure propagation is not chaotic or random. Rather, the seizure (reflected by an elevation of high frequency power) preferentially propagates along the network that contains the seizure onset zone.

Significance

Taken together, these findings further undergird the fundamental role of resting state networks, provide novel insights into the network-influenced behavior of seizures, and potentially identify additional targets for surgical disconnection including informing the location for the completion of multiple subpial transections (MSPTs).     

The relationship between antiglycation activity and procyanidin and phenolic content in commercial grape seed products

Eight commercial grape seed products (GSPs) were assessed for their inhibition of the formation of advanced glycation end-products in vitro. All 8 commercial GSPs included in this study were potent inhibitors of advanced glycation end-product formation with IC(50) values ranging from 2.93 to 20.0?μg/mL. Total procyanidin content ranged from 60% to 73%. HPLC-DAD-ELSD results indicate that (+)-catechin, (-)-epicatechin, procyanidin B1, and procyanidin B2 were predominant and ubiquitously present in all the products under study, while gallic acid and procyanidin B4 were present in relatively minor amounts. The IC(50) values correlated with total phenolic content, and multiple regression analysis indicated that IC(50) is a linear function of the concentration of gallic acid and procyanidins B1, B2, and B4. Based on this study, GSPs have the potential to complement conventional diabetes medication toward disease management and prevention.     

Possible role of exosomes containing RNA in mediating nontargeted effect of ionizing radiation

Communication between irradiated and un-irradiated (bystander) cells can cause damage in cells that are not directly targeted by ionizing radiation, a process known as the bystander effect. Bystander effects can also lead to chromosomal/genomic instability within the progeny of bystander cells, similar to the progeny of directly irradiated cells. The factors that mediate this cellular communication can be transferred between cells via gap junctions or released into the extracellular media following irradiation, but their nature has not been fully characterized. In this study we tested the hypothesis that the bystander effect mediator contains an RNA molecule that may be carried by exosomes. MCF7 cells were irradiated with 2 Gy of X rays and the extracellular media was harvested. RNase treatment abrogated the ability of the media to induce early and late chromosomal damage in bystander cells. Furthermore, treatment of bystander cells with exosomes isolated from this media increased the levels of genomic damage. These results suggest that the bystander effect, and genomic instability, are at least in part mediated by exosomes and implicate a role for RNA.     

Characterization of mutations causing rifampicin and isoniazid resistance of Mycobacterium tuberculosis in Syria

In order to characterize mutations causing rifampicin and isoniazid resistance of M. tuberculosis in Syria, 69 rifampicin resistant (Rif(r)) and 72 isoniazid resistant (Inh(r)) isolates were screened for point mutations in hot spots of the rpoB, katG and inhA genes by DNA sequencing and real time PCR. Of 69 Rif(r) isolates, 62 (90%) had mutations in the rifampin resistance determining region (RRDR) of the rpoB gene, with codons 531 (61%), 526 (13%), and 516 (8.7%) being the most commonly mutated. We found two new mutations (Asp516Thr and Ser531Gly) described for the first time in the rpoB-RRDR in association with rifampicin resistance. Only one mutation (Ile572Phe) was found outside the rpoB-RRDR. Of 72 Inh(r) strains, 30 (41.6%) had a mutation in katGcodon315 (with Ser315Thr being the predominant alteration), and 23 (32%) harbored the inhA(-15C-->T) mutation. While the general pattern of rpoB-RRDR and katG mutations reflected those found worldwide, the prevalence of the inhA(-15C-->T mutation was above the value found in most other countries, emphasizing the great importance of testing the inhA(-15C-->T) mutation for prediction of isoniazid resistance in Syria. Sensitivity of a rapid test using real time PCR and 3'-Minor groove binder (MGB) probes in detecting Rif(r) and Inh(r) isolates was 90% and 69.4%, respectively. This demonstrates that a small set of MGB-probes can be used in real time PCR in order to detect most mutations causing resistance to rifampicin and isoniazid.     

Applying digital technology to promote active and healthy confinement lifestyle during pandemics in the elderly

Although recognized as effective measures to curb the spread of the COVID19 outbreak, social distancing and home confinement have generated a mental health burden with older adults who are considered to be more vulnerable to psychosocial strains. To date, the application of digital technologies in response to COVID-19 pandemic has been narrowed to public-health needs related to containment and mitigation. However, information and communications technology (ICT)-based initiatives directed toward prediction and prevention of psychosocial support are still limited. Given the power of digital health solutions to allow easy and accurate characterization and intervention for health and disease, as well as to flatten the COVID19 incidence curves in many countries, our ECLB-COVID19 consortium is highlighting the importance of providing innovative ICT-based solutions (ICT-COVID-Companion) to improve elderly physical and mental health, thereby preventing/dampening psychosocial strain during pandemics. Based on innovative approaches (e.g., emotional/social computing, open social platform, interactive coaching, gamification, fitness-tracker, internet of things) and smart digital solutions (smartwatch/smartphone), smart companions must provide safe personalised physical, mental and psychosocial health surveillance. Additionally, by delivering personalised multi-dimension crisis-oriented health recommendations, such innovative crisis-oriented solutions would help (i) facilitate a user’s adherence to active and healthy confinement lifestyle (AHCL), (ii) achieve a rapid psychosocial recovery in case of depression issues and (iii) enhance preparedness for eventual future pandemics.     

Root growth and lignification of two wheat species differing in their sensitivity to NaCl, in response to salt stress

Application of a 100-mM NaCl salt stress to wheat seedlings of a salt-tolerant (Triticum durum var. Ben Béchir) and a salt-sensitive (Triticum aestivum var. Tanit) species decreases the fresh and dry weights of roots especially in the salt-sensitive species, and slightly increases the ratio of dry to fresh weight, especially in the salt-resistant species. All peroxidase activities are increased by salt stress, the water-soluble peroxidase activity being increased much more in the salt-sensitive than in the salt-tolerant species, while the opposite result is observed with the cell-wall peroxidase activity. Some water-soluble peroxidases have been hypothesised to have auxin oxidase activity (which might explain the effect observed on the root biomass), while the cell-wall peroxidases would be involved in lignification. Histochemical observation confirms a more intense lignification in the root cells of the salt-tolerant species compared to the sensitive species, under the effect of NaCl.     

Glutathione and phytochelatin contents in tomato plants exposed to cadmium

The effect of cadmium on growth and contents of glutathione (GSH) and phytochelatins (PCs) were investigated in roots and leaves of tomato plants (Lycopersicon esculentum Mill. cv. 63/5 F1). The accumulation of Cd increased with external Cd concentrations and was considerably higher in roots than in leaves. Dry mass production decreased under Cd treatment especially in leaves. In both roots and leaves, exposure to Cd caused an appreciable decline in GSH contents and increase in PCs synthesis proportional to Cd concentrations in the growth medium. At the same Cd concentration, PCs production was higher in roots than in leaves. The implication of glutathione in PC synthesis was strongly suggested by the use of buthionine sulfoximine (BSO). The major fraction of Cd accumulated by tomato roots was in the form of a Cd-PCs complex.     

Angiotensin 1–7 prevents the excessive force loss resulting from 14- and 28-day denervation in mouse EDL and soleus muscle

Denervation leads to muscle atrophy, which is described as muscle mass and force loss, the latter exceeding expectation from mass loss. The objective of this study was to determine the efficiency of angiotensin (Ang) 1–7 at reducing muscle atrophy in mouse extensor digitorum longus (EDL) and soleus following 14- and 28-d denervation periods. Some denervated mice were treated with Ang 1–7 or diminazene aceturate (DIZE), an ACE2 activator, to increase Ang 1–7 levels. Ang 1–7/DIZE treatment had little effect on muscle mass loss and fiber cross-sectional area reduction. Ang 1–7 and DIZE fully prevented the loss of tetanic force normalized to cross-sectional area and accentuated the increase in twitch force in denervated muscle. However, they did not prevent the shift of the force–frequency relationship toward lower stimulation frequencies. The Ang 1–7/DIZE effects on twitch and tetanic force were completely blocked by A779, a MasR antagonist, and were not observed in MasR^−/− muscles. Ang 1–7 reduced the extent of membrane depolarization, fully prevented the loss of membrane excitability, and maintained the action potential overshoot in denervated muscles. Ang 1–7 had no effect on the changes in α-actin, myosin, or MuRF-1, atrogin-1 protein content or the content of total or phosphorylated Akt, S6, and 4EPB. This is the first study that provides evidence that Ang 1–7 maintains normal muscle function in terms of maximum force and membrane excitability during 14- and 28-d periods after denervation.