Berberine for prevention of dementia associated with diabetes and its comorbidities: A systematic review

Background A growing number of epidemiological studies indicate that metabolic syndrome (MetS) and its associated features play a key role in the development of certain degenerative brain disorders, including Alzheimer’s disease and vascular dementia. Produced by several different medicinal plants, berberine is a bioactive alkaloid with a wide range of pharmacological effects, including antidiabetic effects. However, it is not clear whether berberine could prevent the development of dementia in association with diabetes. Objective To give an overview of the therapeutic potential of berberine as a treatment for dementia associated with diabetes. Search strategy Database searches A and B were conducted using PubMed and ScienceDirect. In search A, studies on berberine’s antidementia activities were identified using “berberine” and “dementia” as search terms. In search B, recent studies on berberine’s effects on diabetes were surveyed using “berberine” and “diabetes” as search terms. Inclusion criteria Clinical and preclinical studies that investigated berberine’s effects associated with MetS and cognitive dysfunction were included. Data extraction and analysis Data from studies were extracted by one author, and checked by a second; quality assessments were performed independently by two authors. Results In search A, 61 articles were identified, and 22 original research articles were selected. In search B, 458 articles were identified, of which 101 were deemed relevant and selected. Three duplicates were removed, and a total of 120 articles were reviewed for this study. The results demonstrate that berberine exerts beneficial effects directly in the brain: enhancing cholinergic neurotransmission, improving cerebral blood flow, protecting neurons from inflammation, limiting hyperphosphorylation of tau and facilitating β-amyloid peptide clearance. In addition, evidence is growing that berberine is effective against diabetes and associated disorders, such as atherosclerosis, cardiomyopathy, hypertension, hepatic steatosis, diabetic nephropathy, gut dysbiosis, retinopathy and neuropathy, suggesting indirect benefits for the prevention of dementia. Conclusion Berberine could impede the development of dementia via multiple mechanisms: preventing brain damages and enhancing cognition directly in the brain, and indirectly through alleviating risk factors such as metabolic dysfunction, and cardiovascular, kidney and liver diseases. This study provided evidence to support the value of berberine in the prevention of dementia associated with MetS

Theranostic Fibers for Simultaneous Imaging and Drug Delivery

New methods for creating theranostic systems with simultaneous encapsulation of therapeutic, diagnostic, and targeting agents are much sought after. This work reports for the first time the use of coaxial electrospinning to prepare such systems in the form of core–shell fibers. Eudragit S100 was used to form the shell of the fibers, while the core comprised poly(ethylene oxide) loaded with the magnetic resonance contrast agent Gd(DTPA) (Gd(III) diethylenetriaminepentaacetate hydrate) and indomethacin as a model therapeutic agent. The fibers had linear cylindrical morphologies with clear core–shell structures, as demonstrated by electron microscopy. X-ray diffraction and differential scanning calorimetry proved that both indomethacin and Gd(DTPA) were present in the fibers in the amorphous physical form. This is thought to be a result of intermolecular interactions between the different components, the presence of which was suggested by infrared spectroscopy. In vitro dissolution tests indicated that the fibers could provide targeted release of the active ingredients through a combined mechanism of erosion and diffusion. The proton relaxivities for Gd(DTPA) released from the fibers into tris buffer increased (r1 = 4.79–9.75 s–1 mM–1; r2 = 7.98–14.22 s–1 mM–1) compared with fresh Gd(DTPA) (r1 = 4.13 s–1 mM–1 and r2 = 4.40 s–1 mM–1), which proved that electrospinning has not diminished the contrast properties of the complex. The new systems reported herein thus offer a new platform for delivering therapeutic and imaging agents simultaneously to the colon

Electrospun medicated shellac nanofibers for colon-targeted drug delivery

Medicated shellac nanofibers providing colon-specific sustained release were fabricated using coaxial electrospinning. A solution of 7.5 g shellac and 1.5 g of ferulic acid (FA) in 10 mL ethanol was used as the core fluid, and a mixture of ethanol and N,N-dimethylformamide (8/10 v/v) as the shell. The presence of the shell fluid was required to prevent frequent clogging of the spinneret. The diameters of the fibers (D) can be manipulated by varying the ratio of shell to core flow rates (F), according to the equation D = 0.52F−0.19. Scanning electron microscopy images revealed that fibers prepared with F values of 0.1 and 0.25 had linear morphologies with smooth surfaces, but when the shell fluid flow rate was increased to 0.5 the fiber integrity was compromised. FA was found to be amorphously distributed in the fibers on the basis of X-ray diffraction and differential scanning calorimetry results. This can be attributed to good compatibility between the drug and carrier: IR spectra indicated the presence of hydrogen bonds between the two. In vitro dissolution tests demonstrated that there was minimal FA release at pH 2.0, and sustained release in a neutral dissolution medium. The latter occurred through an erosion mechanism. During the dissolution processes, the shellac fibers were gradually converted into nanoparticles as the FA was freed into solution, and ultimately completely dissolved

High omega arachidonic acid/docosahexaenoic acid ratio induces mitochondrial dysfunction and altered lipid metabolism in human hepatoma cells

Background Non-alcoholic fatty liver disease (NAFLD) is a common cause of liver disease worldwide and is a growing epidemic. A high ratio of omega-6 fatty acids to omega-3 fatty acids in the diet has been implicated in the development of NAFLD. However, the inflicted cellular pathology remains unknown. A high ratio may promote lipogenic pathways and contribute to ROS-mediated damage, perhaps leading to mitochondrial dysfunction. Therefore, these parameters were investigated to understand their contribution to NAFLD development. Aim To examine the effect of increasing ratios of omega-6:3 fatty acids on mitochondrial function and lipid metabolism mediators. Methods HepG2-derived VL-17A cells were treated with normal (1:1, 4:1) and high (15:1, 25:1) ratios of omega-6: omega-3 fatty acids (arachidonic (AA): docosahexaenoic (DHA)) at various time points. Mitochondrial activity and function was examined via MTT assay and Seahorse XF24 analyzer, respectively. Triglyceride accumulation was determined by using EnzyChrom™ and levels of ROS were measured by fluorescence intensity. Protein expression of the mediators of lipogenic, lipolytic and endocannabinoid pathways was assessed by Western blotting. Results High AA:DHA ratio decreased mitochondrial activity (p<0.01; upto 80%) and promoted intracellular triglyceride accumulation (p<0.05; 40-70%). Mechanistically, it altered the mediators of lipid metabolism; increased the expression of stearoyl-CoA desaturase (p<0.05; 22-35%), decreased the expression of peroxisome proliferator-activated receptor-alpha (p<0.05; 30-40%) and increased the expression of cannabinoid receptor 1 (p<0.05; 31%). Furthermore, the high ratio increased ROS production (p<0.01; 74-115%) and reduced mitochondrial respiratory functions such as basal and maximal respiration, ATP production, spare respiratory capacity and proton leak (p<0.01; 35-68%). Conclusion High AA:DHA ratio induced triglyceride accumulation, increased oxidative stress and disrupted mitochondrial functions. Stimulation of lipogenic and steroidal transcription factors may partly mediate these effects and contribute to NAFLD development

Medicated Janus fibers fabricated using a Teflon-coated side-by-side spinneret

A family of medicated Janus fibers that provides highly tunable biphasic drug release was fabricated using a side-by-side electrospinning process employing a Teflon-coated parallel spinneret. The coated spinneret facilitated the formation of a Janus Taylor cone and in turn high quality integrated Janus structures, which could not be reliably obtained without the Teflon coating. The fibers prepared had one side consisting of polyvinylpyrrolidone (PVP) K60 and ketoprofen, and the other of ethyl cellulose (EC) and ketoprofen. To modulate and tune drug release, PVP K10 was doped into the EC side in some cases. The fibers were linear and had flat morphologies with an indent in the center. They provide biphasic drug release, with the PVP K60 side dissolving very rapidly to deliver a loading dose of the active ingredient, and the EC side resulting in sustained release of the remaining ketoprofen. The addition of PVP K10 to the EC side was able to accelerate the second stage of release; variation in the dopant amount permitted the release rate and extent this phase to be precisely tuned. These results offer the potential to rationally design systems with highly controllable drug release profiles, which can complement natural biological rhythms and deliver maximum therapeutic effects

Nanofibers fabricated using triaxial electrospinning as zero order drug delivery systems

A new strategy for creating functional trilayer nanofibers through triaxial electrospinning is demonstrated. Ethyl cellulose (EC) was used as the filament-forming matrix in the outer, middle, and inner working solutions and was combined with varied contents of the model active ingredient ketoprofen (KET) in the three fluids. Triaxial electrospinning was successfully carried out to generate medicated nanofibers. The resultant nanofibers had diameters of 0.74 ± 0.06 μm, linear morphologies, smooth surfaces, and clear trilayer nanostructures. The KET concentration in each layer gradually increased from the outer to the inner layer. In vitro dissolution tests demonstrated that the nanofibers could provide linear release of KET over 20 h. The protocol reported in this study thus provides a facile approach to creating functional nanofibers with sophisticated structural features

Acetate induces growth arrest in colon cancer cells through modulation of mitochondrial function

Acetate is one of the main short chain fatty acids produced in the colon when fermentable carbohydrates are digested. It has been shown to affect normal metabolism, modulating mitochondrial function and fatty acid oxidation. Currently, there is no clear consensus regarding the effects of acetate on tumorigenesis and cancer metabolism. Here, we investigate the metabolic effects of acetate on colon cancer. HT29 and HCT116 colon cancer cell lines were treated with acetate and its effect on mitochondrial proliferation, reactive oxygen species, density, permeability transition pore, cellular bioenergetics, gene expression of acetyl-CoA synthetase 1 (ACSS1) and 2 (ACSS2) and lipid levels were investigated. Acetate was found to reduce proliferation of both cell lines under normoxia as well as reducing glycolysis; it was also found to increase both oxygen consumption and ROS levels. Cell death observed was independent of ACSS1/2 expression. Under hypoxic conditions, reduced proliferation was maintained in the HT29 cell line but no longer observed in the HCT116 cell line. ACSS2 expression together with cellular lipid levels was increased in both cell lines under hypoxia which may partly protect cells from the anti-proliferative effects of reversed Warburg effect caused by acetate. The findings from this study suggest that effect of acetate on proliferation is a consequence of its impact on mitochondrial metabolism and during normoxia is independent of ACCS1/2 expression