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Specificity protein 1 (SP1) was found to play a critical role in the regulation of TGF-β1 driven epithelial-mesenchymal transition (EMT). Recent clinical findings demonstrated a significant drop in the expression of miR-128-3p with the cancer progression in breast cancer patients. However, the impact of miR-128-3p on the SP1 expression in breast cancer remains unknown. Herein, we evaluated the role of miR-128-3p mimics in suppressing EMT of breast cancer cell lines by regulating the TGF-β1/SP1 axis.miR-128-3p interaction with SP1 was detected by in silico tools and dual-luciferase reporter assay. qPCR, western blot, and immunocytochemistry experiments were conducted for determining the expression levels of miR-128-3p and EMT markers with and without the treatment of miR-128-3p mimics. Further, to understand the effect of miR-128-3p mimics on cancer progression, experiments such as wound healing assay, transwell assay, adhesion assay, and cell cycle analysis were performed.A significant inverse relation between SP1 and miR-128-3p levels was found in MCF-7 and MDA-MB-231 cell lines. miR-128-3p overexpression impeded the SP1 mediated EMT markers in TGF-β1 stimulated cells by inhibiting the SP1 nuclear function. Further, treatment with miR-128-3p mimics significantly reduced the migration, invasion and spreading capability of TGF-β1 stimulated cells. Flow cytometry results showed the impeding role of miR-128-3p on the cell cycle progression.Upregulated miR-128-3p inhibited SP1, thereby limiting the TGF-β1 induced EMT in MCF-7 and MDA-MB-231 cell lines for the first time. This study may pave the path to explore novel miRNA therapeutics for eradicating advanced breast cancer cases.

Diabetic wounds are one of the debilitating complications that affect up to 20% of diabetic patients. Despite the advent of extensive therapies, the recovery rate is unsatisfactory, and approximately, 25% of patients undergo amputation, thereby demanding alternative therapeutic strategies. On the basis of the individual therapeutic roles of the miR-155 inhibitor and mesenchymal stem cells (MSC)-derived exosomes, we conjectured that the combination of the miR-155 inhibitor and MSC-derived exosomes would have synergy in diabetic wound healing. Herein, miR-155-inhibitor-loaded MSC-derived exosomes showed synergistic effects in keratinocyte migration, restoration of FGF-7 levels, and anti-inflammatory action, leading to accelerated wound healing mediated by negative regulation of miR-155, using an

The discovery of microRNAs (miRNAs) has been one of the revolutionary developments and has led to the advent of new diagnostic and therapeutic opportunities for the management of cancer. In this regard, miRNA dysregulation has been shown to play a critical role in various stages of tumorigenesis, including tumor invasion, metastasis as well as angiogenesis. Therefore, miRNA profiling can provide accurate fingerprints for the development of diagnostic and therapeutic platforms. This review discusses the recent discoveries of miRNA- based tools for early detection of cancer as well as disease monitoring in cancers that are common, like breast, lung, hepatic, colorectal, oral and brain cancer. Based on the involvement of miRNA in different cancers as oncogenic miRNA or tumor suppressor miRNA, the treatment with miRNA inhibitors or mimics is recommended. However, the stability and targeted delivery of miRNA remain the major limitations of miRNA delivery. In relation to this, several nanoparticle-based delivery systems have been reported which have effectively delivered the miRNA mimics or inhibitors and showed the potential for transforming these advanced delivery systems from bench to bedside in the treatment of cancer metastasis and chemoresistance. Based on this, we attempted to uncover recently reported advanced nanotherapeutic approaches to deliver the miRNAs in the management of different cancers.

Fostering pulmonary research for managing pulmonary threat requires a potential alternative approach mimicking the in vivo complexities. This review expounds on lung-on-chip microfluidic simulator devices to foster pulmonary drug discovery and personalized medicine.

Develop a platform for co-delivering clobetasol propionate (CP) and cyclosporine (CyA) to the epidermis and dermis to treat psoriasis.The transfersomes were prepared by thin-film hydration method. Transfersomes were characterised by dynamic light scattering and transmission electron microscope (TEM). Then, the gel stability, viscosity, pH, and spreadability were measured. Cytotoxicity of the CyA-loaded transfersome embedded in CP-dispersed gel (TEG-CyA-CP) was assessed on both human keratinocyte cell line (HaCaT) and Jurkat cells.Nanoscale (150 nm) transferosomes with high CyA encapsulation efficiency (86%) were made. TEG-CyA-CP demonstrated higher viscosity (4808.8 ± 12.01 mPas), which may help control dual drug release.The developed TEG-CyA-CP represents a promising fit-to-purpose delivery platform for the dual-site co-delivery of CyA and CP in treating psoriasis.

Cisplatin resistance is one of the major concerns in the treatment of oral squamous cell carcinoma (OSCC). Accumulating evidence suggests microRNA (miRNA) dysregulation as one of the mediators of chemoresistance. Toward this, our previous study revealed the role of exosomal microRNA-155 (miR-155) in cisplatin resistance via downregulation of FOXO3a, a direct target of miR-155, and induction of epithelial-to-mesenchymal transition in OSCC. In the present study, we demonstrate the therapeutic potential of miR-155 inhibitor-laden exosomes in the sensitization of a cisplatin-resistant (cisRes) OSCC 3D tumor spheroid and xenograft mouse model. The cisRes OSSC 3D tumor spheroid model recapitulated the hallmarks of solid tumors such as enhanced hypoxia, reactive oxygen species, and secretory vascular endothelial growth factor. Further treatment with miR-155 inhibitor-loaded exosomes showed the upregulation of FOXO3a and induction of the mesenchymal-to-epithelial transition with improved sensitization to cisplatin in cisRes tumor spheroids and xenograft mouse model. Moreover, the exosomal miR-155 inhibitor suppressed the stem-cell-like property as well as drug efflux transporter protein expression in cisplatin-resistant tumors. Taken together, our findings, for the first time, established that the miR-155 inhibitor-loaded exosomes reverse chemoresistance in oral cancer, thereby providing an alternative therapeutic strategy for the management of refractory oral cancer patients.

Exosomes facilitate cross-talk amongst tumor cells, and thus also possess the potential to influence tumor-microenvironment and chemo-resistance. miRNAs, the important constituent of exosomes, are often dysregulated in cancer. They have been shown to play an essential role in tumor progression, metastasis, invasion, and resistance developed against different therapies. Acquisition of cisplatin-chemoresistance remains a major hurdle in the effective treatment of oral squamous cell carcinoma (OSCC). In this study, we demonstrate the importance of exosome-mediated miR-30a transfer in conferring cisplatin sensitivity in the otherwise resistant OSCC cells. Notably, miR-30a was found to be significantly reduced in exosomes isolated from the serum of OSCC patients, especially those having disease-recurrence, post cisplatin treatment. In conjunction with the findings in clinical samples, decreased miR-30a expression was observed in vitro in the cisplatin-resistant cultured OSCC cells compared to the cisplatin-sensitive cells. Besides, we identified Beclin1, an autophagy-related marker, as a target of miR-30a and found it to be overexpressed in cisplatin-resistant OSCC cells, thus indicating at its possible negative-regulation by miR30a. Exosomes from the cisplatin-resistant cells that have been transfected with miR-30a mimics, when delivered to the naïve cisplatin-resistant cells, caused not only the significant enhancements in miR-30a expression but also a concomitant decrease in Beclin1 and Bcl2 expression (autophagic and anti-apoptotic marker). More importantly, this together resulted in the sensitization of cisplatin-resistant cells. Thus, our study highlighted the role of exosomal-mediated miR-30a transfer in regaining sensitivity of the cisplatin-resistant OSCC cells via Beclin1 and Bcl2 regulation and hence suggests at its potential therapeutic role.

Cisplatin is used as chemotherapeutic drug for oral squamous cell carcinoma (OSCC). However, OSCC cells develop resistance following long-term cisplatin exposure. Resistance against cisplatin chemo-therapy is accredited to the process of epithelial-to-mesenchymal transition, which in-turn has been linked to tumor-recurrence. miRNA deregulation, a common event in cancer, plays contributory role in chemo-resistance. Exosomes acts as the natural cargo for miRNA and facilitates inter-cell communication in the tumor micro-environment. Hence, exosomal-mediated miRNA transference may play essential role in drug resistance and serve as a target for cancer-therapy. miR-155 upregulation in OSCC has been described, however, its relevance in the observed chemo-resistance is unclear and also, if exosomes have any role in miR-155 regulation remain elusive. In the present study, we document for the first time the critical role of exosomes in mediating increments in miR-155 expression in OSCC cells that have acquired cisplatin resistance (cisRes cells). Importantly, exosomal transfer from cisRes to the cisplatin sensitive (cisSens) cells was found to confer significant miR-155 induction in the recipient cisSens cells. Restoration of miR-155 expression in cisSens cells following miR-155 mimics treatment led to epithelial to mesenchymal transition, enhancements in their migratory potential as well as acquisition of resistant phenotype. Notably, similar augmentations in the migratory and chemo-resistant traits were seen upon delivery of exosomes from cisRes to the recipient cisSens cells. Overall, our findings establish the significance of exosomal-mediated miR-155 shuttling in the cisplatin-chemoresistance, commonly observed in OSCC cells, thereby providing rationale for targeting miR-155 signalling for oral cancer therapy.

Piezoelectric materials strive to articulate smart materials and transduce electric fields by applying mechanical pressure and vice versa. This study demarcates augmented cartilage regeneration from the praxis of the smart material intervention that denotes the method of the utilized piezoelectric mechanism. The smart piezoelectric nanohybrid is developed from poly(3-hydroxybutyrate

Piezoelectric materials strive to articulate smart materials and transduce electric fields by applying mechanical pressure and vice versa. This study demarcates augmented cartilage regeneration fro...

Cancer hallmarks help in understanding the diversity of various neoplasms. Epithelial cancers play an immense role in the tumor biology through Epithelial-Mesenchymal Transition (EMT) process. Receptor tyrosine kinase, as well as phosphatidyl ionositol-3 kinase pathways, play an important role in the regulation of cell proliferation, survival, and differentiation during EMT. Till date, numerous studies have shown modulation in the expression profile of potential targets like CD44, EGFR, and Rac in epithelial cancers. CD44 interacts with EGFR and recruits other molecules which further activate the Rac pathway intermediates. This review mainly focused on modulation of genes like CD44, EGFR, and Rac pathway intermediates which play a crucial role in the tumor progression, metastasis, proliferation, and invasion characteristics in epithelial cancers with EMT properties. Hence, targeting Rac pathway might be a more strategically relevant approach in treating epithelial cancers.

Diabetes Mellitus (DM) is one of the major metabolic disorders and its severity leads to death. Enhancement in hyperglycaemic conditions of DM gives rise to endothelial impairment in small and large blood vessels contributing towards microvascular and macrovascular complications respectively. The pathogenesis of diabetic complications is associated with interruption of various signal transduction pathways due to epigenetic modifications such as aberrant histone modifications, DNA methylation and expression of miRNAs along with the long non-coding RNAs (lncRNAs). Amongst these epigenetic alterations, modulated expressions of miRNAs confer to apoptosis and endothelial dysfunction of organs that gives rise to vascular complications. In this review, we principally focussed on physiological role of miR29 family in DM and have discussed crosstalk between miR29 family and numerous genes involved in signal transduction pathways of Diabetic vascular complications. Incidences of diabetic retinopathy exploiting the role of miR29 in regulation of EMT process, differential expression patterns of miR29 and promising therapeutic role of miR29 have been discussed. We have summarised the therapeutic role of miR29 in podocyte impairment and how miR29 regulates the expressions of profibrotic, inflammatory and ECM encoding genes in renal fibrosis under diabetic conditions. We have also highlighted impact of miR29 expression patterns in cardiac angiopathy, cardiomyocyte’s apoptosis and cardiac fibrosis. Additionally, we have also presented the contradictory actions of miR29 family in amelioration as well as in enhancement of diabetic complications.

Carbon-based nanostructures with nanometer dimensions have been identified as potential photoluminescence probes for bioimaging due to their biocompatibility, tunable bandgap, and resistance to photobleaching. However, the influence of structural features of carbon quantum dots (CQDs) and graphene quantum dots (GQDs) in bioimaging has not been explored previously. In the present investigation, we elucidated the mechanism of higher PL in GQDs as compared to CQDs as a function of their structural features. TEM and AFM studies revealed that CQDs were spherical (size ~5 nm), while GQDs showed zigzag edges (size ~3 nm). Further, XRD and NMR studies confirmed that CQDs and GQDs show amorphous and crystalline structures with greater sp2 clusters, respectively. While both the QDs demonstrated multicolor fluorescence against variable excitations with similar lifetime, GQDs showed 7-fold higher QY than CQDs. Bioimaging studies in 2D cell culture, 3D tumoroids, and in vivo suggested a greater intensity of fluorescence in GQDs than CQDs. Additionally, rapid cell internalization was observed in GQDs owing to their positive surface potential by heterogeneous atomic (N and S) doping. Moreover, both CQDs and GQDs have demonstrated better time dependent stability for fluorescence properties. Taken together, the proposed mechanism elucidates the greater PL intensity in GQDs due to quantum confinement effect, crystallinity, and surface edge effects and is a better candidate for bioimaging amongst the carbon family.

Tunneling nanotubes (TNTs) are thin, F-actin-based membranous protrusions that connect distant cells and can provide e a novel mechanism for intercellular communication. By establishing cytoplasmic continuity between interconnected cells, TNTs enable the bidirectional transfer of nuclear and cytoplasmic cargo, including organelles, nucleic acids, drugs, and pathogenic molecules. TNT-mediated nucleic acid transfer provides a unique opportunity for donor cells to directly alter the genome, transcriptome, and metabolome of recipient cells. TNTs have been reported to transport DNA, mitochondrial DNA, mRNA, viral RNA, and non-coding RNAs, such as miRNA and siRNA. This mechanism of transfer is observed in physiological as well as pathological conditions, and has been implicated in the progression of disease. Herein, we provide a concise overview of TNTs’ structure, mechanisms of biogenesis, and the functional effects of TNT-mediated intercellular transfer of nucleic acid cargo. Furthermore, we highlight the potential translational applications of TNT-mediated nucleic acid transfer in cancer, immunity, and neurological diseases.

MicroRNAs (miRNA) is vital for gene expression regulation and normal kidney function. Mainly, miRNA-30a is responsible for the homeostasis of podocytes. In the diabetic nephropathic condition, miRNA-30a is directly and primarily suppressed by hyperglycemic kidney induced Notch signaling pathway leads to podocyte damage and apoptosis. Thus, transferring the exogenous miRNA-30a to podocytes might improve albuminuria as well as podocytes injury. The deprived stability, poor targetability, and low specificity in vivo are critical limitations to attain this objective. This investigation reports the specific and efficient delivery of miRNA-30a mimic via cyclo(RGDfC)-gated polymeric-nanoplexes with dendrimer templates to alleviate podocyte conditions. The nanoplexes able to protect RNase enzyme and to exhibit greater cellular uptake viaαvβ3 receptor selective binding in HG treated podocytes. The nanoplexes up-regulated the expression level of miRNA-30a and repress the elevated Notch-1 signaling in HG exposed podocytes. The critical results of in vivo experimentation attribute marked suppression of Notch-1 in streptozotocin (STZ) induced diabetic C57BL/6 mice and reduced glomerular expansion and fibrosis in the glomerular area. Developed nanoplexes represents an efficient platform for the targeted delivery of exogenous miRNA to podocytes. The approach developed herein could be extrapolated to other gene therapeutics and other kidney-related diseases.

RhoA/Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) has appeared as a potential therapeutic target in numerous diseases, because of its preventing action on various enzymes providing antioxidant and cytoprotective action. Progression and pathophysiology of diabetic nephropathy have also shown potential involvement of oxidative stress and inflammatory pathways. In the present study, we investigated the effect of kaempferol on hyperglycemia-induced activation of RhoA kinase and associated inflammatory signaling cascade. Currently there is only small literature available on the mechanism of anti-diabetic and nephroprotective action of this compound, which creates a void. Therefore, we focused here on the investigation of molecular mechanisms for kaempferol by means of in vitro testing, using rat (NRK-52E) and human renal tubular epithelial cells (RPTEC). Our findings suggest that kaempferol inhibits hyperglycemia-induced activation of RhoA and decreased oxidative stress, pro-inflammatory cytokines (TNF-α and IL-1β) and fibrosis (TGF-β1 expression, extracellular matrix protein expression) in NRK-52E and RPTEC cells. Therefore, kaempferol can be used as a potential therapeutic for the treatment of diabetic nephropathy.

In order to investigate the possible role of butter oil (BO) and omega-3 fatty acids-rich fish oil (O3FO) in the delivery of donepezil hydrochloride microemulsion (DH-ME) to the brain via intranasal route, the present study was conducted. DH:BO and DH:O3FO binary mixtures (9:1 to 1:9) were prepared by simple physical mixing and subjected to in vitro diffusion study. Ratios of DH:BO and DH:O3FO, which showed the highest diffusion, were selected for further development of microemulsion (ME). Globule sizes of DH-BO-ME and DH-O3FO-ME were found to be 87.66 ± 5.23 nm and 88.59 ± 8.23 nm, respectively. Nasal histopathological study and in vitro cytotoxicity study revealed the safety of the formulation. Higher percentage of nasal diffusion was found with DH-BO-ME (71.22 ± 1.21%) and DH-O3FO-ME (62.16 ± 1.23%) in comparison to DH-ME (59.69 ± 1.74%) and DH solution (55.01 ± 1.19%), which was further supported by in vitro cell permeability study. After intranasal administration, %bioavailability of drug in the rat brain (Sprague-Dawley rats)(on the basis of DH-ME IV) was higher with DH-BO-ME (313.59 ± 12.98%) and DH-O3FO-ME (361.73 ± 15.15%) in comparison to DH-ME (168.62 ± 6.60%) and DH solution (8.960 ± 0.23%). The results of ex vivo diffusion study and in vivo pharmacokinetic study suggested that BO and O3FO helped in enhancing the nasal permeability and the brain uptake of drug when administered intranasally.

PURPOSE: As epigenetic modifications like chromatin histone modifications have been suggested to play a role in the pathophysiology of Diabetic Nephropathy (DN) and are also found to be regulated by microRNAs. Our main purpose was to explore the role of microRNA in histone modulations associated with DN. There is downregulation of miR-29b due to advanced glycation end products in diabetes. Histone Deacetylase-4 (HDAC4) is amongst the histone modulators which promotes podocytes’ impairment and upregulates transforming growth factor-1 (TGF-β1) leading to renal fibrosis. Moreover, macrophage infiltration causes podocytes’ apoptosis and IL-6 mediated inflammation. As miR-29b is downregulated in diabetes and HDAC4, TGF-β1 and IL-6 could be the possible therapeutic targets in DN, our study was focussed on unveiling the role of miR-29b in modulation of HDAC4 and hence, in podocyte dysfunction and renal fibrosis in DN. METHODS: In silico analysis and luciferase assay were done to study the interaction between miR-29b and HDAC4. In-vitro DN model was developed in podocytes and miR-29b mimics were transfected. Also, podocytes were co-cultured with macrophage and miR-29b mimics were transfected. At the end, in-vivo DN model was generated in C57BL/6 J male mice and the effect of miR-29b mimics was reconfirmed. RESULTS: It was found that miR-29b targets the 3′ untranslated region of HDAC4. In both in-vitro and in-vivo DN model, downregulation of miR-29b and subsequent increase in HDAC4 expression was observed. The miR-29b mimics suppressed podocytes’ inflammation mediated through macrophages and attenuated HDAC4 expression, glomerular damage and renal fibrosis. CONCLUSION: This study concludes that miR-29b regulates the expression of HDAC4 which plays a role in controlling renal fibrosis and podocytes’ impairment in DN. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40200-019-00469-0) contains supplementary material, which is available to authorized users.

Hyperglycemia is one of the major risk factors responsible for memory impairment in diabetes which may lead to Alzheimer's disease (AD) at a later stage. MicroRNAs are a class of non-coding RNAs that are found to play a role in diabetes. Downregulation of microRNA-29b in diabetes is well reported. Moreover, microRNA-29b is also reported to target the 3' UTR of β-secretase (BACE-1) enzyme which is involved in the formation of amyloid-beta (Aβ) in AD via cleavage of amyloid precursor protein (APP). Therefore, the present study was designed to elucidate whether microRNA-29b could be a link between diabetes and dementia. In the in vitro and in vivo diabetic model, we found downregulation of microRNA-29b due to hyperglycemia. After human microRNA-29b treatment, there was a significant improvement in the short-term and spatial memory in diabetic mice. Also, the human microRNA-29b treatment decreased oxidative stress and BACE-1 activity in diabetes. The present findings revealed that the downregulation of microRNA-29b in diabetes could be associated with memory impairment and increased BACE-1 activity. These results would give a future direction to study the role played by microRNAs in diabetes-associated memory impairment and hence aid in the development of therapeutics to treat the same.

Small interfering RNA (siRNA) are synthetic RNA duplex designed to specifically knockdown the abnormal gene to treat a disease at cellular and molecular levels. In spite of their high potency, specificity, and therapeutic potential, the full-fledged utility of siRNA is predominantly limited to in vitro set-up. Till date, Onpattro is the only USFDA approved siRNA therapeutics available in the clinic. The lack of a reliable in vivo siRNA delivery carrier remains a foremost obstacle towards the clinical translation of siRNA therapeutics. To address the obstacles associated with siRNA delivery, we tested a dendrimer-templated polymeric approach involving a USFDA approved carrier (albumin) for in vitro as well as in vivo delivery of siRNA. The developed approach is simple in application, enhances the serum stability, avoids in vivo RNase-degradation and mediates cytosolic delivery of siRNA following the endosomal escape process. The successful in vitro and in vivo delivery of siRNA, as well as targeted gene knockdown potential, was demonstrated by HDAC4 inhibition in vitro diabetic nephropathy (DN) podocyte model as well as in vivo DN C57BL/6 mice model. The developed approach has been tested using HDAC4 siRNA as a model therapeutics, while the application can also be extended to other gene therapeutics including micro RNA (miRNA), plasmids oligonucleotides, etc.

Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting millions of people worldwide. Diabetes is associated with various complications like nephropathy, neuropathy, retinopathy, diabetic foot, cognitive impairment, and many more. Evidence suggests that cognitive dysfunction is a rising complication of diabetes which adversely affects the brain of patients suffering from diabetes. Age-related memory impairment is a complication having its major effect on people suffering from diabetes and Alzheimer's. Patients suffering from diabetes are at two times higher risk of developing cognitive dysfunction as compared with normal individuals. Multiple factors which are involved in diabetes related complications are found to play a role in the development of neurodegeneration in Alzheimer's. The problem of insulin deficiency and insulin resistance is well reported in diabetes but there are many studies which suggest dysregulation of insulin levels as a reason behind the development of Alzheimer's. As the link between diabetes and Alzheimer disease (AD) is deepening, there is a need to understand the plausible tie-ins between the two. Emerging role of major factors like insulin imbalance, advanced glycation end products and micro-RNA's involved in diabetes and Alzheimer's have been discussed here. This review helps in understanding the plausible mechanism underlying the pathophysiology of amyloid beta (Aβ) plaque formation and tau hyperphosphorylation as well provides information about studies carried out in this area of research. The final thought is to enhance the scientific knowledge on this correlation and develop future therapeutics to treat the same.

Diseases of the posterior segment of the eye are difficult to treat due to lesser bioavailability of therapeutics at the posterior segment of the eye. Current clinical interventions involve administering drugs via invasive routes (Intravitreal, Retrobulbar, or Peribulbar) that bear the least patient compliance. Several nanocarriers strategies have shown a remarkable potential to deliver the loaded therapeutic to the posterior tissues of the eye. However, no one platform report was available to demarcate the most effective delivery system out of the recommended approaches. This investigation aimed at exploring a suitable and efficient non-invasive topically administrable nanocarriers system for the delivery of the drug to the posterior segment of the eye. Dexamethasone (DEX, a corticosteroid used for ocular inflammation) was selected as a model drug. The nanocarriers were formulated (size ~120 nm) and studied their potential at a common platform to deliver the drug to the posterior segment of the eye. The nanocarriers were analyzed for their in vitro drug release profile in simulated tear fluid (STF) depicting sustained release of DEX up to 24 h, ex-vivo corneal permeability, using excised goat cornea, cytotoxicity potential using human retinal pigment epithelium ARPE-19 cell lines, HET CAM assay to evaluate ocular irritancy, electrical resistance measurement across monolayers of Rabbit corneal epithelial cells SIRC and ARPE-19 cells and stability profiles, real-time qPCR IL-6 gene expression in ARPE-19 inflammation model. Ex-vivo corneal permeability demonstrated that the highest percentage of DEX was permeated by DEX-NLCs and lowest by DEX-SLNs. All the nanocarriers except DEX-CUBs depicted no cytotoxicity in ARPE-19 cells. All the nanocarriers depicted the change in electrical resistance measurement across monolayers of Rabbit corneal epithelial cells SIRC and ARPE-19 cells. They were also found to reduce the levels of IL-6 in gene expression assay depicting successful invitro delivery to ARPE-19 cells. However, only NLCs and NMFs were selected further as they demonstrated better potential to permeate after ex vivo and in vitro permeability studies. Further, in-vivo fluorescence imaging studies in Wistar rats were also performed with coumarin-6 loaded nanocarriers to deduce the effective and suitable candidate to deliver a drug to the posterior segment of the eye with the highest biosafety and permeability.

In the treatment of cancer, there are three significant limitations causing high mortality and recurrence rates among cancer patients. First, the escape of tumor cells from the immune system; second, the development of multi-drug resistance (MDR) to chemotherapeutic drugs; and, third, the noxious metastases of cancer cells. Exosomes are vesicular cargos involved in the transportation of miRNA, mRNA and proteins from one cell to another cell. This review details the current understanding of the exosomal transmission of miRNA and crosstalk with the downstream consequences, ultimately leading to the progression and metastasis of cancer. Further, this review also discusses how exosomal miRNA can provide promising novel targets for the treatment and detection of cancer.

Diabetic Nephropathy (DN), a chronic progressive kidney disease, is a major complication of diabetes mellitus. Dysregulation of histone deacetylases (HDACs) gene has been implicated in the pathogenesis of DN. Hence, the HDAC-inhibitors have emerged as a novel class of therapeutic agents in DN, however, the currently available HDAC4-inhibitors are mostly nonselective in nature as well as inhibit multiple HDACs. RNA interference of HDAC4 (HDAC4 siRNA) has shown immense promise, but the clinical translation has been impeded due to lack of a targeted, specific and in vivo applicable delivery modality. In the present investigation, we examined Cyclo(RGDfC) (cRGD) truncated polymeric nanoplex with dendrimeric templates for targeted HDAC4 Gene Silencing. The developed nanoplex exhibited enhance encapsulation of siRNA and offered superior protection against serum RNase nucleases degradation. The nanoplex was tested on podocytes (in vitro) wherein it showed selective binding to the αvβ3 integrin receptor, effective cellular uptake and significant in vitro gene silencing. The in vivo experiments showed remarkable suppression of the HDAC4 and inhibition in the progression of renal fibrosis in STZ induced DN C57BL/6 mice model. Histopathological and toxicological studies revealed non-significant abnormality/toxicity with the nanoplex. Conclusively, nanoplex was found as a promising tactic for targeted therapy of podocytes and could be extended for other kidney related ailments.

This investigation reports a novel nanoGold-core multifunctional dendrimer for pulsatile chemo-, photothermal- and photodynamic- therapy of rheumatoid arthritis (RA). Architecturally, the nanocomposites comprised of a nanoGold (Au) at the focal whose surface is functionalized by hydroxy-terminated thiolated-dendrons following Au-thiol bond formation to produce nanoGold-core multifunctional dendrimer (Au-DEN). The surface hydroxyl groups of Au-DEN were then conjugated with methotrexate (MTX; a disease-modifying first line anti-rheumatic drug; DMARD; 74.29 ± 0.48% loading) to form Au-DEN-MTX-NPs (Particle size: 100.15 ± 28.36 nm; poly dispersibility index, PDI: 0.39 ± 0.02; surface zeta potential, ζ: −22.45 ± 1.06 mV). MTX was strategically selected to serve as an anti-rheumatic DMARD as well as a targeting ligand to attain selective localization of the formulation in arthritic tissue via folate receptors upregulated on arthritic tissues. The docking study was performed to confirm the viable binding efficiency of MTX towards β-folate receptors that are overexpressed on arthritic tissues taking folic acid as a reference standard. The IR780, a NIR active bioactive was also loaded in Au-DEN-MTX NPs to offer photothermal benefit upon irradiation with NIR laser (wavelength: 808 nm). The hypothesis was tested by elucidation of in vitro drug release profile, photothermal activity, cellular uptake (Fluorescence and confocal laser scanning microscopy; CLSM), cell viability assay (MTT protocol) and Intracellular reactive oxygen species (ROS) generation in mouse macrophage RAW264.7 cells and Lipopolysaccharide (LPS) activated RAW264.7 cells. Furthermore, the hemolytic toxicity and stability studies were also investigated to determine the blood compatibility as well as ideal storage condition of NPs. The outcome of this investigations presents developed multifunctional targeted NPs to be potential therapeutics for the improved treatment of RA. The approach can also be applied to other clinical interventions involving countering inflammatory conditions.

Glioblastoma is one of the most rapaciously growing cancer within the brain with an average lifespan of 12-15 months (5-year survival3-4%). Doxorubicin (DOX) is clinically utilized as a first line drug in the treatment of Glioblastoma, however, its restricted entry into the brain via the blood-brain barrier (BBB), limited blood-tumor barrier (BTB) permeability, hemotoxicity, short mean half-life of 1-3 hr as well as rapid body clearance results in tremendously diminished bioactivity in glioblastoma. Dendrimer-Cationized-Albumin (dCatAlb) was synthesized following the carboxyl activation technique and the synthesized biopolymer was characterized by FTIR, MALDI-TOF and zeta potential. The prepared dCatAlb was encrusted on DOX-loaded PLGA nanoparticle core to develop a novel hybrid DOX nanoformulation (dCatAlb-pDNP; particle size: 156 ± 10.85 nm; ƺ: -10.0 ± 2.1 mV surface charge). The formulated dCatAlb-pDNP showed a unique pH-dependent DOX release profile, diminished hemolytic toxicity, higher drug uptake (0.001) and cytotoxicity in U87MG glioblastoma cells, increase levels of caspase-3 gene in U87MG cells (approximately 5.35-fold higher) inferred that anticancer activity is primarily taking place through caspase-mediated apoptosis mechanism. The developed novel DOX nanoformulation also showed superior trans-epithelial permeation transport across monolayer bEnd.3 cells as well as notable biocompatibility and stability. The dCatAlb-pDNP showed enhanced BBB permeation efficacy as confirmed permeation assay in bEnd.3 cell-based model. The long-term formulation stability of developed nanoformulations was studied by storing them at 5 ± 2 °C and 30 ± 2 °C/60 ± 5% Relative Humidity (% RH) in the stability chamber for a period of 60 days (ICHQ1A (R2)). The outcomes of this investigation evidently indicate that dCatAlb-pDNP offers superior anticancer activity of DOX in glioblastoma cells while significantly improving its BBB permeation. The developed formulation is a biocompatible, safer and commercially viable approach to delivering DOX selectively in sustained manner glioblastoma while countering its hemolytic toxic effect, which is a major ongoing issue with conventional DOX injectable available in the market today.

RNA interference (RNAi) therapeutics (siRNA, miRNA, etc.) represent an emerging medicinal remedy for a variety of ailments. However, their low serum stability and low cellular uptake significantly restrict their clinical applications. Exosomes are biologically derived nanodimensional vesicle ranging from a few nanometers to a hundred. In the last few years, several reports have been published demonstrating the emerging applications of these exogenous membrane vesicles, particularly in carrying different RNAi therapeutics to adjacent or distant targeted cells. In this report, we explored the numerous aspects of exosomes from structure to clinical implications with special emphasis on their application in delivering RNAi-based therapeutics. siRNA and miRNA have attracted great interest in recent years due to their specific application in treating many complex diseases including cancer. We highlight strategies to obviate the challenges of their low bioavailability for gene therapy.