Adipose tissue macrophage-derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity.

Management of chronic obesity-associated metabolic disorders is a key challenge for biomedical researchers. During chronic obesity, visceral adipose tissue (VAT) undergoes substantial transformation characterized by a unique lipid-rich hypoxic AT microenvironment which plays a crucial role in VAT dysfunction, leading to insulin resistance (IR) and type 2 diabetes. Here, we demonstrate that obese AT microenvironment triggers the release of miR-210-3p microRNA-loaded extracellular vesicles from adipose tissue macrophages, which disseminate miR-210-3p to neighboring adipocytes, skeletal muscle cells, and hepatocytes through paracrine and endocrine actions, thereby influencing insulin sensitivity. Moreover, EVs collected from Dicer-silenced miR-210-3p-overexpressed bone marrow-derived macrophages induce glucose intolerance and IR in lean mice. Mechanistically, miR-210-3p interacts with the 3'-UTR of GLUT4 mRNA and silences its expression, compromising cellular glucose uptake and insulin sensitivity. Therapeutic inhibition of miR-210-3p in VAT notably rescues high-fat diet-fed mice from obesity-induced systemic glucose intolerance. Thus, targeting adipose tissue macrophage-specific miR-210-3p during obesity could be a promising strategy for managing IR and type 2 diabetes.

Feasibility and acceptability of the use of flash glucose monitoring encountered by Indigenous Australians with type 2 diabetes mellitus: initial experiences from a pilot study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is highly prevalent within the Indigenous Australian community. Novel glucose monitoring technology offers an accurate approach to glycaemic management, providing real-time information on glucose levels and trends. The acceptability and feasibilility of this technology in Indigenous Australians with T2DM has not been investigated. OBJECTIVE: This feasibility phenomenological study aims to understand the experiences of Indigenous Australians with T2DM using flash glucose monitoring (FGM). METHODS: Indigenous Australians with T2DM receiving injectable therapy (n = 8) who used FGM (Abbott Freestyle Libre) for 6-months, as part of a clinical trial, participated in semi-structured interviews. Thematic analysis of the interviews was performed using NVivo12 Plus qualitative data analysis software (QSR International). RESULTS: Six major themes emerged: 1) FGM was highly acceptable to the individual; 2) FGM's convenience was its biggest benefit; 3) data from FGM was a tool to modify lifestyle choices; 4) FGM needed to be complemented with health professional support; 5) FGM can be a tool to engage communities in diabetes management; and 6) cost of the device is a barrier to future use. CONCLUSIONS: Indigenous Australians with T2DM had positive experiences with FGM. This study highlights future steps to ensure likelihood of FGM is acceptable and effective within the wider Indigenous Australian community.

Dengue havoc: overview and eco-friendly strategies to forestall the current epidemic.

Dengue fever is a mosquito-borne viral illness that affects over 100 nations around the world, including Africa, America, the Eastern Mediterranean, Southeast Asia, and the Western Pacific. Those who get infected by virus for the second time are at greater risk of having persistent dengue symptoms. Dengue fever has yet to be treated with a long-lasting vaccination or medication. Because of their ease of use, mosquito repellents have become popular as a dengue prevention technique. However, this has resulted in environmental degradation and harm, as well as bioaccumulation and biomagnification of hazardous residues in the ecosystem. Synthetic pesticides have caused a plethora of serious problems that were not foreseen when they were originally introduced. The harm caused by the allopathic medications/synthetic pesticides/chemical mosquito repellents has paved the door to employment of eco-friendly/green approaches in order to reduce dengue cases while protecting the integrity of the nearby environment too. Since the cases of dengue have become rampant these days, hence, starting the medication obtained from green approaches as soon as the disease is detected is advisable. In the present paper, we recommend environmentally friendly dengue management strategies, which, when combined with a reasonable number of vector control approaches, may help to avoid the dengue havoc as well as help in maintaining the integrity of the ecosystem.

Improved metabolic parameters of people with diabetes attending an Aboriginal health service in regional Victoria.

BACKGROUND: Aboriginal and Torres Strait Islander people have higher rates of diabetes and its complications than non-Aboriginal people. Rumbalara Aboriginal Co-operative is the major primary healthcare provider for Aboriginal people in the Greater Shepparton region. AIMS: To evaluate the baseline metabolic parameters and presence of diabetes complications in people with type 2 diabetes attending Rumbalara Aboriginal Co-operative in 2017 and compare it with other Aboriginal and Torres Strait Islander studies and Australian specialist diabetes services. METHODS: Clinical and biochemical characteristics, including diabetes type, age, weight, body mass index (BMI), blood pressure, micro- and macrovascular complications, glycosylated haemoglobin (HbA1c), haemoglobin, renal function, lipid profile, urine albumin:creatinine ratio, diabetes medications, renin angiotensin system inhibition therapies, HMG-CoA reductase inhibitors and antiplatelet agents, were determined. RESULTS: One hundred and twenty-six individuals had diabetes, 121 had type 2 diabetes. One hundred and thirteen identified as Aboriginal and/or Torres Strait Islander. Median age was 57.5 (48-68) years, median HbA1c was 7.8% (6.8-9.6) and median BMI was 33.4 kg/m2 (29-42.3). Compared with other Australian Aboriginal and Torres Strait Islander populations, this population was older and had more obesity, but with better glycaemia management. Compared with specialist diabetes services, this population was of similar age, with greater BMI but comparable HbA1c. CONCLUSIONS: Aboriginal people living with type 2 diabetes attending this regional Aboriginal health service have comparable glycaemic management to specialist diabetes services in Australia, managed largely by primary care physicians with limited access to specialist care for the past 5 years.

miR-210-3p Promotes Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance by Targeting SOCS1-Mediated NF-κB Pathway.

Under the condition of chronic obesity, an increased level of free fatty acids along with low oxygen tension in the adipose tissue creates a pathophysiological adipose tissue microenvironment (ATenv), leading to the impairment of adipocyte function and insulin resistance. Here, we found the synergistic effect of hypoxia and lipid (H + L) surge in fostering adipose tissue macrophage (ATM) inflammation and polarization. ATenv significantly increased miR-210-3p expression in ATMs which promotes NF-κB activation-dependent proinflammatory cytokine expression along with the downregulation of anti-inflammatory cytokine expression. Interestingly, delivery of miR-210-3p mimic significantly increased macrophage inflammation in the absence of H + L co-stimulation, while miR-210-3p inhibitor notably compromised H + L-induced macrophage inflammation through increased production of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of the NF-κB inflammatory signaling pathway. Mechanistically, miR-210 directly binds to the 3'-UTR of SOCS1 mRNA and silences its expression, thus preventing proteasomal degradation of NF-κB p65. Direct delivery of anti-miR-210-3p LNA in the ATenv markedly rescued mice from obesity-induced adipose tissue inflammation and insulin resistance. Thus, miR-210-3p inhibition in ATMs could serve as a novel therapeutic strategy for managing obesity-induced type 2 diabetes.

Evaluation of spore inoculum and confirmation of pathway genetic blueprint of T13αH and DBAT from a Taxol-producing endophytic fungus.

Taxol (paclitaxel), a plant-derived anticancer drug, has been among the most successful anticancer drugs of natural origin. Endophytic fungi have been proposed as a prominent alternative source for Taxol and its intermediate Baccatin III, however the very low yields remain a hinderance to their commercial utilization. Significant research efforts towards this end are underway globally. Here, we report the results on our earlier reported Taxol-producing endophytic fungus, Fusarium solani from the standpoint of spores as seed inoculum and media selection for enhanced Taxol and baccatin III yields. Spores produced on M1D medium with 94.76% viability were used for further media optimization for Taxol and Baccatin III production in five different liquid media under static and shaker condition at different cultivation days. Taxol and Baccatin III when quantified through competitive inhibition enzyme immunoassay (CIEIA), showed maximum production at 136.3 µg L-1 and 128.3 µg L-1, respectively in the modified flask basal broth (MFBB) under shaking condition. Further, two important genes of this pathway, namely taxane 13α-hydroxylase (T13αH) and 10-deacetylbaccatin III-10-ß-O-acetyltransferase (DBAT) have been identified in this fungus. These findings are hoped to assist in further manipulation and metabolic engineering of the parent F. solani strain towards the enhanced production of Taxol and baccatin III.

Identification and Detection of Bioactive Peptides in Milk and Dairy Products: Remarks about Agro-Foods.

Food-based components represent major sources of functional bioactive compounds. Milk is a rich source of multiple bioactive peptides that not only help to fulfill consumers 'nutritional requirements but also play a significant role in preventing several health disorders. Understanding the chemical composition of milk and its products is critical for producing consistent and high-quality dairy products and functional dairy ingredients. Over the last two decades, peptides have gained significant attention by scientific evidence for its beneficial health impacts besides their established nutrient value. Increasing awareness of essential milk proteins has facilitated the development of novel milk protein products that are progressively required for nutritional benefits. The need to better understand the beneficial effects of milk-protein derived peptides has, therefore, led to the development of analytical approaches for the isolation, separation and identification of bioactive peptides in complex dairy products. Continuous emphasis is on the biological function and nutritional characteristics of milk constituents using several powerful techniques, namely omics, model cell lines, gut microbiome analysis and imaging techniques. This review briefly describes the state-of-the-art approach of peptidomics and lipidomics profiling approaches for the identification and detection of milk-derived bioactive peptides while taking into account recent progress in their analysis and emphasizing the difficulty of analysis of these functional and endogenous peptides.

Tuberculosis in Chronic Kidney Disease.

INTRODUCTION: Given the increasing prevalence of chronic kidney disease (CKD) in tuberculosis (TB) endemic areas, a merging of CKD and TB epidemics could have significant public health implications, especially in low to middle income countries like India, which is experiencing rapid increase in CKD prevalence. The aim of this study is to analyze the prevalence of TB in patients with CKD. METHODS: A prospective study was done on 160 patients with CKD at Safdarjung Hospital, New Delhi, both with and without dialysis. The patients were investigated to detect any form of TB. RESULTS: 22 patients showed evidence of tubercular infection (13.7%). Of these 22 subjects, 17 had extra-pulmonary and only 5 had pulmonary TB. TB infection was more prevalent among the patients on dialysis (18) than those who were not on dialysis (4). CONCLUSION: Therefore, we infer that TB is more common in patients of CKD and patients of CKD need to be screened for TB more so due to their over lapping signs and symptoms.

Fungal 7-epi-10-deacetyltaxol produced by an endophytic Pestalotiopsis microspora induces apoptosis in human hepatocellular carcinoma cell line (HepG2).

BACKGROUND: Paclitaxel (taxol) is a potent anticancer drug that is used in the treatment of a wide variety of cancerous. In the present study, we identified a taxol derivative named 7-epi-10-deacetyltaxol (EDT) from the culture of an endophytic fungus Pestalotiopsis microspora isolated from the bark of Taxodium mucronatum. This study was carried out to investigate the effects of fungal EDT on cell proliferation, the induction of apoptosis and the molecular mechanisms of apoptosis in human hepatoma HepG2 cells in vitro. METHODS: The endophytic fungus was identified by traditional and molecular taxonomical characterization and the fungal EDT was purified using column chromatography and confirmed by various spectroscopic and chromatographic comparisons with authentic paclitaxel. We studied the in vitro effects of EDT on HepG2 cells for parameters such as cell cycle distribution, DNA fragmentation, reactive oxygen species (ROS) generation and nuclear morphology. Further, western blot analysis was used to evaluate Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), p38-mitogen activated protein kinase (MAPK) and poly [ADP-ribose] polymerase (PARP) expression. RESULTS: We demonstrate that the fungal EDT exhibited significant in vitro cytotoxicity in HepG2 cells. We investigated cytotoxicity mechanism of EDT in HepG2 cells. The results showed nuclear condensation and DNA fragmentation were observed in cells treated with fungal EDT. Besides, the fungal EDT arrested HepG2 cells at G2/M phase of cell cycle. Furthermore, fungal EDT induced apoptosis in HepG2 cells in a dose-dependent manner associated with ROS generation and increased Bax/Bcl-2 ratio, p38 MAPKs and PARP cleavage. CONCLUSIONS: Our data show that EDT induced apoptotic cell death in HepG2 cells occurs through intrinsic pathway by generation of ROS mediated and activation of MAPK pathway. This is the first report for 7-epi-10-deacetyltaxol (EDT) isolated from a microbial source.

Splenic Epidermoid Cyst in a Five-Year-Old Child.

Splenic epidermoid cysts are rare non-parasitic true cysts affecting the spleen. We report a five-year-old child who presented with an abdominal lump associated with pain of 15 days. Ultrasonography of the abdomen showed a huge cystic lesion of obscure origin. At laprotomy a huge unilocular cyst involving upper part of spleen containing pultaceous fluid was seen and its removal necessitated splenectomy. Histopathological findings were consistent with splenic epidermoid cyst. Thus histopathology helped in elucidating the aetiology and diagnosis.

Ceramic nanoparticles: Recompense, cellular uptake and toxicity concerns.

Over the past few years, nanoparticles and their role in drug delivery have been the centre of attraction as new drug delivery systems. Various forms of nanosystems have been designed, such as nanoclays, scaffolds and nanotubes, having numerous applications in areas such as drug loading, target cell uptake, bioassay and imaging. The present study discusses various types of nanoparticles, with special emphasis on ceramic nanocarriers. Ceramic materials have high mechanical strength, good body response and low or non-existing biodegradability. In this article, the various aspects concerning ceramic nanoparticles, such as their advantages over other systems, their cellular uptake and toxicity concerns are discussed in detail.

Evidence of more ion channels inhibited by celecoxib: KV1.3 and L-type Ca(2+) channels.

BACKGROUND: Celecoxib, a selective inhibitor of cyclooxygenase-2, can directly modulate many voltage-activated potassium, sodium and calcium channels and alter functioning of excitable cells. The inhibitory and facilitating effects of celecoxib on ion channels occur at low micromolar concentrations, bordering on therapeutic concentrations achievable in the clinical setting. The experiments described here were performed with the goals (1) to increase the range of ion channels tested, and (2) to examine possible differences in celecoxib's effects on channels from different species. FINDINGS: The channels examined in this study using patch-clamp and intracellular recording methods were human KV1.3 channels expressed in CHO cells, L-type Ca(2+) channels (LTCC) from guinea pig cardiomyocytes, and LTCCs from Drosophila larval body-wall muscles. Celecoxib inhibited KV1.3 currents with IC50 of 5.0 µM at the end of 200 ms pulses to +20 mV. Celecoxib inhibited peak currents through guinea pig and Drosophila LTCCs with IC50s of 10.6 and 76.0 µM, respectively. CONCLUSIONS: As blockade of KV1.3 channels is associated with suppression of inflammatory immune reactions, the finding that celecoxib can inhibit these channels raises a question of possible contribution of KV1.3 inhibition to the anti-inflammatory effects of celecoxib. On the other hand, the Ca(2+) channel results are consistent with previous observations indicating that, in contrast to K(+) channels, strength of celecoxib effects on LTCCs strongly varies from species to species.

A masquerade presenting with diplopia.

BACKGROUND: Diplopia can often be a diagnostic challenge in the general practice setting. Differentials broadly include orbital pathology and neuromuscular aetiologies. Familiarity with the causes and subsequent investigations can help deliver efficient and effective patient care. OBJECTIVE: This article presents a unique case to illustrate the diagnostic approach to diplopia and highlights a commonly encountered yet often overlooked condition as a differential to diplopia in general practice. DISCUSSION: John Murtagh's manual identifies seven 'masquerades' as diagnoses that are commonly missed in general practice. The Murtagh model can be appropriately applied to diplopia in reminding practitioners of differentials that can easily slip from one's mind, yet can be diagnosed promptly with simple investigations. Atypical presentations of common disease processes should always be considered within the diagnostic framework for practitioners.

Rethinking production of Taxol® (paclitaxel) using endophyte biotechnology.

Taxol® (generic name paclitaxel) represents one of the most clinically valuable natural products known to mankind in the recent past. More than two decades have elapsed since the notable discovery of the first Taxol®-producing endophytic fungus, which was followed by a plethora of reports on other endophytes possessing similar biosynthetic potential. However, industrial-scale Taxol® production using fungal endophytes, although seemingly promising, has not seen the light of the day. In this opinion article, we embark on the current state of knowledge on Taxol® biosynthesis focusing on the chemical ecology of its producers, and ask whether it is actually possible to produce Taxol® using endophyte biotechnology. The key problems that have prevented the exploitation of potent endophytic fungi by industrial bioprocesses for sustained production of Taxol® are discussed.

Biotechnological potential of plant-associated endophytic fungi: hope versus hype.

The potential of endophytes, particularly endophytic fungi, capable of demonstrating desirable functional traits worth exploitation using red biotechnology is well established. However, these discoveries have not yet translated into industrial bioprocesses for commercial production of biopharmaceuticals using fungal endophytes. Here, we define the current challenges in transforming curiosity driven discoveries into industrial scale endophyte biotechnology. The possible practical, feasible, and sustainable strategies that can lead to harnessing fungal endophyte-mediated pharmaceutical products are discussed.

Celecoxib and ion channels: a story of unexpected discoveries.

Celecoxib (Celebrex), a highly popular selective inhibitor of cyclooxygenase-2, can modulate ion channels and alter functioning of neurons and myocytes at clinically relevant concentrations independently of cyclooxygenase inhibition. In experimental systems varying from Drosophila to primary mammalian and human cell lines, celecoxib inhibits many voltage-activated Na(+), Ca(2+), and K(+) channels, including NaV1.5, L- and T-type Ca(2+) channels, KV1.5, KV2.1, KV4.3, KV7.1, KV11.1 (hERG), while stimulating other K(+) channels-KV7.2-5 and, possibly, KV11.1 (hERG) channels under certain conditions. In this review, we summarize the information currently available on the effects of celecoxib on ion channels, examine mechanistic aspects of drug action and the concomitant changes at the cellular and organ levels, and discuss these findings in the therapeutic context.

Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency.

Mitochondrial dysfunction is a significant factor in human disease, ranging from systemic disorders of childhood to cardiomyopathy, ischaemia and neurodegeneration. Cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, is a frequent target. Lower eukaryotes possess alternative respiratory-chain enzymes that provide non-proton-translocating bypasses for respiratory complexes I (single-subunit reduced nicotinamide adenine dinucleotide dehydrogenases, e.g. Ndi1 from yeast) or III + IV [alternative oxidase (AOX)], under conditions of respiratory stress or overload. In previous studies, it was shown that transfer of yeast Ndi1 or Ciona intestinalis AOX to Drosophila was able to overcome the lethality produced by toxins or partial knockdown of complex I or IV. Here, we show that AOX can provide a complete or substantial rescue of a range of phenotypes induced by global or tissue-specific knockdown of different cIV subunits, including integral subunits required for catalysis, as well as peripheral subunits required for multimerization and assembly. AOX was also able to overcome the pupal lethality produced by muscle-specific knockdown of subunit CoVb, although the rescued flies were short lived and had a motility defect. cIV knockdown in neurons was not lethal during development but produced a rapidly progressing locomotor and seizure-sensitivity phenotype, which was substantially alleviated by AOX. Expression of Ndi1 exacerbated the neuronal phenotype produced by cIV knockdown. Ndi1 expressed in place of essential cI subunits produced a distinct residual phenotype of delayed development, bang sensitivity and male sterility. These findings confirm the potential utility of alternative respiratory chain enzymes as tools to combat mitochondrial disease, while indicating important limitations thereof.

Temperature and functional plasticity of L-type Ca2+ channels in Drosophila.

The question of optimization of ion channel function to surrounding temperatures in poikilothermic organisms remains largely uninvestigated. Here, we addressed it by studying the temperature-dependence of L-type Ca2+ channels (LTCCs) in Drosophila larval muscles in the context of their modulation by protein kinase A (PKA). LTCC currents were recorded between 4 and 30°C. Different aspects of LTCC function reached maxima between 15 and 25°C: conductance, tail current amplitude, inactivation rate, and the level of basal up-regulation by PKA (26% at 21°C). Anomalous temperature-dependencies of LTCC conductance and kinetics were similar in control and in the presence of the PKA inhibitor H-89. Analysis of deactivation kinetics revealed excessive tail currents at lower temperatures (up to 15°C), indicative of voltage-dependent facilitation of LTCCs. Tail current magnitude gradually decreased with temperature from a maximum at 15°C until a nearly complete disappearance at 30°C. Elimination of excessive tail currents at higher temperatures coincided with unusual slowing of inactivation, suggesting disruption of the facilitation by rising temperature, possibly through depletion of the pool of contributing channels. Overall, these results suggest the presence of a physiological plasticity optimum of LTCC function in the temperature range of normal Drosophila development.

Potassium channels in Drosophila: historical breakthroughs, significance, and perspectives.

Drosophila has enabled important breakthroughs in K(+) channel research, including identification and fi rst cloning of a voltage-activated K(+) channel, Shaker, a founding member of the K(V)1 family. Drosophila has also helped in discovering other K(+) channels, such as Shab, Shaw, Shal, Eag, Sei, Elk, and also Slo, a Ca(2+) - and voltage-dependent K(+) channel. These findings have contributed significantly to our understanding of ion channels and their role in physiology. Drosophila continues to play an important role in ion channel studies, benefiting from an unparalleled arsenal of genetic tools and availability of tens of thousands of genetically modified strains. These tools allow deletion, expression, or misexpression of almost any gene in question with temporal and spatial control. The combination of these tools and resources with the use of forward genetic approach in Drosophila further enhances its strength as a model system. There are many areas in which Drosophila can further help our understanding of ion channels and their function. These include signaling pathways involved in regulating and modulating ion channels, basic information on channels and currents where very little is currently known, and the role of ion channels in physiology and pathology.