Hesperidin guided injured spinal cord neural regeneration with a combination of MWCNT-collagen-hyaluronic acid composite: In-vitro analysis.

Restoring the lost bioelectrical signal transmission along with the appropriate microenvironment is one of the major clinical challenges in spinal cord regeneration. In the current research, we developed a polysaccharide-based protein composite Multiwalled Carbon Nanotubes (MWCNTs)/ Collagen (Col)/ Hyaluronic acid (HA) composite with Hesperidin (Hes) natural compound to investigate its combined therapeutic effect along with biocompatibility, antioxidant activity, and electrical conductivity. The multifunctional composites were characterized via FT-IR, XRD, SEM, HR-TEM, BET, C.V, and EIS techniques. The electrical conductivity and modulus of the MWCNT-Col-HA-Hes were 0.06 S/cm and 12.3 kPa, similar to the native spinal cord. The in-vitro Cytotoxicity, cell viability, antioxidant property, and cell migration ability of the prepared composites were investigated with a PC-12 cell line. In-vitro studies revealed that the multifunctional composites show higher cell viability, antioxidant, and cell migration properties than the control cells. Reduction of ROS level indicates that the Hes presence in the composite could reduce the cell stress by protecting it from oxidative damage and promoting cell migration towards the lesion site. The developed multifunctional composite can provide the antioxidant microenvironment with compatibility and mimic the native spinal cord by providing appropriate conductivity and mechanical strength for spinal cord tissue regeneration.

CD44 tagged hyaluronic acid - chitosan liposome carrier for the delivery of berberine and doxorubicin into lung cancer cells.

Liposomes are unique biomolecular, capable of loading both hydrophilic and hydrophobic molecules and delivered into the biological system. Liposomes (L) coated with hyaluronic acid (HA) and chitosan (CS) carrier system was fabricated. Berberine (BER) and doxorubicin (DOX) were encapsulated to enhance drug proliferation and therapeutic effect in lung cancer cells. The FTIR, XRD, SEM, and TEM techniques were carried out for functional group identification, crystallinity, and surface morphology analysis, respectively. In-vitro drug release confirms the sustained release of BER and DOX in various physiological environments. HA-CS@BER&DOX-L has good penetration ability and higher cytotoxicity effect in the A549 cells, and the IC50 value of HA-CS@BER&DOX-L is 89.19 µg/300 µL. The pure liposome showed a negligible cytotoxicity effect, and the HA-CS@BER&DOX-L could efficiently induce the apoptosis of A549 cells. The cellular uptake analysis of the HA-CS@BER&DOX-L effectively targeted and entered the A549 cells and clearly observed C. elegans images. Hence, the proposed system will be a potential treatment methodology to enhance the cytotoxicity of the A549 cancer cells and be useful to future drug administration methodology development.

In-Silico molecular screening of natural compounds as a potential therapeutic inhibitor for Methicillin-resistant Staphylococcus aureus inhibition.

Methicillin-resistant Staphylococcus aureus (MRSA) is a life-threatening superbug causing infectious diseases such as pneumonia, endocarditis, osteomyelitis, etc. Conventional antibiotics are ineffective against MRSA infections due to their resistance mechanism against the antibiotics. The Penicillin Binding Protein (PBP2a) inhibits the activity of antibiotics by hydrolyzing the ß-lactam ring. Thus, alternate treatment methods are needed for the treatment of MRSA infections. Natural bioactive compounds exhibit good inhibition efficiency against MRSA infections by hindering its enzymatic mechanism, efflux pump system, etc. The present work deals with identifying potential and non-toxic natural bioactive compounds (ligands) through molecular docking studies through StarDrop software. Various natural bioactive compounds which are effective against MRSA infections were docked with the protein (6VVA). The ligands having good binding energy values and pharmacokinetic and drug-likeness properties have been illustrated as potential ligands for treating MRSA infections. From this exploration, Luteolin, Kaempferol, Chlorogenic acid, Sinigrin, Zingiberene, 1-Methyl-4-(6-methylhepta-1,5-dien-2-yl)cyclohex-1-ene, and Curcumin have found with good binding energies of -8.6 kcal/mol, -8.4 kcal/mol, -8.2 kcal/mol, -7.5 kcal/mol, -7.4 kcal/mol, -7.3 kcal/mol, and -7.2 kcal/mol, respectively.

Synergistic effect of polymer functionalized graphene oxide system for breast cancer treatment.

The multifaceted drug carrier system is an emerging trend in delivering chemotherapeutic drugs and photosensitizers for the synergistic effect. In this work, we have designed a functionalized graphene oxide (GO) based carrier system for combined chemo-photodynamic therapeutic effects. Doxorubicin (DOX) and rose bengal (RB) were entrapped on the surface of GO via hydrophobic and π-π stacking interactions. The functional group determination, crystalline properties, surface morphology, and hydrodynamic size were evaluated using FT-IR, XRD, SEM, TEM, AFM, and DLS analysis. At 24 h, the entrapment efficiency was 65 % DOX and 40.92 % RB, and the loading capacities were 16.9 % DOX and 5.68 % RB observed at 30 min. The drug release percentage was higher in pH-2.6 rather than in pH-5.5, 6.8, and 7.4 pH environments. The in-vitro toxicity analysis using the LDH assay reveals that the DOX and RB co-loaded carriers had a significant cytotoxic effect on MCF-7 cells, indicating that the carrier could improve the therapeutic efficacy of DOX. Morphological changes were studied using inverted light microscopy; the cells were irradiated with a laser 525 nm 10 J/cm2 for 2 min 51 sec, and it was observed that the DOX and RB co-loaded carrier with laser-irradiated cells exposed the high-level morphological changes with the occurrence of apoptotic cell death. Compared to free DOX, the DOX/RB co-loaded carrier + laser had an efficient anticancer activity, as confirmed by DAPI staining cell uptake, flow cytometry, and intracellular ROS generation analysis. The DOX and RB co-loaded carrier clearly exhibits the RB-mediated photodynamic action on MCF-7 cells in response to external laser light irradiation. It permits an on-demand dual-payload release to trigger an instantaneous photodynamic and chemo treatment for cancer cell eradication. Finally, the ensuing dual-agent release is probable to successfully fight cancer via a synergistic effect.

Engineered Hyaluronic Acid-Based Smart Nanoconjugates for Enhanced Intracellular Drug Delivery.

Bacterial polysaccharides can be easily modified to offer dual stimuli-responsive drug delivery systems with double targeting potential. In this research work, bacterial polysaccharides hyaluronic acid (HA) were functionalized with α-tocopherol polyethylene glycol succinate (TPGS) and cholic acid (CA) to form multifunctional polysaccharides nanoconjugates (TPGS-HA-CA). Smart nanoconjugates were synthesized by forming a redox-responsive disulfide bond, and it is composed of double targeting ligands. Doxorubicin (DOX) encapsulated smart nanoconjugates were exhibited an average size of 200 nm with a uniform core-shell structure. It serves the pH-responsive side chain modulation of TPGS-HA-CA, which affords a high degree of swelling at acidic pH. Under the pH 5.0 it shows 57% of release due to the side chain modulation of C-H/N-H. Polysaccharides nanoconjugates exhibited the double stimuli-responsive drug delivery by rapid disassembly of disulfide linkage, which exhibited 72% drug release (pH 5.0+GSH 10 mM). In cytotoxic studies, DOX@TPGS-HA-CA exhibited a higher cytotoxic effect compared to DOX. Hyaluronic acid functionalization with CA, TPGS increases cell internalization, and dual stimuli activity promotes more cell death. Overall, multifunctional polysaccharides hydrogel nanoconjugates is a prospective material that has great potential for targeting breast cancer therapy.

Phytochemicals of Cocculus hirsutus deciphered SARS-CoV-2 inhibition by targeting main proteases in molecular docking, simulation, and pharmacological analyses.

The COVID-19 pandemic is spreading rapidly due to the outbreak of novel coronavirus SARS-CoV-2 across the globe. Anti-COVID-19 drugs are urgently required in this situation. In this regard, the discovery of promising new anti-COVID-19 moieties is expected from traditional medicine. The study is aimed to discover phytochemicals of Cocculus hirsutus having anti-COVID-19 activity via inhibiting main proteases of SARS-CoV-2. Main proteases (Mpro) of SARS-CoV-2 serve as a protuberant target for anti-COVID-19 drug discovery because it is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription that makes it an attractive drug target. Recent studies indicated the utility of C. hirsutus in the treatment of viral disorders like Dengue. Phytochemicals from C. hirsutus were docked against SARS-CoV-2 main proteases (6LU7, 5R7Y, 5R7Z, 5R80, 5R81, 5R82) using the PyRx virtual screen tool and discovery studio visualizer. Further, molecular dynamics simulations were performed (for 100 ns) to see conformational stability for all complexes. Pharmacokinetic properties and drug-likeness prediction of selected C. hirsutus phytoconstituents were also performed. Betulin, coclaurine, and quinic acid of C. hirsutus were found promising with significant binding affinity to SARS-CoV-2 Mpro in comparison to control. They have shown stable interactions with the amino acid residues present on the active site of most of the SARS-CoV-2 Mpro and were found as promising anti-COVID-19 candidates. These compounds could be potential leads for the development of target-specific anti-COVID-19 therapeutics while ethnomedicinal uses of this herb could further needed for its detailed antiviral therapeutic exploration.Communicated by Ramaswamy H. Sarma.

Retraction of "Cisplatin-Loaded Graphene Oxide/Chitosan/Hydroxyapatite Composite as a Promising Tool for Osteosarcoma-Affected Bone Regeneration".

[This retracts the article DOI: 10.1021/acsomega.8b02090.].

Recent Developments in Methicillin-Resistant Staphylococcus aureus (MRSA) Treatment: A Review.

Staphylococcus aureus (S. aureus) is a Gram-positive bacterium that may cause life-threatening diseases and some minor infections in living organisms. However, it shows notorious effects when it becomes resistant to antibiotics. Strain variants of bacteria, viruses, fungi, and parasites that have become resistant to existing multiple antimicrobials are termed as superbugs. Methicillin is a semisynthetic antibiotic drug that was used to inhibit staphylococci pathogens. The S. aureus resistant to methicillin is known as methicillin-resistant Staphylococcus aureus (MRSA), which became a superbug due to its defiant activity against the antibiotics and medications most commonly used to treat major and minor infections. Successful MRSA infection management involves rapid identification of the infected site, culture and susceptibility tests, evidence-based treatment, and appropriate preventive protocols. This review describes the clinical management of MRSA pathogenesis, recent developments in rapid diagnosis, and antimicrobial treatment choices for MRSA.

Matrix Metalloproteinases in Chemoresistance: Regulatory Roles, Molecular Interactions, and Potential Inhibitors.

Cancer is one of the major causes of death worldwide. Its treatments usually fail when the tumor has become malignant and metastasized. Metastasis is a key source of cancer recurrence, which often leads to resistance towards chemotherapeutic agents. Hence, most cancer-related deaths are linked to the occurrence of chemoresistance. Although chemoresistance can emerge through a multitude of mechanisms, chemoresistance and metastasis share a similar pathway, which is an epithelial-to-mesenchymal transition (EMT). Matrix metalloproteinases (MMPs), a class of zinc and calcium-chelated enzymes, are found to be key players in driving cancer migration and metastasis through EMT induction. The aim of this review is to discuss the regulatory roles and associated molecular mechanisms of specific MMPs in regulating chemoresistance, particularly EMT initiation and resistance to apoptosis. A brief presentation on their potential diagnostic and prognostic values was also deciphered. It also aimed to describe existing MMP inhibitors and the potential of utilizing other strategies to inhibit MMPs to reduce chemoresistance, such as upstream inhibition of MMP expressions and MMP-responsive nanomaterials to deliver drugs as well as epigenetic regulations. Hence, manipulation of MMP expression can be a powerful tool to aid in treating patients with chemo-resistant cancers. However, much still needs to be done to bring the solution from bench to bedside.

Enhanced Doxorubicin Delivery in Folate-Overexpressed Breast Cancer Cells Using Mesoporous Carbon Nanospheres.

Nanoparticle-based drug delivery reveals the safety and effectiveness and avoids premature drug release from the nanocarrier. These nanoparticles improve the bioavailability and stability of the drug against chemical and enzymatic degradation and facilitate targeted drug delivery. Herein, targeted folic acid-conjugated oxidized mesoporous carbon nanospheres (Ox-MPCNPs) were successfully fabricated and developed as antitumoral doxorubicin delivery for targeted breast cancer therapy. Fourier transform infrared spectroscopy studies confirmed that the doxorubicin was successfully bound on the Ox-MPCNP through hydrogen bonding and π-π interactions. X-ray diffraction studies showed that the synthesized doxorubicin-loaded Ox-MPCNP is semi-crystalline. The surface morphology of the synthesized doxorubicin-loaded Ox-MPCNP (DOX/Ox-MPCNP-Cys-PAsp-FA) was studied by scanning electron microscopy and high-resolution transmission electron microscopy, which demonstrates a sphere-shaped morphology. The cytotoxic effects of DOX/Ox-MPCNP-Cys-PAsp-FA were studied in MCF-7 breast cancer cells using the CytoTox96 assay kit. The study confirmed the cytotoxic effects of the synthesized nanospheres in vitro. Moreover, DOX/Ox-MPCNP-Cys-PAsp-FA-treated cells displayed efficient cell apoptosis and cell death in flow cytometry analysis. The mitochondrial fragmentation and nucleus damages were further confirmed by fluorescence microscopy. Thus, the approach used to construct the DOX/Ox-MPCNP-Cys-PAsp-FA carrier provides excellent opportunities for the targeted treatment of breast cancer.

Natural Drug-Loaded Bimetal-Substituted Hydroxyapatite-Polymeric Composite for Osteosarcoma-Affected Bone Repair.

Repairing segmental bone deformities after resection of dangerous bone tumors is a long-standing clinical issue. The study's main objective is to synthesize a natural bioactive compound-loaded bimetal-substituted hydroxyapatite (BM-HA)-based composite for bone regeneration. The bimetal (copper and cadmium)-substituted HAs were prepared by the sol-gel method and reinforced with biocompatible polyacrylamide (BM-HA/PAA). Umbelliferone (UMB) drug was added to the BM-HA/PAA composite to enhance anticancer activity further. The composite's formation was confirmed by various physicochemical investigations, such as FT-IR, XRD, SEM, EDAX, and HR-TEM techniques. The bioactivity was assessed by immersing the sample in simulated body fluid for 1, 3, and 7 days. The zeta potential values of BM-HA/PAA and BM-HA/PAA/UMB are -36.4 mV and -49.4 mV, respectively. The in vitro viability of the prepared composites was examined in mesenchymal stem cells (MSCs). It shows the ability of the composite to produce osteogenic bone regeneration without any adverse effects. From the gene expression and PCR results, the final UMB-loaded composite induced osteogenic markers, such as Runx, OCN, and VEFG. The prepared bimetal substituted polyacrylamide reinforced HA composite loaded with UMB drug has the ability for bone repair/regenerations.

Fabrication of substituted hydroxyapatite-starch-clay bio-composite coated titanium implant for new bone formation.

The clay/polymeric matrices have much attention from researchers in bio-medical applications due to their numerous uses. This study introduces new orthopedic titanium (Ti) implant with increasing bio-activity by treating the surface of the Ti implant with bio-compatible composite coating. Wollastonite (WST) clay combined minerals (Mg2+and Gd3+) substituted hydroxyapatite (HAP)/Starch composite was prepared using in-situ co-precipitation method. It was successfully coated on the orthopedic grade Ti plate by the Electrophoretic Deposition (EPD) method. The functionality, phase, morphology, and bio-activity analysis of the composite were evaluated by FT-IR, XRD, HR-TEM, and SEM analysis, respectively. The mechanical property, i.e., Vickers microhardness value of the MHAP/Starch/WST composite coated Ti plate, showed 242 ± 1.92 Hv. The in-vitro MG-63 osteoblast cells viability, differentiation, and Ca mineralization of MHAP/Starch/WST composite suggests that this new implant will be used for bone regeneration application after careful evaluation of in-vivo and clinical studies.

Enhanced bone tissue regeneration via bioactive electrospun fibrous composite coated titanium orthopedic implant.

One of the very reliable, attractive, and cheapest techniques for synthesizing nanofibers for biomedical applications is electrospinning. Here, we have created a novel nanofibrous composite coated Ti plate to mimic an Extra Cellular Matrix (ECM) of native bone in order to enhance the bone tissue regeneration. An electrospun fibrous composite was obtained by the combination of minerals (Zn, Mg, Si) substituted hydroxyapatite (MHAP)/Polyethylene Glycol (PEG)/Cissus quadrangularis (CQ) extract. Fibrous composite's functionality, phase characteristics, and morphology were evaluated by FT-IR, XRD, and SEM techniques, respectively. The average fiber diameter of MHAP/PVA had decreased from ~274 to ~255 nm after incorporating PEG polymer. That further increased from ~255 to ~275 nm after adding CQ extract. Besides the bioactivity in SBF solution, the degradable nature was confirmed by immersing the fibrous composite in Tris-HCL solution. The degradable studies evaluate that the composite was degraded depending on time, and it degrades about 9.42% after 7 days of immersion. Osteoblasts like MG-63 cells differentiation, proliferation, and calcium deposition were also determined. These results show that this new fibrous composite exhibits advanced osteoblasts properties. Thus, we concluded that this new fibrous scaffold coated Ti implant could act as a better implant to mimic ECM of bone structure and to improve osteogenesis during bone regeneration.

Biomacromolecules of chitosan - Bacopa saponin based LipL32 gene delivery system for leptospirosis therapy.

Leptospirosis is a severe bacterial infectious disease caused by the organisms belonging to the genus of Leptospira. The chitosan/Bacopa saponin/tripolyphosphate (CS/BS/TPP) nanoparticles conjugated with recombinant DNA vaccines were designed against Leptospirosis. Chitosan, a polysaccharide is suitable for delivery of drug, and gene due to its bio-compatible and biodegradable properties. Bacopa saponins are used for the induction of the immune response against microbial infections. The recombinant DNA vaccine construct was composed of the leptospiral outer membrane LipL32 gene tagged with EGFP and hGMCSF adjuvant in the pVAX1 mammalian expression vector along with the Cytomegalovirus (CMV) promoter. These recombinant DNA vaccine constructs was termed as pVAX1-EGFP-LipL32 and pVAX1-EGFP-hGMCSF-LipL32, and these constructs were conjugated with CS/BS/TPP nanoparticles by using the ionic gelation technique. Thus, CS/BS/TPP conjugated nanoparticle DNA vaccine was confirmed by functionality (FT-IR), crystalline nature (XRD) and surface charge (Zeta potential). The 90% encapsulation efficiency was observed in the conjugated nanoparticle DNA vaccine. In contrast, cell viability analysis validated that the synthesized DNA conjugated CS/BS/TPP nanoparticles showed low cytotoxicity up to 10 mg/mL. The results showed here are the initial establishment of DNA vaccine conjugated nanoparticles, which can be used as a potential anti-leptospiral vaccine.

Correction to Cisplatin-Loaded Graphene Oxide/Chitosan/Hydroxyapatite Composite as a Promising Tool for Osteosarcoma-Affected Bone Regeneration.

[This corrects the article DOI: 10.1021/acsomega.8b02090.].

Calcium alginate nanoparticle crosslinked phosphorylated polyallylamine to the controlled release of clindamycin for osteomyelitis treatment.

Osteomyelitis is one of the infections of the bone, and the treatment needs to the infection problems. Here, a local therapeutic approach for efficient drug delivery systems was designed to enhance the antibiotic drug's therapeutic activity. Calcium-Alginate nanoparticle (Ca-Alg) crosslinked phosphorylated polyallylamine (PPAA) was prepared through the salting-out technique, and it achieved 82.55% encapsulation of Clindamycin drug. The physicochemical characterizations of FTIR, SEM/EDX, TEM, and XRD were investigated to confirm the materials nature and formation. Clindamycin loaded Ca-Alg/PPAA system showed sustained Clindamycin release from the carrier. Cell viability was assessed in bone-related cells by Trypan blue assay and MTT assay analysis method. Both assay results exhibited better cell viability of synthesized materials against MG63 cells. MIC value of Ca-Alg/PPAA/Clindamycin in the Methicillin-resistant Staphylococcus aureus (MRSA) pathogen was 275 µg/mL, and it was 120 µg/mL for Enterobacter cloacae pathogen. The materials promising material for Osteomyelitis affected bone regeneration without any destructive effect and speedy recovery of infected parts from these investigations.

Retinal photoreceptors targeting SA-g-AA coated multilamellar liposomes carrier system for cytotoxicity and cellular uptake evaluation.

Here, the retinal targeting SA-g-AA coated multilamellar liposomes carrier synthesized to deliver the bioactive agents into the retinal region of the eye. The multilayered targeting macromolecules of liposomes prepared using a layer-by-layer assembly. The curcumin (CUR) and Rhodamine B (RhB) dyes loaded in a multilamellar vesicle (MLV) were synthesised by the lipid film hydration method. The sodium alginate grafted acrylic acid (SA-g-AA) conjugated with riboflavin (RB) was coated over MLV by O/W emulsion method followed by ionotropic gelation. FT-IR and 1H NMR spectroscopy techniques used to analyse the structural features of the MLV-SA-g-AA-RB. The results of DLS and TEM revealed that the carrier could be of uniform spheres, with a low polydispersity index, and outstanding performance in phrases of dye encapsulation and extended-release ability. An MTT assay investigated cell viability against Fibroblast WS1, and human embryonic stem cells-derived retinal pigment epithelial cells (hESC-RPE) implied that the carrier is of excellent biocompatibility. Retina targeting nature of the system confirmed via cellular uptake results revealed that the increases the dye concentration in the cells. Overall, the outcomes suggested that carriers could lead to the improvement of a feasible two photoreceptors targeting drug carriers, and it has the potential to deliver the multidrug in the retinal region of the eye.