Severity of gallstone, sludge or microlithiasis induced pancreatitis - all of the same?

BACKGROUND/AIM: Severity of microlithiasis and sludge-induced pancreatitis in comparison to gallstone-induced pancreatitis has never been studied for a lack of definition. In order to understand whether bile duct obstruction or other mechanisms contribute to biliary pancreatitis severity we performed a monocentric, retrospective cohort study. METHODS: In this retrospective cohort study 263 patients with acute biliary pancreatitis treated at a tertiary care center from 2005 to 2021 were stratified according to the recent consensus definition for microlithiasis and sludge. The gallstone-pancreatitis cohort was compared to microlithiasis, sludge and suspected stone passage pancreatitis cohorts in terms of pancreatitis outcome, liver function and EUS/ERCP results using one-way ANOVA and Chi2 test. Multinomial logistic regression analysis was performed to correct for bias. RESULTS: Microlithiasis and sludge-induced pancreatitis classified according to the revised Atlanta classification, did not present with a milder course than gallstone-induced pancreatitis (p = 0.62). Microlithiasis and sludge showed an increase in bilirubin on the day of admission to hospital, which was not significantly different from gallstone-induced pancreatitis (p = 0.36). The likelihood of detecting biliary disease on EUS resulting in bile duct clearance was highest on the day of admission and day 1, respectively. CONCLUSION: Microlithiasis and sludge induce gallstone-equivalent impaired liver function tests and induce pancreatitis with similar severity compared with gallstone-induced acute biliary pancreatitis.

Therapeutic potential of stem cells in regeneration of liver in chronic liver diseases: Current perspectives and future challenges.

The deposition of extracellular matrix and hyperplasia of connective tissue characterizes chronic liver disease called hepatic fibrosis. Progression of hepatic fibrosis may lead to hepatocellular carcinoma. At this stage, only liver transplantation is a viable option. However, the number of possible liver donors is less than the number of patients needing transplantation. Consequently, alternative cell therapies based on non-stem cells (e.g., fibroblasts, chondrocytes, keratinocytes, and hepatocytes) therapy may be able to postpone hepatic disease, but they are often ineffective. Thus, novel stem cell-based therapeutics might be potentially important cutting-edge approaches for treating liver diseases and reducing patient' suffering. Several signaling pathways provide targets for stem cell interventions. These include pathways such as TGF-ß, STAT3/BCL-2, NADPH oxidase, Raf/MEK/ERK, Notch, and Wnt/ß-catenin. Moreover, mesenchymal stem cells (MSCs) stimulate interleukin (IL)-10, which inhibits T-cells and converts M1 macrophages into M2 macrophages, producing an anti-inflammatory environment. Furthermore, it inhibits the action of CD4+ and CD8+ T cells and reduces the activity of TNF-α and interferon cytokines by enhancing IL-4 synthesis. Consequently, the immunomodulatory and anti-inflammatory capabilities of MSCs make them an attractive therapeutic approach. Importantly, MSCs can inhibit the activation of hepatic stellate cells, causing their apoptosis and subsequent promotion of hepatocyte proliferation, thereby replacing dead hepatocytes and reducing liver fibrosis. This review discusses the multidimensional therapeutic role of stem cells as cell-based therapeutics in liver fibrosis.

Advances in therapeutic applications of silver nanoparticles.

Nanotechnology is one of the most appealing area for developing new applications in biotechnology and medicine. For decades, nanoparticles have been extensively studied for a variety of biomedical applications. Silver has evolved into a potent antibacterial agent that can be used in a variety of nanostructured materials of various shapes and sizes. Silver nanoparticles (AgNP) based antimicrobial compounds are employed in a wide range of applications, including medicinal uses, surface treatment and coatings, the chemical and food industries, and agricultural productivity. When designing formulations for specific applications, the size, shape, and surface area of AgNPs are all crucial structural aspects to consider. Different methods for producing AgNPs with varying sizes and forms that are less harmful have been devised. The anticancer, anti-inflammatory, antibacterial, antiviral, and anti-angiogenic properties of AgNPs have been addressed in this review, as well as their generation and processes. Herein, we have reviewed the advances in therapeutic applications of AgNPs, as well as their limitations and barriers for future applications.

Antimicrobial and anti-viral effects of selenium nanoparticles and selenoprotein based strategies: COVID-19 and beyond.

Deficiency of selenium (Se) has been described in a significant number of COVID-19 patients having a higher incidence of mortality, which makes it a pertinent issue to be addressed clinically for effective management of the COVID-19 pandemic. Se nanoparticles (SeNPs) provide a unique option for managing the havoc caused by the COVID-19 pandemic. SeNPs possess promising anti-inflammatory and anti-fibrotic effects by virtue of their nuclear factor kappa-light-chain-stimulator of activated B cells (NFκB), mitogen-activated protein kinase (MAPKs), and transforming growth factor-beta (TGF-ß) modulatory activity. In addition, SeNPs possess remarkable immunomodulatory effects, making them a suitable option for supplementation with a much lower risk of toxicity compared to their elemental counterpart. Further, SeNPs have been shown to curtail viral and microbial infections, thus, making it a novel means to halt viral growth. In addition, it can be administered in the form of aerosol spray, direct injection, or infused thin-film transdermal patches to reduce the spread of this highly contagious viral infection. Moreover, a considerable decrease in the expression of selenoprotein along with enhanced expression of IL-6 in COVID-19 suggests a potential association among selenoprotein expression and COVID-19. In this review, we highlight the unique antimicrobial and antiviral properties of SeNPs and the immunomodulatory potential of selenoproteins. We provide the rationale behind their potentially interesting properties and further exploration in the context of microbial and viral infections. Further, the importance of selenoproteins and their role in maintaining a successful immune response along with their association to Se status is summarized.

Spotlight on liver macrophages for halting liver disease progression and injury.

INTRODUCTION: Over the past two decades, understanding of hepatic macrophage biology has provided astounding details of their role in the progression and regression of liver diseases. The hepatic macrophages constitute resident macrophages, Kupffer cells, and circulating bone marrow monocyte-derived macrophages, which play a diverse role in liver injury and repair. Imbalance in the macrophage population leads to pathological consequences and is responsible for the initiation and progression of acute and chronic liver injuries. Further, distinct populations of hepatic macrophages and their high heterogeneity make their complex role enigmatic. The unique features of distinct phenotypes of macrophages have provided novel biomarkers for defining the stages of liver diseases. The distinct mechanisms of hepatic macrophages polarization and recruitment have been at the fore front of research. In addition, the secretome of hepatic macrophages and their immune regulation has provided clinically relevant therapeutic targets. AREAS COVERED: Herein, we have highlighted the current understanding in the area of hepatic macrophages, and their role in the progression of liver injury. EXPERT OPINION: It is essential to ascertain the physiological and pathological role of evolutionarily conserved distinct macrophage phenotypes in different liver diseases before viable approaches may see a clinical translation.

A comprehensive overview of CRISPR/Cas 9 technology and application thereof in drug discovery.

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-Cas technology possesses revolutionary potential to positively affect various domains of drug discovery. It has initiated a rise in the area of genetic engineering and its advantages range from classical science to translational medicine. These genome editing systems have given a new dimension to our capabilities to alter, detect and annotate specified gene sequences. Moreover, the ease, robustness and adaptability of the CRISPR/Cas9 technology have led to its extensive utilization in research areas in such a short period of time. The applications include the development of model cell lines, understanding disease mechanisms, discovering disease targets, developing transgenic animals and plants, and transcriptional modulation. Further, the technology is rapidly growing; hence, an overlook of progressive success is crucial. This review presents the current status of the CRISPR-Cas technology in a tailor-made format from its discovery to several advancements for drug discovery alongwith future trends associated with possibilities and hurdles including ethical concerns.

Sensing and 3D printing technologies in personalized healthcare for the management of health crises including the COVID-19 outbreak.

A major threat that has surrounded human civilization since the beginning of the year 2020 is the outbreak of coronavirus disease 2019 (COVID-19). It has been declared a pandemic by the World Health Organization and significantly affected populations globally, causing medical and economic despair. Healthcare chains across the globe have been under grave stress owing to shortages of medical equipments necessary to address a pandemic. Furthermore, personal protective equipment supplies, mandatory for healthcare staff for treating severely ill patients, have been in short supply. To address the necessary requisites during the pandemic, several researchers, hospitals, and industries collaborated to meet the demand for these medical equipments in an economically viable manner. In this context, 3D printing technologies have provided enormous potential in creating personalized healthcare equipment, including face masks, face shields, rapid detection kits, testing swabs, biosensors, and various ventilator components. This has been made possible by capitalizing on centralized large-scale manufacturing using 3D printing and local distribution of verified and tested computer-aided design files. The primary focus of this study is, "How 3D printing is helpful in developing these equipments, and how it can be helpful in the development and deployment of various sensing and point-of-care-testing (POCTs) devices for the commercialization?" Further, the present study also takes care of patient safety by implementing novel 3D printed health equipment used for COVID-19 patients. Moreover, the study helps identify and highlight the efforts made by various organizations toward the usage of 3D printing technologies, which are helpful in combating the ongoing pandemic.

Ameliorative effect of cerium oxide nanoparticles against Freund's complete adjuvant-induced arthritis.

Aim: To assess the mechanistic effects of cerium oxide nanoparticles (CONPs) on Freund's complete adjuvant (FCA)-induced rheumatoid arthritis in rats. Methods: CONPs were characterized and evaluated in vitro (RAW 264.7 macrophages) and in vivo (FCA-induced rheumatoid arthritis model). Results:In vitro treatment with CONPs significantly reduced lipopolysaccharide-induced oxidative stress (as evident from dichlorodihydrofluorescein diacetate staining), diminished mitochondrial stress (as observed with tetraethylbenzimidazolylcarbocyanine iodide staining) and reduced superoxide radicals. In vivo, CONPs exhibited anti-rheumatoid arthritis activity, as evident from results of paw volume, x-ray, clinical scoring, levels of cytokines (IL-17, IL-1ß, TNF-α and TGF-ß1) and histology. Conclusion: We provide preclinical proof that CONPs may be a novel futuristic nanoparticle-based approach for therapy of rheumatoid arthritis.

Gene therapy: Comprehensive overview and therapeutic applications.

Gene therapy is the product of man's quest to eliminate diseases. Gene therapy has three facets namely, gene silencing using siRNA, shRNA and miRNA, gene replacement where the desired gene in the form of plasmids and viral vectors, are directly administered and finally gene editing based therapy where mutations are modified using specific nucleases such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short tandem repeats (CRISPR)/CRISPR-associated protein (Cas)-associated nucleases. Transfer of gene is either through transformation where under specific conditions the gene is directly taken up by the bacterial cells, transduction where a bacteriophage is used to transfer the genetic material and lastly transfection that involves forceful delivery of gene using either viral or non-viral vectors. The non-viral transfection methods are subdivided into physical, chemical and biological. The physical methods include electroporation, biolistic, microinjection, laser, elevated temperature, ultrasound and hydrodynamic gene transfer. The chemical methods utilize calcium- phosphate, DAE-dextran, liposomes and nanoparticles for transfection. The biological methods are increasingly using viruses for gene transfer, these viruses could either integrate within the genome of the host cell conferring a stable gene expression, whereas few other non-integrating viruses are episomal and their expression is diluted proportional to the cell division. So far, gene therapy has been wielded in a plethora of diseases. However, coherent and innocuous delivery of genes is among the major hurdles in the use of this promising therapy. Hence this review aims to highlight the current options available for gene transfer along with the advantages and limitations of every method.

Biomedical applications of polysaccharide nanoparticles for chronic inflammatory disorders: Focus on rheumatoid arthritis, diabetes and organ fibrosis.

Polysaccharides are biopolymers distinguished by their complex secondary structures executing various roles in microorganisms, plants, and animals. They are made up of long monomers of similar type or as a combination of other monomeric chains. Polysaccharides are considered superior as compared to other polymers due to their diversity in charge and size, biodegradability, abundance, bio-compatibility, and less toxicity. These natural polymers are widely used in designing of nanoparticles (NPs) which possess wide applications in therapeutics, diagnostics, delivery and protection of bioactive compounds or drugs. The side chain reactive groups of polysaccharides are advantageous for functionalization with nanoparticle-based conjugates or therapeutic agents such as small molecules, proteins, peptides and nucleic acids. Polysaccharide NPs show excellent pharmacokinetic and drug delivery properties, facilitate improved oral absorption, control the release of drugs, increases in vivo retention capability, targeted delivery, and exert synergistic effects. This review updates the usage of polysaccharides based NPs particularly cellulose, chitosan, hyaluronic acid, alginate, dextran, starch, cyclodextrins, pullulan, and their combinations with promising applications in diabetes, organ fibrosis and arthritis.

Critical neurological features of COVID-19: Role of imaging methods and biosensors for effective diagnosis.

COVID-19 is a respiratory infection that has been declared as a global health crisis by the WHO. It mainly affects the respiratory system. Apart from respiratory system, it also affects other organs as well including the brain. Numerous emerging reports have demonstrated that the COVID-19 has detrimental effects on neurological functions, and can lead to severe impairment of the central nervous system (CNS). The neurological manifestations linked with COVID-19 include headache, anosmia, encephalitis, epileptic seizures, Guillain-Barre syndrome, stroke and intracerebral hemorrhage alongwith multiple others complications. The CNS related complications may be severe and are linked with poor diagnosis which may worsen the condition. Therefore, there is a need to precisely understand the neurological sequelae along with upcoming clinical outcomes. Here, we present a brief review of the neurological complications and symptoms associated with COVID-19 along with brain imaging findings. Further, we have discussed about the emerging biosensing approaches which may aid in rapid, precise and mass diagnosis of COVID-19.

Silver nanoparticle based multifunctional approach for combating COVID-19.

COVID-19 is a highly contagious and widespread disease that has strained the global healthcare system to the hilt. Silver nanoparticles (AgNPs) are well known for their potent antimicrobial, antiviral, immunomodulatory and biosensing properties. AgNPs have been found to be potential antiviral agent that act against many deadly viruses and is presumed to be effective against COVID-19. AgNPs can generate free radicals and reactive oxygen species (ROS) leading to apoptosis mediated cell death thereby inhibiting viral infection. The shape and size of AgNPs play an important role in its biomedical applications as alterations may result in variable biological interaction and activity. Herein, we propose that AgNPs can be utilized for effective management of the ongoing COVID-19 pandemic by highlighting the current status of AgNPs in the fight against COVID-19.

Allium sativum derived carbon dots as a potential theranostic agent to combat the COVID-19 crisis.

Coronavirus disease 2019 (COVID-19) is one of the worst pandemics to have hit the humanity. The manifestations are quite varied, ranging from severe lung infections to being asymptomatic. Hence, there is an urgent need to champion new tools to accelerate the end of this pandemic. Compromised immunity is a primary feature of COVID-19. Allium sativum (AS) is an effective dietary supplement known for its immune-modulatory, antibacterial, anti-inflammatory, anticancer, antifungal, and anti-viral properties. In this paper, it is hypothesized that carbon dots (CDs) derived from AS (AS-CDs) may possess the potential to downregulate the expression of pro-inflammatory cytokines and revert the immunological aberrations to normal in case of COVID-19. CDs have already been explored in the world of nanobiomedicine as a promising theranostic candidates for bioimaging and drug/gene delivery. The antifibrotic and antioxidant effects of AS are elaborated, as demonstrated in several studies. It is found that the most active constituent of AS, allicin has a highly potent antioxidant and reactive oxygen species (ROS) scavenging effect. The antibacterial, antifungal, and anti-viral effects along with their capability of negating inflammatory effects and cytokine storm are discussed. The synthesis of theranostic CDs from AS may provide a novel weapon in the therapeutic armamentarium for the management of COVID-19 infection and, at the same time, could act as a diagnostic agent for COVID-19.

Methionine as a double-edged sword in health and disease: Current perspective and future challenges.

Methionine is one of the essential amino acids and plays a vital role in various cellular processes. Reports advocate that methionine restriction and supplementation provide promising outcomes, and its regulation is critical for maintaining a healthy life. Dietary methionine restriction in houseflies and rodents has been proven to extend lifespan. Contrary to these findings, long-term dietary restriction of methionine leads to adverse events such as bone-related disorders, stunted growth, and hyperhomocysteinemia. Conversely, dietary supplementation of methionine improves hepatic steatosis, insulin resistance, inflammation, fibrosis, and bone health. However, a high level of methionine intake shows adverse effects such as hyperhomocysteinemia, reduced body weight, and increased cholesterol levels. Therefore, dietary methionine in a safe dose could have medicinal values. Hence, this review is aimed to provide a snapshot of the dietary role and regulation of methionine in the modulation of health and age-related diseases.

Tumor-Specific Delivery of 5-Fluorouracil-Incorporated Epidermal Growth Factor Receptor-Targeted Aptamers as an Efficient Treatment in Pancreatic Ductal Adenocarcinoma Models.

BACKGROUNDS & AIMS: Fluoropyrimidine c (5-fluorouracil [5FU]) increasingly represents the chemotherapeutic backbone for neoadjuvant, adjuvant, and palliative treatment of pancreatic ductal adenocarcinoma (PDAC). Even in combination with other agents, 5FU efficacy remains transient and limited. One explanation for the inadequate response is insufficient and nonspecific delivery of 5FU to the tumor. METHODS: We designed, generated, and characterized 5FU-incorporated systematic evolution of ligands by exponential enrichment (SELEX)-selected epidermal growth factor receptor (EGFR)-targeted aptamers for tumor-specific delivery of 5FU to PDAC cells and tested their therapeutic efficacy in vitro and in vivo. RESULTS: 5FU-EGFR aptamers reduced proliferation in a concentration-dependent manner in mouse and human pancreatic cancer cell lines. Time-lapsed live imaging showed EGFR-specific uptake of aptamers via clathrin-dependent endocytosis. The 5FU-aptamer treatment was equally effective in 5FU-sensitive and 5FU-refractory PDAC cell lines. Biweekly treatment with 5FU-EGFR aptamers reduced tumor burden in a syngeneic orthotopic transplantation model of PDAC, in an autochthonously growing genetically engineered PDAC model (LSL-KrasG12D/+;LSL-Trp53flox/+;Ptf1a-Cre [KPC]), in an orthotopic cell line-derived xenograft model using human PDAC cells in athymic mice (CDX; Crl:NU-Foxn1nu), and in patient-derived organoids. Tumor growth was significantly attenuated during 5FU-EGFR aptamer treatment in the course of follow-up. CONCLUSIONS: Tumor-specific targeted delivery of 5FU using EGFR aptamers as the carrier achieved high target specificity; overcame 5FU resistance; and proved to be effective in a syngeneic orthotopic transplantation model, in KPC mice, in a CDX model, and in patient-derived organoids and, therefore, represents a promising backbone for pancreatic cancer chemotherapy in patients. Furthermore, our approach has the potential to target virtually any cancer entity sensitive to 5FU treatment by incorporating 5FU into cancer cell-targeting aptamers as the delivery platform.

Decorin as a possible strategy for the amelioration of COVID-19.

Coronavirus pandemic has emerged as an extraordinary healthcare crisis in modern times. The SARS-CoV-2 novel coronavirus has high transmission rate, is more aggressive and virulent in comparison to previously known coronaviruses. It primarily attacks the respiratory system by inducing cytokine storm that causes systemic inflammation and pulmonary fibrosis. Decorin is a pluripotent molecule belonging to a leucine rich proteoglycan group that exerts critical role in extracellular matrix (ECM) assembly and regulates cell growth, adhesion, proliferation, inflammation, and fibrogenesis. Interestingly, decorin has potent anti-inflammatory, cytokine inhibitory, and anti-fibrillogenesis effects which make it a potential drug candidate against the COVID-19 related complications especially in the context of lung fibrosis. Herein, we postulate that owing to its distinctive pharmacological actions and immunomodulatory effect, decorin can be a promising preclinical therapeutic agent for the therapy of COVID-19.

It's all about the spaces between cells: role of extracellular matrix in liver fibrosis.

Liver fibrosis is one of the leading complications of a variety of chronic liver disorders, including the nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver cirrhosis and liver failure. The progression of liver fibrosis is driven by chronic inflammation, which activates the secretory fibroblasts to the myofibroblast phenotype. These specialized liver cells are called as hepatic stellate cells (HSCs). The excessive extracellular matrix (ECM) secretion creates a large number of complications. Fibrosis is the result of imbalance between the matrix synthesizing and matrix degrading factors. The major ECM proteins include the matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), lysyl oxidases (LOX), lysyl oxidase-like (LOXLs) enzymes, tenascins and others. These ECM proteins present novel avenues for the therapeutics of liver fibrosis. The current review highlights the major role played by these critical matrix proteins in liver fibrosis. Further, some of the targeted formulations used against these proteins are discussed and suggestions are provided to select the course of research for successful clinical translation of basic research findings for the amelioration of liver fibrosis.

Role of nanotechnology behind the success of mRNA vaccines for COVID-19.

The emergency use authorization (EUA) by the US-FDA for two mRNA-based vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) has brought hope of addressing the COVID-19 pandemic which has killed more than two million people globally. Nanotechnology has played a significant role in the success of these vaccines. Nanoparticles (NPs) aid in improving stability by protecting the encapsulated mRNA from ribonucleases and facilitate delivery of intact mRNA to the target site. The overwhelming success of these two mRNA based vaccines with ~95% efficacy in phase III clinical trials can be attributed to their unique nanocarrier, the "lipid nanoparticles" (LNPs). LNPs are unique compared with bilayered liposomes and provide improved stability of the cargo, possess rigid morphology, and aid in better cellular penetration. This EUA is a major milestone and showcases the immense potential of nanotechnology for vaccine delivery and for fighting against future pandemics. Currently, these two vaccines are aiding in the alleviation of the COVID-19 health crisis and demonstrate the potential utility of nanomedicine for tackling health problems at the global level.

Can bilirubin nanomedicine become a hope for the management of COVID-19?

Bilirubin has been proven to possess significant anti-inflammatory, antioxidant and antiviral activities. Recently, it has been postulated as a metabolic hormone. Further, moderately higher levels of bilirubin are positively associated with reduced risk of cardiovascular diseases, diabetes, metabolic syndrome and obesity. However, due to poor solubility the therapeutic delivery of bilirubin remains a challenge. Nanotechnology offers unique advantages which may be exploited for improved delivery of bilirubin to the target organ with reduced risk of systemic toxicity. Herein, we postulate the use of intravenous administration or inhalational delivery of bilirubin nanomedicine (BNM) to combat systemic dysfunctions associated with COVID-19, owing to the remarkable preclinical efficacy and optimistic results of various clinical studies of bilirubin in non-communicable disorders. BNM may be used to harness the proven preclinical pharmacological efficacy of bilirubin against COVID-19 related systemic complications.