New concepts in Gastroenterology

From Fat to Inflammation

An adaptable lifestyle can enhance the therapeutic decision on Type 2 diabetes mellitus (T2DM). We aim to evaluate the possible influence of increased plain water intake on the biochemical and cardiovascular parameters of persons with and without type 2 diabetes in a typical black African population. In this study, we hypothesized that there is a significant impact of increased plain water intake on biomarker of T2DM in both non-diabetic and diabetic individuals. One hundred participants, on their consent, participated in this study (case-control); fifty participants each - diabetic (test group) and nondiabetic (control group) were recruited from Sagamu Local Government, Nigeria, West Africa. There was a reduction in adiponectin expression in both groups after the duration of improved water intake. Glucose concentration decreased significantly (p<0.05) in the control group and non-significantly in the diabetes group after the treatment. There were negative correlations of adiponectin levels with total cholesterol, HDL, and LDL in both control and diabetic groups and a positive correlation with triglycerides in the control group. There was a non-significant decrease in the systolic and diastolic blood pressure in the diabetic group, whereas a non-significant increase was observed in the control group. The heart rate was non-significantly decreased in both groups. The evidence that short-duration exposure to plain water intake can improve glycemic parameters in diabetic patients is limited whereas there is a significant positive impact of increased plain water intake on the blood glucose level of nondiabetic individuals. Hence Black African population, with pre-diabetes, may benefit from increased plain water intake preventing T2DM.

Berberine (BBR) and silybin (SIY) are natural compounds obtained from Berberidaceae members and Silybum marianum (L.) Gaertn., respectively. These compounds have been demonstrated to regulate lipid metabolism and indue hepatoprotective effects, establishing their importance for the treatment of liver injury. Combination therapy has shown promise in treating ailments with complex pathophysiology, such as liver diseases. However, the inconsistent dissolution and poor absorption of BBR and SIY limit their efficacy.

This study compared the salt formulation (BSS) and physical mixture (BSP) of BBR and SIY for their efficacy in treating nonalcoholic fatty liver disease (NAFLD).

The formation of the BSS was confirmed using various techniques, including nuclear magnetic resonance spectroscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, and powder X-ray diffractometry. In addition, dissolution, trans-epithelial permeability, and bioavailability experiments were conducted to evaluate the absorption and distribution of drugs. Pharmacodynamics and mechanisms were investigated through in vivo experiments.

BSS form demonstrated synchronized dissolution of both components, unlike BSP. Additionally, the transepithelial permeability results revealed that BSS exhibited superior penetration and absorption of both BBR and SIY in comparison to BSP. Furthermore, BSS significantly increased the bioavailability of SIY in both plasma and the liver (2.2- and 4.5-fold, respectively) when compared with BSP. Moreover, BSS demonstrated a more potent inhibitory effect on lipid production in HepG2 cells than BSP. In mouse models (BALB/c) of NAFLD, BSS improved disease outcomes, as evidenced by decreased adipose levels, normalized blood lipid levels, and reduced liver parenchyma injury. Preliminary transcriptomics analysis suggested that BSS achieved its anti-NAFLD effect by regulating the expression of fatty acid transporter CD36, recombinant fatty acid binding protein 4, and stearyl coenzyme A dehydrogenase 1, which are associated with the synthesis and uptake of fatty acid-related proteins.

The study demonstrated that compared with physical mixing, salification improved the efficacy of BBR and SIY, as demonstrated in animal experiments. These findings provide valuable insights into the development of more effective treatments for NAFLD and provide new possibilities for combination therapies.

Nonalcoholic fatty liver disease (NAFLD) is described by too much hepatic fat deposition causing steatosis, which further develops into nonalcoholic steatohepatitis (NASH), defined by necroinflammation and fibrosis, progressing further to hepatic cirrhosis, hepatocellular carcinoma, and liver failure. NAFLD is linked to different aspects of the metabolic syndrome like obesity, insulin resistance, hypertension, and dyslipidemia, and its pathogenesis involves several elements including diet, obesity, disruption of lipid homeostasis, and a high buildup of triglycerides and other lipids in liver cells. It is therefore linked to an increase in the susceptibility to developing diabetes mellitus and cardiovascular diseases. Several interventions exist regarding its management, but the availability of natural sources through diet will be a benefit in dealing with the disorder due to the immensely growing dependence of the population worldwide on natural sources owing to their ability to treat the root cause of the disease. Anthocyanins (ACNs) are naturally occurring polyphenolic pigments that exist in the form of glycosides, which are the glucosides of anthocyanidins and are produced from flavonoids via the phenyl propanoid pathway. To understand their mode of action in NAFLD and their therapeutic potential, the literature on in vitro, in vivo, and clinical trials on naturally occurring ACN-rich sources was exhaustively reviewed. It was concluded that ACNs show their potential in the treatment of NAFLD through their antioxidant properties and their efficacy to control lipid metabolism, glucose homeostasis, transcription factors, and inflammation. This led to the conclusion that ACNs possess efficacy in the amelioration of NAFLD and the various features associated with it. However, additional clinical trials are required to justify the potential of ACNs in NAFLD.

La stéatose hépatique non alcoolique (NAFLD) est décrite par un dépôt excessif de graisse hépatique provoquant une stéatose, qui évolue ensuite en stéatohépatite non alcoolique (NASH), définie par une nécroinflammation et une fibrose, évoluant ensuite vers une cirrhose hépatique, un carcinome hépatocellulaire et une insuffisance hépatique. La NAFLD est liée à différents aspects du syndrome métabolique comme l’obésité, la résistance à l’insuline, l’hypertension et la dyslipidémie, et sa pathogenèse implique plusieurs éléments, notamment l’alimentation, l’obésité, la perturbation de l’homéostasie lipidique et une accumulation élevée de triglycérides et d’autres lipides dans les cellules hépatiques. Elle est donc liée à une augmentation de la susceptibilité à développer un diabète sucré et des maladies cardiovasculaires. Plusieurs interventions existent concernant sa gestion, mais la disponibilité de sources naturelles par le biais de l’alimentation sera un avantage dans la lutte contre ce trouble en raison de la dépendance immensément croissante de la population mondiale à l’égard des sources naturelles en raison de leur capacité à traiter la cause profonde de la maladie. Les anthocyanes (ACN) sont des pigments polyphénoliques naturels qui existent sous forme de glycosides, qui sont les glucosides des anthocyanidines et sont produits à partir de flavonoïdes via la voie phényl propanoïde. Pour comprendre leur mode d’action dans la NAFLD et leur potentiel thérapeutique, la littérature sur les essais in vitro, in vivo et cliniques sur les sources naturelles riches en ACN a été examinée de manière exhaustive. Il a été conclu que les ACN montrent leur potentiel dans le traitement de la NAFLD grâce à leurs propriétés antioxydantes et leur efficacité à contrôler le métabolisme des lipides, l’homéostasie du glucose, les facteurs de transcription et l’inflammation. Cela a conduit à la conclusion que les ACN possèdent une efficacité dans l’amélioration de la NAFLD et des diverses caractéristiques qui y sont associées. Cependant, des essais cliniques supplémentaires sont nécessaires pour justifier le potentiel des ACN dans la NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease all over the world, and no drug is approved for the treatment of NAFLD. Bavachinin (BVC) is proven to possess liver-protecting effect against NAFLD, but its mechanism is still blurry.

With the use of Click Chemistry-Activity‐Based Protein Profiling (CC-ABPP) technology, this study aims to identify the target of BVC, and investigate the mechanism by which BVC exerts its liver-protecting effect.

The high fat diet induced hamster NAFLD model is introduced to investigate BVC’s lipid-lowering and liver-protecting effects. Then, a small molecular probe of BVC is designed and synthesized based on the CC-ABPP technology, and BVC’s target is fished out. A series of experiments are performed to identify the target, including competitive inhibition assay, surface-plasmon resonance (SPR), cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) assay, and co-immunoprecipitation (Co-IP). Afterward, the pro-regeneration effects of BVC are validated in vitro and in vivo through flow cytometry, immunofluorescence, and the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL).

In the hamster NAFLD model, BVC shows lipid-lowing effect and improvement on the histology. PCNA is identified as the target of BVC with the method mentioned above, and BVC facilitates the interaction between PCNA and DNA polymerase delta. BVC promotes HepG2 cells proliferation which is inhibited by T2AA, an inhibitor suppresses the interaction between PCNA and DNA polymerase delta. In NAFLD hamsters, BVC enhances PCNA expression and liver regeneration, reduces hepatocyte apoptosis.

This study suggests that, besides the anti-lipemic effect, BVC binds to the pocket of PCNA facilitating its interaction with DNA polymerase delta and pro-regeneration effect, thereby exerts the protective effect against HFD induced liver injury.

The expression of various isoforms of aquaporins (AQPs) in different tissues and organs of the body makes it a viable candidate for being responsible for maintaining cell stability and integrity as their involvement has been well documented in a number of pathophysiological conditions of the human body. Any alteration in the cellular environment brought about by these AQPs creates severe downstream effects like changes in cellular osmolality, volume, ionic composition, signaling pathways and even in the levels of intracellular second messengers and, as such, facilitates the occurrence of diseases like cancer. The altered equilibrium of water, extracellular ions and amino acid neurotransmitters caused by neuronal destruction and oxidative stress in neurodegenerative diseases proposed the role of these AQPs in these diseased conditions as well. The association of AQPs in a variety of inflammatory processes like lung injury, brain edema, neuromyelitis optica, and colitis as manifested through their dysregulation both in animal and human diseases is truly an eye opener for their role in protection and reaction to various noxious stimuli including bacterial infection. Renal diseases like nephrogenic diabetes inspidus, autosomal dominant polycystic kidney disease and acute kidney injury are some of the pathophysiological conditions related to malfunctioning of aquaporins. Besides, the malfunctioning of aquaglyceroporins like AQP7 and AQP9 makes them responsible for disorders like obesity, nonalcoholic fatty liver disease and non-alcoholic steatohepatitis. In this review article, we present our current understanding of the role of AQPs in the causation of these metabolic disorders and how targeting them holds promising therapeutic potential for most of these diseases like cancer, renal diseases and even cardiovascular disorders.

Metabolic syndrome is a collection of abnormalities including insulin resistance, hypertension, dyslipidemia, type 2 diabetes, obesity, inflammation, non-alcoholic fatty liver disease, etc. The metabolic syndrome results in a dramatic five-fold elevation in the risk of developing type-2 diabetes and a two-fold heightened risk of developing cardiovascular diseases. It is fast becoming a major global health challenge, cause of mortality and morbidity. Regardless of advances in understanding the mechanisms involved in the pathogenesis of metabolic syndrome, available therapies are still not effective. Nanotechnology is marked as an upcoming tool with a wide range of applications in biomedicine, especially for the management of metabolic syndrome and its associated disorders such as diabetes, obesity, etc. because the nanotechnology utilizes nanoscaled drugs and therapeutics that can reach specific target sites, which helps in improving drug delivery systems, early disease detection and diagnosis using nano-imaging techniques. Therefore, nanotechnology increases bioavailability, permeability, compatibility, the effectiveness of treatment and reduced adverse effects. In this review, we will describe the role of nanomaterial-based therapeutics in managing metabolic disorders such as non-alcoholic fatty liver disease, obesity, insulin resistance, glucose intolerance which all increase the risk of developing cardiovascular diseases and diabetes.