Unravelling the progress and potential of drug-eluting stents and drug-coated balloons in cardiological insurgencies.

AIM: Coronary artery disease (CAD) is the leading cause of mortality. Though percutaneous transluminal angioplasty followed by stenting is still the default treatment of choice for revascularization of obstructive CAD, the high rate of restenosis compromises the outcomes of endovascular procedures. To overcome restenosis, drug-eluting stents (DES) and drug-coated balloons (DCB) are designed that release antiproliferative drugs like sirolimus, paclitaxel, everolimus, etc., over time to inhibit cell growth and proliferation. Our review aims to summarize the challenges and progress of DES/DCBs in clinical settings. MATERIAL AND METHODS: The comprehensive review, search and selection encompasses in relevant articles through Google Scholar, Springer online, Cochrane library and PubMed that includes research articles, reviews, letters and communications, various viewpoints, meta-analyses, randomized trials and quasi-randomized trials. Several preclinical and clinical data have been included from National Institutes of Health and clinicaltrials.gov websites. KEY FINDINGS: Challenges like delayed endothelialization, stent thrombosis (ST), and inflammation was prominent in first-generation DES. Second-generation DES with improved designs and drug coatings enhanced biocompatibility with fewer complications. Gradual absorption of bioresorbable DES over time mitigated long-term issues associated with permanent implants. Polymer-free DES addressed the inflammation concerns but still, they leave behind metallic stents in the vasculature. As an alternative therapeutic strategy, DCB were developed to minimize inflammation in the vessel. Although both DES and DCBs have shown considerable progress, challenges persist. SIGNIFICANCE: This review illustrates the advancements in the designs, preparation technologies, biodegradable materials, and drugs used as well as challenges associated with DES and DCBs in clinical settings.

Exploring Astrocytes Involvement and Glutamate Induced Neuroinflammation in Chlorpyrifos-Induced Paradigm Of Autism Spectrum Disorders (ASD).

Autism spectrum disorders (ASD) are neurodevelopmental disorders manifested mainly in children, with symptoms ranging from social/communication deficits and stereotypies to associated behavioral anomalies like anxiety, depression, and ADHD. While the patho-mechanism is not well understood, the role of neuroinflammation has been suggested. Nevertheless, the triggers giving rise to this neuroinflammation have not previously been explored in detail, so the present study was aimed at exploring the role of glutamate on these processes, potentially carried out through increased activity of inflammatory cells like astrocytes, and a decline in neuronal health. A novel chlorpyrifos-induced paradigm of ASD in rat pups was used for the present study. The animals were subjected to tests assessing their neonatal development and adolescent behaviors (social skills, stereotypies, sensorimotor deficits, anxiety, depression, olfactory, and pain perception). Markers for inflammation and the levels of molecules involved in glutamate excitotoxicity, and neuroinflammation were also measured. Additionally, the expression of reactive oxygen species and markers of neuronal inflammation (GFAP) and function (c-Fos) were evaluated, along with an assessment of histopathological alterations. Based on these evaluations, it was found that postnatal administration of CPF had a negative impact on neurobehavior during both the neonatal and adolescent phases, especially on developmental markers, and brought about the generation of ASD-like symptoms. This was further corroborated by elevations in the expression of glutamate and downstream calcium, as well as certain cytokines and neuroinflammatory markers, and validated through histopathological and immunohistochemical results showing a decline in neuronal health in an astrocyte-mediated cytokine-dependent fashion. Through our findings, conclusive evidence regarding the involvement of glutamate in neuroinflammatory pathways implicated in the development of ASD-like symptoms, as well as its ability to activate further downstream processes linked to neuronal damage has been obtained. The role of astrocytes and the detrimental effect on neuronal health are also concluded. The significance of our study and its findings lies in the evaluation of the involvement of chlorpyrifos-induced neurotoxicity in the development of ASD, particularly in relation to glutamatergic dysfunction and neuronal damage.

Ultrasound-Responsive Nanodroplet-Based Targeted Therapy via Conversion to Microbubbles.

Ultrasound-based therapy is appealing as it can be used via a wireless approach at remote parts of the body including the brain. Microbubbles are commonly used in such therapy due to their highly sound-responsive property. However, the larger size of microbubbles limits selective targeting in vitro/in vivo. Here, we report the design of nanodroplets of 70-130 nm in size that can be easily converted to microbubbles via ultrasound exposure. The advantage of this approach is that smaller nanodroplets can be used for cell/subcellular targeting, and next, they can be used for therapy by converting to microbubbles. More specifically, folate/dopamine-terminated perfluorohexane nanodroplets are designed that are loaded with a molecular drug. These nanodroplets are used for selective cell targeting, followed by ultrasound-induced microbubble conversion that is associated with drug release and intracellular reactive oxygen species generation. This approach has been used for selective cell therapy applications. The designed nanodroplet and approach can be used for the enhanced therapeutic performance of existing drugs.

Gamut of glycolytic enzymes in vascular smooth muscle cell proliferation: Implications for vascular proliferative diseases.

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the media of the blood vessels and are responsible for maintaining vascular tone. Emerging evidence confirms that VSMCs possess high plasticity. During vascular injury, VSMCs switch from a "contractile" phenotype to an extremely proliferative "synthetic" phenotype. The balance between both strongly affects the progression of vascular remodeling in many cardiovascular pathologies such as restenosis, atherosclerosis and aortic aneurism. Proliferating cells demand high energy requirements and to meet this necessity, alteration in cellular bioenergetics seems to be essential. Glycolysis, fatty acid metabolism, and amino acid metabolism act as a fuel for VSMC proliferation. Metabolic reprogramming of VSMCs is dynamically variable that involves multiple mechanisms and encompasses the coordination of various signaling molecules, proteins, and enzymes. Here, we systemically reviewed the metabolic changes together with the possible treatments that are still under investigation underlying VSMC plasticity which provides a promising direction for the treatment of diseases associated with VSMC proliferation. A better understanding of the interaction between metabolism with associated signaling may uncover additional targets for better therapeutic strategies in vascular disorders.

Protein Delivery to the Cytosol and Cell Nucleus via Micellar Nanocarrier-Based Nonendocytic Uptake.

Although efficient cell nucleus delivery of exogenous materials can greatly improve their biochemical activity, this is strictly restricted by cellular uptake and intracellular trafficking processes. In the current approach, synthetic carriers are designed for cell delivery of exogenous materials via endocytosis, and nucleus delivery can be achieved via endosomal escape. Here, we demonstrate that a nonendocytic cell uptake approach can be adapted for protein delivery to the cell nucleus. We have designed a phenylboronic acid-terminated micellar carrier that can bind with protein in the presence of green tea polyphenol and deliver protein into the cytosol via the nonendocytic approach. Using this approach, four different proteins are delivered to the cytosol within 15 min, and low-molecular weight proteins are delivered to the nucleus. The designed approach can be extended for delivering macromolecular drugs to subcellular targets for a more efficient therapy.

Nuclear Transport of the Molecular Drug via Nanocarrier-Based Nonendocytic Cellular Uptake.

Although subcellular targeting can enhance the therapeutic performance of most drugs, such targeting requires appropriate carrier-based delivery that can bypass endosomal/lysosomal trafficking. Recent works show that nanocarriers can be designed for direct cell membrane translocation and nonendocytic uptake, bypassing the usual endocytosis processes. Here we show that this approach can be adapted for the rapid cell nucleus delivery of molecular drugs. In particular, a guanidinium-terminated nanocarrier is used to create a weak interaction-based carrier-drug nanoassembly for direct membrane translocation into the cytosol. The rapid and extensive entry of a drug-loaded nanocarrier into the cell without any vesicular coating and affinity of the drug to the nucleus allows their nucleus labeling. Compared to endocytotic uptake that requires more than hours for cell uptake followed by predominant lysosomal entrapment, this nonendocytic uptake labels the nucleus within a few minutes without any lysosomal trafficking. This approach may be utilized for nanocarrier-based subcellular targeting of drugs for more effective therapy.

Biodegradable Poly(trehalose) Nanoparticle for Preventing Amyloid Beta Aggregation and Related Neurotoxicity.

Trehalose is a disaccharide that is capable of inhibiting protein aggregation and activating cellular autophagy. It has been shown that a polymer or nanoparticle form, terminated with multiple trehalose units, can significantly enhance the anti-amyloidogenic performance and is suitable for the treatment of neurodegenerative diseases. Here, we report a trehalose-conjugated polycarbonate-co-lactide polymer and formulation of its nanoparticles having multiple numbers of trehalose exposed on the surface. The resultant poly(trehalose) nanoparticle inhibits the aggregation of amyloid beta peptides and disintegrates matured amyloid fibrils into smaller fragments. Moreover, the poly(trehalose) nanoparticle lowers extracellular amyloid ß oligomer-driven cellular stress and enhances cell viability. The presence of biodegradable polycarbonate components in the poly(trehalose) nanoparticle would enhance their application potential as an anti-amyloidogenic material.

Efficient Synergistic Antibacterial Activity of α-MSH Using Chitosan-Based Versatile Nanoconjugates.

The application of antimicrobial peptides has emerged as an alternative therapeutic tool to encounter against multidrug resistance of different pathogenic organisms. α-Melanocyte stimulating hormone (α-MSH), an endogenous neuropeptide, is found to be efficient in eradicating infection of various kinds of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA). However, the chemical stability and efficient delivery of these biopharmaceuticals (i.e., α-MSH) to bacterial cells with a significant antibacterial effect remains a key challenge. To address this issue, we have developed a chitosan-cholesterol polymer using a single-step, one-pot, and simple chemical conjugation technique, where α-MSH is loaded with a significantly high amount (37.7%), and the final product is obtained as chitosan-cholesterol α-MSH polymer-drug nanoconjugates. A staphylococcal growth inhibition experiment was performed using chitosan-cholesterol α-MSH and individual controls. α-MSH and chitosan-cholesterol both show bacterial growth inhibition by a magnitude of 50 and 79%, respectively. The killing efficiency of polymer-drug nanoconjugates was very drastic, and almost no bacterial colony was observed (∼100% inhibition) after overnight incubation. Phenotypic alternation was observed in the presence of α-MSH causing changes in the cell structure and shape, indicating stress on Staphylococcus aureus. As a further consequence, vigorous cell lysis with concomitant release of the cellular material in the nearby medium was observed after treatment of chitosan-cholesterol α-MSH nanoconjugates. This vigorous lysis of the cell structure is associated with extensive aggregation of the bacterial cells evident in scanning electron microscopy (SEM). The dose-response experiment was performed with various concentrations of chitosan-cholesterol α-MSH nanoconjugates to decipher the degree of the bactericidal effect. The concentration of α-MSH as low as 1 pM also shows significant inhibition of bacterial growth (∼40% growth inhibition) of Staphylococcus aureus. Despite playing an important role in inhibiting bacterial growth, our investigation on hemolytic assay shows that chitosan-cholesterol α-MSH is significantly nontoxic at a wide range of concentrations. In a nutshell, our analysis demonstrated novel antimicrobial activity of nanoparticle-conjugated α-MSH, which could be used as future therapeutics against multidrug-resistant Staphylococcus aureus and other types of bacterial cells.

Short Peptoid Evolved from the Key Hydrophobic Stretch of Amyloid-ß42 Peptide Serves as a Potent Therapeutic Lead of Alzheimer's Disease.

Amyloid-ß 42(Aß42), an enzymatically cleaved (1-42 amino acid long) toxic peptide remnant, has long been reported to play the key role in Alzheimer's disease (AD). Aß42 also plays the key role in the onset of other AD-related factors including hyperphosphorylation of tau protein that forms intracellular neurofibrillary tangles, imbalances in the function of the neurotransmitter acetylcholine, and even generation of reactive oxygen species (ROS), disrupting the cytoskeleton and homeostasis of the cell. To address these issues, researchers have tried to construct several strategies to target multiple aspects of the disease but failed to produce any clinically successful therapeutic molecules. In this article, we report a new peptoid called RA-1 that was designed and constructed from the hydrophobic stretch of the Aß42 peptide, 16KLVFFA21. This hydrophobic stretch is primarily responsible for the Aß42 peptide aggregation. Experimental study showed that the RA-1 peptoid is stable under proteolytic conditions, can stabilize the microtubule, and can inhibit the formation of toxic Aß42 aggregates by attenuating hydrophobic interactions between Aß42 monomers. Furthermore, results from various intracellular assays showed that RA-1 inhibits Aß42 fibril formation caused by the imbalance in AchE activity, reduces the production of cytotoxic reactive oxygen species (ROS), and promotes neurite outgrowth even in the toxic environment. Remarkably, we have also demonstrated that our peptoid has significant ability to improve the cognitive ability and memory impairment in in vivo rats exposed to AlCl3 and d-galactose (d-gal) dementia model. These findings are also validated with histological studies. Overall, our newly developed peptoid emerges as a multimodal potent therapeutic lead molecule against AD.

Direct Cellular Delivery of Exogenous Genetic Material and Protein via Colloidal Nano-Assemblies with Biopolymer.

Direct cytosolic delivery of large biomolecules that bypass the endocytic pathways is a promising strategy for therapeutic applications. Recent works have shown that small-molecule, nanoparticle, and polymer-based carriers can be designed for direct cytosolic delivery. It has been shown that the specific surface chemistry of the carrier, nanoscale assembly between the carrier and cargo molecule, good colloidal stability, and low surface charge of the nano-assembly are critical for non-endocytic uptake processes. Here we report a guanidinium-terminated polyaspartic acid micelle for direct cytosolic delivery of protein and DNA. The polymer delivers the protein/DNA directly to the cytosol by forming a nano-assembly, and it is observed that <200 nm size of colloidal assembly with near-zero surface charge is critical for efficient cytosolic delivery. This work shows the importance of size and colloidal property of the nano-assembly for carrier-based cytosolic delivery of large biomolecules.

Neuroimmune crosstalk and evolving pharmacotherapies in neurodegenerative diseases.

Neurodegeneration is characterized by gradual onset and limited availability of specific biomarkers. Apart from various aetiologies such as infection, trauma, genetic mutation, the interaction between the immune system and CNS is widely associated with neuronal damage in neurodegenerative diseases. The immune system plays a distinct role in disease progression and cellular homeostasis. It induces cellular and humoral responses, and enables tissue repair, cellular healing and clearance of cellular detritus. Aberrant and chronic activation of the immune system can damage healthy neurons. The pro-inflammatory mediators secreted by chief innate immune components, the complement system, microglia and inflammasome can augment cytotoxicity. Furthermore, these inflammatory mediators accelerate microglial activation resulting in progressive neuronal loss. Various animal studies have been carried out to unravel the complex pathology and ascertain biomarkers for these harmful diseases, but have had limited success. The present review will provide a thorough understanding of microglial activation, complement system and inflammasome generation, which lead the healthy brain towards neurodegeneration. In addition to this, possible targets of immune components to confer a strategic treatment regime for the alleviation of neuronal damage are also summarized.

Post-stroke depression: Chaos to exposition.

Cerebral ischemia contributes to significant disabilities worldwide, impairing cognitive function and motor coordination in affected individuals. Stroke has severe neuropsychological outcomes, the major one being a stroke. Stroke survivors begin to show symptoms of depression within a few months of the incidence that overtime progresses to become a long-term ailment. As the pathophysiology for the progression of the disease is multifactorial and complex, it limits the understanding of the disease mechanism completely. Meta-analyses and randomized clinical trials have shown that intervening early with tricyclic antidepressants and selective serotonin receptor inhibitors can be effective. However, these pharmacotherapies possess several limitations that have given rise to newer approaches such as brain stimulation, psychotherapy and rehabilitation therapy, which in today's time are gaining attention for their beneficial results in post-stroke depression (PSD). The present review highlights numerous factors like lesion location, inflammatory mediators and genetic abnormalities that play a crucial role in the development of depression in stroke patients. Further, we have also discussed various mechanisms involved in post-stroke depression (PSD) and strategies for early detection and diagnosis using biomarkers that may revolutionize treatment for the affected population. Towards the end, along with the preclinical scenario, we have also discussed the various treatment approaches like pharmacotherapy, traditional medicines, psychotherapy, electrical stimulation and microRNAs being utilized for effectively managing PSD.

Cerebro-renal interaction and stroke.

Stroke is an event causing a disturbance in cerebral function leading to death and disability worldwide. Both acute kidney injury and chronic kidney disease (CKD) are associated with an increased risk of stroke and cerebrovascular events. The underlying mechanistic approach between impaired renal function and stroke is limitedly explored and has attracted researchers to learn more for developing therapeutic intervention. Common risk factors such as hypertension, hyperphosphatemia, atrial fibrillation, arteriosclerosis, hyperhomocysteinemia, blood-brain barrier disruption, inflammation, etc. are observed in the general population, but are high in renal failure patients. Also, risk factors like bone mineral metabolism, uremic toxins, and anemia, along with the process of dialysis in CKD patients, eventually increases the risk of stroke. Therefore, early detection of risks associated with stroke in CKD is imperative, which may decrease the mortality associated with it. This review highlights mechanisms by which kidney dysfunction can lead to cerebrovascular events and increase the risk of stroke in renal impairment.

The Role of Inflammasomes in Atherosclerosis and Stroke Pathogenesis.

Inflammation is a devastating outcome of cerebrovascular diseases (CVD), namely stroke and atherosclerosis. Numerous studies over the decade have shown that inflammasomes play a role in mediating inflammatory reactions post cellular injury occurring after a stroke or a rupture of an atherosclerotic plaque. In view of this, targeting these inflammatory pathways using different pharmacological therapies may improve outcomes in patients with CVD. Here, we review the mechanisms by which inflammasomes drive the pathogenesis of stroke and atherosclerosis. Also, discussed here are the possible treatment strategies available for inhibiting inflammasomes or their up-stream/down-stream mediators.

Migraine and Ischemic Stroke: Deciphering the Bidirectional Pathway.

Migraine and stroke are common, disabling neurological conditions with several theories being proposed to explain this bidirectional relationship. Migraine is considered as a benign neurological disorder, but research has revealed a connection between migraine and stroke, predominantly those having migraine with aura (MA). Among migraineurs, females with MA are more susceptible to ischemic stroke and may have a migrainous infarction. Migrainous infarction mostly occurs in the posterior circulation of young women. Although there are several theories about the potential relationship between MA and stroke, the precise pathological process of migrainous infarction is not clear. It is assumed that cortical spreading depression (CSD) might be one of the essential factors for migrainous infarction. Other factors that may contribute to migrainous infarction may be genetic, hormonal fluctuation, hypercoagulation, and right to left cardiac shunts. Antimigraine drugs, such as ergot alkaloids and triptans, are widely used in migraine care. Still, they have been found to cause severe vasoconstriction, which may result in the development of ischemia. It is reported that patients with stroke develop migraines during the recovery phase. Both experimental and clinical data suggest that cerebral microembolism can act as a potential trigger for MA. Further studies are warranted for the treatment of migraine, which may lead to a decline in migraine-related stroke. In this present article, we have outlined various potential pathways that link migraine and stroke.

Peptide Hydrogels as Platforms for Sustained Release of Antimicrobial and Antitumor Drugs and Proteins.

A charged synthetic peptide-based noncytotoxic hydrogelator was employed in encapsulation, storage, and sustainable release of different kinds of drugs, namely, ciprofloxacin (CP), an antibiotic; 5-fluorouracil (5-FU), an anticancer drug and proteins like lysozyme and bovine serum albumin (BSA). Hydrogelation of the peptide and its coassembly with the drug molecules were studied to obtain mechanistic details. All of the different cargos were capable of sustained and efficient release from the delivery platform. The drugs were found to retain their activity post release, while the proteins showed complete retention of their secondary structure. While about 80% CP was released at physiological pH over a period of 3 days, 5-FU was better released (73%) at an acidic pH (5.5) in comparison to the physiological pH (68%). Lysozyme was better released (82%) than BSA (43%) owing to the smaller size of the former and negative charge on the latter. Such biocompatible multicargo-releasing platforms from simple economically viable biomaterials, capable of sustained and tissue-specific release of cargo, are extremely promising in topical delivery of therapeutics.

Co-assembly of charge complementary peptides and their applications as organic dye/heavy metal ion (Pb2+, Hg2+) absorbents and arsenic(iii/v) detectors.

Learning from nature, molecular self-assembly has been used extensively to generate interesting materials using a bottom up approach. The enthusiasm in this field of research stems from the unique properties of these materials and their diverse applications. The field has not been limited to studying assembly of similar types of molecules but extended to multi component systems via the co-assembly phenomenon. We have designed two charge complementary peptides to study their co-assembly in mechanistic detail in the present work. The cooperative self-assembly is mainly driven by electrostatic interaction that is aided by aromatic interactions, hydrogen bonding interactions and hydrophobic interactions. The hydrogels obtained have been employed in waste water remediation. Both the self-assembled and co-assembled hydrogels are capable of removal of different kinds of organic dyes (cationic, anionic and neutral) and toxic metal ions (Ni2+, Co2+, Pb2+ and Hg2+) individually and as a mixture from water with high efficiency. Additionally, the peptides developed in this study can act as ion sensors and detect arsenic in its most toxic (III/V) oxidation states. Molecular understanding of the assembly process is of fundamental importance in the rational design of such simple, robust yet economically viable materials with versatile and novel applications.