Category Archives: BioFactors

Promotion of degradative autophagy by 6‐bromoindirubin‐3′‐oxime attenuates neuropathy

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Promotion of degradative autophagy by 6-bromoindirubin-3′-oxime attenuates neuropathy

Tunicamycin increases peripheral neuropathy subsequently treatment with 6-BIO reduces peripheral neuropathy and increases degradative autophagy and reduces secretory autophagy.


Abstract

Damage to the central or peripheral nervous system causes neuropathic pain. Endoplasmic reticulum (ER) stress plays a role in peripheral neuropathy. Increase in ER stress is seen in diabetic neuropathy. Inducers of ER stress also give rise to peripheral neuropathy. ER stress leads to the formation of autophagosome but as their degradation is also stalled during ER stress accumulation of autophagosomes is seen. Accumulation of autophagosomes has deleterious effects on cells. In the present study, we show that treatment with tunicamycin (TM) (ER stress inducer) in mice leads to peripheral neuropathy as assessed by Von Frey and Hot plate method. Administration of a promoter of autophagy viz. 6-bromoindirubin-3′-oxime (6-BIO) subsequent to ER stress induced by TM exhibits a decrease in peripheral neuropathy. 6-BIO was also effective in reducing diabetic peripheral neuropathy. To understand the type of autophagy activated, SH-SY5Y cells were treated with 6-BIO after TM treatment. Levels of cathepsin D (CTSD), a marker for degradative autophagy was higher in cells treated with 6-BIO after TM treatment compared to only TM-treated SH-SY5Y cells while levels of Rab8A,—a marker for secretory autophagy was reduced. Furthermore, in parallel during ER stress secretory, we noted increased levels of lysozyme in autophagosomes destined for secretion. Cells treated with 6-BIO showed reduction of lysozyme in secretory autophagosomes. This shows that 6-BIO increased degradative autophagy and reduced the secretory autophagy. 6-BIO also reduced the caspase-3 activity in 6-BIO-treated cells. Thus, 6-BIO reduced neuropathy in animals by activating degradative autophagy and reducing the secretory autophagy.

Stachydrine, N‐acetylornithine and trimethylamine N‐oxide levels as candidate milk biomarkers of maternal consumption of an obesogenic diet during lactation

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Stachydrine, N-acetylornithine and trimethylamine N-oxide levels as candidate milk biomarkers of maternal consumption of an obesogenic diet during lactation

Reverting to a healthy maternal diet during lactation normalizes the altered milk metabolome found in obese rats. Stachydrine, N-acetylornithine and TMAO levels are proposed as candidate biomarkers of maternal consumption of an obesogenic diet during lactation.


Abstract

We aimed to evaluate whether improving maternal diet during lactation in diet-induced obese rats reverts the impact of western diet (WD) consumption on the metabolome of milk and offspring plasma, as well as to identify potential biomarkers of these conditions. Three groups of dams were followed: control-dams (CON-dams), fed with standard diet (SD); WD-dams, fed with WD prior and during gestation and lactation; and reversion-dams (REV-dams), fed as WD-dams but moved to SD during lactation. Metabolomic analysis was performed in milk at lactation days 5, 10, and 15, and in plasma from their male and female offspring at postnatal day 15. Milk of WD-dams presented, throughout lactation and compared to CON-dams, altered profiles of amino acids and of the carnitine pool, accompanied by changes in other polar metabolites, being stachydrine, N-acetylornithine, and trimethylamine N-oxide the most relevant and discriminatory metabolites between groups. The plasma metabolome profile was also altered in the offspring of WD-dams in a sex-dependent manner, and stachydrine, ergothioneine and the acylcarnitine C12:1 appeared as the top three most discriminating metabolites in both sexes. Metabolomic changes were largely normalized to control levels both in the milk of REV-dams and in the plasma of their offspring. We have identified a set of polar metabolites in maternal milk and in the plasma of the offspring whose alterations may indicate maternal intake of an unbalanced diet during gestation and lactation. Levels of these metabolites may also reflect the beneficial effects of implementing a healthier diet during lactation.

The anticancer/cytotoxic effect of a novel gallic acid derivative in non‐small cell lung carcinoma A549 cells and peripheral blood mononuclear cells from healthy individuals and lung cancer patients

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The anticancer/cytotoxic effect of a novel gallic acid derivative in non-small cell lung carcinoma A549 cells and peripheral blood mononuclear cells from healthy individuals and lung cancer patients

This article presents a series of novel derivatives from gallic acid with antioxidant / anticancer properties. These compounds were studied on lymphocytes from healthy individuals and lung cancer patients. Also, gallic acid and its derivatives were examined on non-small cell carcinoma cell line. The anticancer effect of these compounds was revealed which should be confirmed with further future investigations.


Abstract

Gallic acid (GA) is a naturally occurring polyphenol with a strong antioxidant capacity. GA stimulates the apoptosis of cancer cells, thereby suppressing cancer cell invasion. However, the low oral permeability of GA limits its therapeutic use. In order to enhance the antioxidant capacity and oral permeability of GA, a series of compounds analogous to GA were synthesized: 4-methoxybenzenesulfonamide (MBS), 3,4-dimethoxybenzenesulfonamide (DMBS) and 3,4,5-trimethoxybenzenesulfonamide (TMBS). In the new compounds, hydroxyl groups were replaced with various numbers of methoxy groups (stronger electron-donating groups), to increase hydrophobicity and oral permeability compared to GA. In addition, the carboxylic group was replaced with a sulfonyl group (a stronger electron-withdrawing group), to increase the molecular polarity and antioxidative activities of the compounds. The cell counting kit-8 (CCK-8) assay was used to detect the effect of GA, MBS, DMBS, and TMBS on cell proliferation and apoptosis in peripheral blood mononuclear cells (PBMCs) from healthy individuals and non-small cell lung carcinoma A549 cells. Additionally, the comet assay was used to assess the genotoxicity of these compounds in PBMCs from healthy individuals, lung cancer patients, and A549 cells. Compared to untreated cells, TMBS reduced DNA damage more effectively than GA in PBMCs from lung cancer patients and healthy donors. Furthermore, in comparison to GA, TMBS was more cytotoxic in A549 cells. Moreover, TMBS was not cytotoxic in healthy PBMCs, suggesting that TMBS demonstrates therapeutic potential in cancer.

Insights into the antiosteoporotic mechanism of the soy‐derived isoflavone genistein: Modulation of the Wnt/beta‐catenin signaling

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Insights into the antiosteoporotic mechanism of the soy-derived isoflavone genistein: Modulation of the Wnt/beta-catenin signaling

Glucocorticoid-induced osteoporosis (GIO) reduces bone formation, osteoblasts differentiation and function, and accelerates osteoblast and osteocyte apoptosis. Genistein induces bone remodeling through Wnt/β-catenin pathway activation in osteoblast and osteocytes. Genistein could represent an interesting new therapeutic approach for the management of GIO patients.


Abstract

Bone remodeling is a process that involves osteoblasts, osteoclasts, and osteocytes, and different intracellular signaling, such as the canonical Wnt/β-catenin pathway. Dysregulations of this pathway may also occur during secondary osteoporosis, as in the case of glucocorticoid-induced osteoporosis (GIO), which accelerates osteoblast and osteocyte apoptosis by reducing bone formation, osteoblast differentiation and function, accelerates in turn osteoblast, and osteocyte apoptosis. Genistein is a soy-derived nutrient belonging to the class of isoflavones that reduces bone loss in osteopenic menopausal women, inhibiting bone resorption; however, genistein may also favor bone formation. The aim of this study was to investigate whether estrogen receptor stimulation by genistein might promote osteoblast and osteocyte function during glucocorticoid challenge. Primary osteoblasts, collected from C57BL6/J mice, and MLO-A5 osteocyte cell line were used to reproduce an in vitro model of GIO by adding dexamethasone (1 μM) for 24 h. Cells were then treated with genistein for 24 h and quantitative Polymerase Chain Reaction (qPCR) and western blot were performed to study whether genistein activated the Wnt/β-catenin pathway. Dexamethasone challenge reduced bone formation in primary osteoblasts and bone mineralization in osteocytes; moreover, canonical Wnt/β-catenin pathway was reduced following incubation with dexamethasone in both osteoblasts and osteocytes. Genistein reverted these changes and this effect was mediated by both estrogen receptors α and β. These data suggest that genistein could induce bone remodeling through Wnt/β-catenin pathway activation.

Nifuroxazide repurposing for protection from diabetes‐induced retinal injury in rats: Implication of oxidative stress and JAK/STAT3 axis

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Nifuroxazide repurposing for protection from diabetes-induced retinal injury in rats: Implication of oxidative stress and JAK/STAT3 axis

Nifuroxazide (Nifu), the potent STAT3 inhibitor successfully protected the diabetic rats against diabetic retinopathy as it ameliorated the retinal structure deterioration. This effect could be attributed to modulating JAK/STAT3 axis and oxidative stress.


Abstract

The prevalence of diabetes mellitus (DM) is alarmingly increasing worldwide. Diabetic retinopathy (DR) is a prevailing DM microvascular complication, representing the major cause of blindness in working-age population. Inflammation is a crucial player in DR pathogenesis. JAK/STAT3 axis is a pleotropic cascade that modulates diverse inflammatory events. Nifuroxazide (Nifu) is a commonly used oral antibiotic with reported JAK/STAT3 inhibition activity. The present study investigated the potential protective effect of Nifu against diabetes-induced retinal injury. Effect of Nifu on oxidative stress, JAK/STAT3 axis and downstream inflammatory mediators has been also studied. Diabetes was induced in Sprague Dawley rats by single intraperitoneal injection of streptozotocin (50 mg/kg). Animals were assigned into four groups: normal, Nifu control, DM, and DM + Nifu. Nifu was orally administrated at 25 mg/kg/day for 8 weeks. The effects of Nifu on oxidative stress, JAK/STAT3 axis proteins, inflammatory factors, tight junction proteins, histological, and ultrastructural alterations were evaluated using spectrophotometry, gene and protein analyses, and histological studies. Nifu administration to diabetic rats attenuated histopathological and signs of retinal injury. Additionally, Nifu attenuated retinal oxidative stress, inhibited JAK and STAT3 phosphorylation, augmented the expression of STAT3 signaling inhibitor SOCS3, dampened the expression of transcription factor of inflammation NF-κB, and inflammatory cytokine TNF-α. Collectively, the current study indicated that Nifu alleviated DR progression in diabetic rats, suggesting beneficial retino-protective effect. This can be attributed to blocking JAK/STAT3 axis in retinal tissues with subsequent amelioration of oxidative stress and inflammation.

Dietary lithium stimulates female fecundity in Drosophila melanogaster

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Dietary lithium stimulates female fecundity in Drosophila melanogaster

Dietary lithium (0.1–5 mM LiCl) improved the lithium status of the female fruit fly Drosophila melanogaster and substantially increased egg production. These findings were accompanied by alterations in mRNA levels of genes encoding proteins involved with chorion formation and yolk protein biosynthesis, which are essential steps in Drosophila oogenesis. (Image created with BioRender.com).


Abstract

The trace element lithium exerts a versatile bioactivity in humans, to some extend overlapping with in vivo findings in the model organism Drosophila melanogaster. A potentially essential function of lithium in reproduction has been suggested since the 1980s and multiple studies have since been published postulating a regulatory role of lithium in female gametogenesis. However, the impact of lithium on fruit fly egg production has not been at the center of attention to date. In the present study, we report that dietary lithium (0.1–5.0 mM LiCl) substantially improved life time egg production in D. melanogaster w 1118 females, with a maximum increase of plus 45% when supplementing 1.0 mM LiCl. This phenomenon was not observed in the insulin receptor mutant InR E19 , indicating a potential involvement of insulin-like signaling in the lithium-mediated fecundity boost. Analysis of the whole-body and ovarian transcriptome revealed that dietary lithium affects the mRNA levels of genes encoding proteins related to processes of follicular maturation. To the best of our knowledge, this is the first report on dietary lithium acting as an in vivo fecundity stimulant in D. melanogaster, further supporting the suggested benefit of the trace element in female reproduction.

Exploring the therapeutic potential of naturally occurring piceatannol in non‐communicable diseases

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Exploring the therapeutic potential of naturally occurring piceatannol in non-communicable diseases

The natural stilbene Piceatannol is having a promising therapeutic potential for the prevention and treatment of a wide variety of complex human diseases like asthma, cancer, diabetes, and so forth.


Abstract

Piceatannol is a naturally occurring hydroxylated resveratrol analogue that can be found in a variety of fruits and vegetables. It has been documented to have a wide range of beneficial effects, including anti-inflammatory, antioxidant, anti-aging, anti-allergic, antidiabetic, neuroprotective, cardioprotective, and chemopreventive properties. Piceatannol has significantly higher antioxidant activity than resveratrol. Piceatannol has been shown in preclinical studies to have the ability to inhibit or reduce the growth of cancers in various organs such as the brain, breast, lung, colon, cervical, liver, prostate, and skin. However, the bioavailability of Piceatannol is comparatively lower than resveratrol and other stilbenes. Several approaches have been reported in recent years to enhance its bioavailability and biological activity, and clinical trials are required to validate these findings. This review focuses on several aspects of natural stilbene Piceatannol, its chemistry, and its mechanism of action, and its promising therapeutic potential for the prevention and treatment of a wide variety of complex human diseases.

Breast cancer diagnosis and management guided by data augmentation, utilizing an integrated framework of SHAP and random augmentation

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Breast cancer diagnosis and management guided by data augmentation, utilizing an integrated framework of SHAP and random augmentation

The use of SHAP for feature engineering alongside random augmentation for data balancing for the diagnosis of breast cancer (BC) proposed some management strategies for BC before and after diagnosis Developed models that could help in the diagnosis of BC by prediction using various machine learning algorithms.


Abstract

Recent research indicates that early detection of breast cancer (BC) is critical in achieving favorable treatment outcomes and reducing the mortality rate associated with it. With the difficulty in obtaining a balanced dataset that is primarily sourced for the diagnosis of the disease, many researchers have relied on data augmentation techniques, thereby having varying datasets with varying quality and results. The dataset we focused on in this study is crafted from SHapley Additive exPlanations (SHAP)-augmentation and random augmentation (RA) approaches to dealing with imbalanced data. This was carried out on the Wisconsin BC dataset and the effectiveness of this approach to the diagnosis of BC was checked using six machine-learning algorithms. RA synthetically generated some parts of the dataset while SHAP helped in assessing the quality of the attributes, which were selected and used for the training of the models. The result from our analysis shows that the performance of the models used generally increased to more than 3% for most of the models using the dataset obtained by the integration of SHAP and RA. Additionally, after diagnosis, it is important to focus on providing quality care to ensure the best possible outcomes for patients. The need for proper management of the disease state is crucial so as to reduce the recurrence of the disease and other associated complications. Thus the interpretability provided by SHAP enlightens the management strategies in this study focusing on the quality of care given to the patient and how timely the care is.

Gut microbiota contribution to selenium deficiency‐induced gut–liver inflammation

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Gut microbiota contribution to selenium deficiency-induced gut–liver inflammation

Se deficient imbalance the intestinal microbiota. Se deficient effects gut–liver axis via lipopolysaccharide. Lactobacillus reuteri could alleviate selenium deficiency-induced gut–liver axis injury.


Abstract

There is limited knowledge about the factors that drive gut–liver axis changes after selenium (Se) deficiency-induced gut or liver injuries. Thus, we tested Se deficiency in mice to determine its effects on intestinal bacterial balance and whether it induced liver injury. Serum Se concentration, lipopolysaccharide (LPS) level, and liver injury biomarkers were tested using a biochemical method, while pathological changes in the liver and jejunum were observed via hematoxylin and eosin stain, and a fluorescence spectrophotometer was used to evaluate intestinal permeability. Tight junction (TJ)-related and toll-like receptor (TLR) signaling-related pathway genes and proteins were tested using quantitative polymerase chain reaction, western blotting, immunohistochemistry, and 16S ribosomal ribonucleic acid gene-targeted sequencing of jejunum microorganisms. Se deficiency significantly decreased glutathione peroxidase activity and disrupted the intestinal flora, with the most significant effect being a decrease in Lactobacillus reuteri. The expression of TJ-related genes and proteins decreased significantly with increased treatment time, whereas supplementation with Se, fecal microbiota transplantation, or L. reuteri reversed these decreases. Signs of liver injury and LPS content were significantly increased after intestinal flora imbalance or jejunum injury, and the levels of TLR signaling-related genes were significantly increased. The results indicated that Se deficiency disrupted the microbiota balance, decreased the expression of intestinal TJ factors, and increased intestinal permeability. By contrast, LPS increased due to a bacterial imbalance, which may induce inflammatory liver injury via the TLR4 signaling pathway.