Immunomodulatory zymosan/ι-carrageenan/ agarose hydrogel for targeting M2 to M1 macrophages (antitumoral).

Several studies have been performed on the immunomodulatory effects of yeast ß-(1,3) glucan, but there is no proper evaluation of the thermal and immunomodulating properties of zymosan (ZM). Thermogravimetry analysis indicated a 54% weight loss of ZM at 270 °C. Circular dichroism showed absorption peaks in the region of 250 to 400 nm, suggesting a helical coil ß-sheet configuration. XRD showed a broad peak at 2θ of 20.38°, indicating the crystalline nature, and the size was found to be 23 nm. ZM is biocompatible and showed no toxicity against L929 and RAW 264.7 cell lines (cell viability > 90%). Immunomodulatory studies with PCR showed upregulation of M1 genes in human differentiated THP-1 macrophage cell lines, which were responsible for antitumor properties. The uptake of ZM particles inside the differentiated THP-1 macrophages and Raw 264.7 cells was confirmed (Video clip). ZM particle uptake via Dectin-1 was identified by competitive receptor blocking. Seaweed derived carrageenan/ZM/agarose hydrogel was successfully prepared (@5 : 5 wt%) and was seen to support the growth of L929 cells (1 × 105 cells per mL) and have a higher swelling (≈250-280%). This study indicates that ZM-based hydrogel could be a potential drug carrier (Rifampicin and Levofloxacin) for targeting tumour-associated macrophages (M2).

Enhancing the degradation rate and biomineralization nature of antiferromagnetic Fe-20Mn alloy by groove pressing.

The Fe-Mn alloys are potential candidates for biodegradable implant applications. However, the very low degradation rates of Fe-Mn alloys in the physiological environment are a major disadvantage. In this study, the degradation rate of a Fe-20Mn alloy was improved using the groove pressing (GP) technique. Hot rolled sheets of 2 mm thickness were subjected to GP operation at 1000°C. Uniform fine-grained (UFG) Fe-Mn alloys were obtained using the GP technique. The influence of GP on the microstructure, mechanical properties, degradation behavior in simulated body fluid (SBF), surface wettability, biomineralization, and cytocompatibility was investigated and compared to the annealed (A Fe-Mn) and rolled (R Fe-Mn) sample. The groove-pressed Fe-Mn (G Fe-Mn) alloy had a grain size of approximately 40 ± 16 µm whereas the A Fe-Mn and R Fe-Mn samples had grain sizes of 303 ± 81 and 117 ± 14.5 µm, respectively. Enhanced strength and elongation were also observed with the G Fe-Mn sample. The potentiodynamic polarization test showed the highest Icorr, lowest polarization resistance, and lowest Ecorr for the G Fe-Mn sample among all other samples indicating its higher degradation rate. The weight loss data from immersion tests also shows that the percentage of weight loss increases with time indicating the accelerated degradation behavior of the sample. The static immersion test showed an enhancement in weight loss of 0.46 ± 0.02% and 1.02 ± 0.05% for R Fe-Mn and G Fe-Mn samples, respectively, than A Fe-Mn sample (0.31 ± 0.03%) after 56 days in immersion in SBF. The greater biomineralization tendency in UFG materials is confirmed by the G Fe-Mn sample's stronger hydroxyapatite deposition. When compared to the A Fe-Mn and R Fe-Mn samples, the G Fe-Mn sample has a better wettability, which promotes higher cell adhesion and vitality, showing higher biocompatibility. This study demonstrates that Fe-20Mn processed by GP has potential applications for the manufacture of biodegradable metallic implants.

Injectable macroporous naturally-derived apatite bone cement as a potential trabecular bone substitute.

In this study, we have formulated a novel apatite bone cements derived from natural sources (i.e. eggshell and fishbone) with improved qualities that is, porosity, resorbability, biological activity, and so forth. The naturally-derived apatite bone cement (i.e. FBDEAp) was prepared by mixing hydroxyapatite (synthesized from fishbone) and tricalcium phosphate (synthesized from eggshell) as a solid phase with a liquid phase (a dilute acidic blend of cement binding accelerator and biopolymers like gelatin and chitosan) with polysorbate (as liquid porogen) to get a desired bone cement paste. The prepared cement paste sets within the clinically acceptable setting time (≤20 min), easily injectable (>85%) through hands and exhibits physiological pH stability (7.3-7.4). The pure apatite phased bone cement was confirmed by x-ray diffraction and Fourier transform infrared spectroscopy analyses. The FBDEAp bone cement possesses acceptable compressive strength (i.e. 5-7 MPa) within trabecular bone range and is resorbable up to 28% in simulated body fluid solution within 12 weeks of incubation at physiological conditions. The FBDEAp is macroporous in nature (average pore size ~50-400 µm) with interconnected pores verified by SEM and micro-CT analyses. The FBDEAp showed significantly increased MG63 cell viability (>125% after 72 h), cell adhesion, proliferation, and key osteogenic genes expression levels (up to 5-13 folds) compared to the synthetically derived, synthetic and eggshell derived as well as synthetic and fishbone derived bone cements. Thus, we strongly believe that our prepared FBDEAp bone cement can be used as potential trabecular bone substitute in orthopedics.

Bio-functionalized carbon dots for signaling immuno-reaction of carcinoembryonic antigen in an electrochemical biosensor for cancer biomarker detection.

Early diagnosis of cancer demands sensitive and accurate detection of cancer biomarkers in blood. Carbon dots (CDs) bio-functionalization with antibodies, peptides or aptamers have played significant role in cancer diagnosis and targeted cancer therapy. Herein, a biosensor for detection of cancer biomarker carcinoembryonic antigen (CEA) in blood serum has been designed using CDs bio-functionalized with HRP-conjugated CEA antibody (CUCDs@CEAAb2) as detection probe. CDs were synthesized by upscaling of cow urine, a nitrogen rich biomass waste, by hydrothermal method. Detection probe based on CDs resulted in 3.5 times higher sensitivity as compared to conventional electrochemical sandwich immunoassay. To further improve the sensor performance, hyper-branched polyethylenimine grafted poly amino aniline (PEI-g-PAANI) was used as the sensing interface, which enabled immobilization of higher amount of capture antibody. Detection of CEA in human blood serum coupled with wide linear range (0.5-50 ng/ml), good specificity, stability, reproducibility and low detection limit (10 pg/ml) signified the excellence of CUCDs based CEA immunosensor. CUCDs exhibited excitation wavelength dependent fluorescence property and showed strong blue emission under UV irradiation. MTT assay indicated that the material is not toxic towards human dental pulp stem cells (hDPSCs) and MG63 osteosarcoma cells (cell viability > 90%). The present study demonstrates a methodology for valorization of animal waste to a cost-effective carbon based functional nanomaterial for clinical detection of cancer biomarkers.

Targeted Drug Designing for Treating Masticatory Myofascial Pain Dysfunction Syndrome: An In Silico Simulation Study.

Background Masticatory Myofascial Pain Dysfunction Syndrome (MMPDS) is a musculoligamentous disorder that shares similarities with temporomandibular joint pain and odontogenic pain. It manifests as dull or aching pain in masticatory muscles, influenced by jaw movement. Computer-aided drug design (CADD) encompasses various theoretical and computational approaches used in modern drug discovery. Molecular docking is a prominent method in CADD that facilitates the understanding of drug-bimolecular interactions for rational drug design, mechanistic studies & the formation of stable complexes with increased specificity and potential efficacy. The docking technique provides valuable insights into binding energy, free energy, and complex stability predictions. Aim The aim of this study was to use the docking technique for myosin inhibitors. Materials and methods Four inhibitors of myosin were chosen from the literature. These compound structures were retrieved from the Zinc15 database. Myosin protein was chosen as the target and was optimized using the RCSB Protein Data Bank. After pharmacophore modeling, 20 novel compounds were found and the SwissDock was used to dock them with the target protein. We compared the binding energies of the newly discovered compounds to those of the previously published molecules with the target. Results The results indicated that among the 20 molecules ZINC035924607 and ZINC5110352 exhibited the highest binding energy and displayed superior properties compared to the other molecules. Conclusion The study concluded that ZINC035924607 and ZINC5110352 exhibited greater binding affinity than the reported inhibitors of myosin. Therefore, these two molecules can be used as a potential and promising lead for the treatment of MMPDS and could be employed in targeted drug therapy.

Local and systemic adverse effects of nanoparticles incorporated in dental materials- a critical review.

Introduction: Nanotechnology is the science and engineering of nanoparticles whose dimensions range from 1 to 100 nm. Nanoparticles have special characteristics like increased surface area, high reactivity, and enhanced mechanical, thermal, and optical properties that make them attractive for use in dental applications. However, the use of nanoparticles in dental materials can have toxic effects on the human body. The objective of this paper is to discuss the toxic effects of various nanoparticles in dental materials, their adverse effect on human health, and measures to overcome such effects. Objectives: Nanoparticles are used in the diagnosis, prevention, and treatment of oral diseases like dental caries, pulpo periodontal lesions, oral cancer, denture stomatitis, and candidiasis. Exposure to nanoparticles may occur to the dental professional, and the patient during procedures like restoration, finishing, and polishing. Such exposure to nanoparticles through inhalation, and ingestion causes toxic effects in the lungs, skin, brain, liver, and kidney. Proper risk assessment methods and preventive measures may help reduce these toxic effects to some extent. Significance: Toxic effects of nanoparticles that are released during dental procedures, their route of exposure, and the concentration at which nanoparticles can induce toxic effects on the human body are discussed in detail in this review. The paper also aims to create awareness among dental professionals, students, and patients regarding nanoparticle exposure and its adverse effects, and methods to prevent and overcome these effects. Currently, it is ignored or taken lightly by the stakeholders and this review may throw light.

High molecular weight heparin-induced angiogenesis mainly mediated via basic fibroblast growth factor-2- an in-vivo (CAM) and in-silico analysis.

Background: High-molecular weight heparin (HMWH), a molecule extensively used as an anticoagulant, shows concentration-dependent angiogenic and anti-angiogenic potential. So far, no studies have reported the interactive potential of HMWH with various pro-angiogenic growth factors under physiological conditions. Haence, we aimed to find the impact of major pro-angiogenic growth factors under HMWH induced angiogenesis. Methods: Chicken Chorioallantoic Membranes (CAMs) are incubated with various concentrations of HMWH. Semiquantitative PCR method was implemented to measure the changes in the transcription level of pro-angiogenic growth factors. The scanning electron microscopic technique is applied to find the morphological changes in CAM. Molecular docking and molecular dynamics simulation studies using NAMD and CHARMM force field discerned the heparin-binding mode with the pro-angiogenic growth factors. Results: HMWH can enhance the transcription level of major pro-angiogenic growth factors, significantly impacting FGF2 under 100 µM concentration. The in-silico analysis reveals that HMWH shows the highest binding affinity with FGF2. Further, molecular dynamics and interaction studies using 1 kDa Heparin against FGF2 showed that the former binds stably with the latter due to a strong salt bridge formation between the sulfate groups and arginine residues (ARG 119 and ARG109). Conclusion: The combined experimental and in-silico analysis results reveal that HMWH can interact with pro-angiogenic growth factors under micromolar concentration while inducing angiogenesis. This observation further supports the therapeutic benefits of HMWH as an angiogenic factor under such low concentration. This technique is used to replenish the blood supply to chronic wounds to speed healing and prevent unnecessary amputations.

Functionally multifaceted alginate/curdlan/agarose-based bilayer fibro-porous dressings for addressing full-thickness diabetic wounds.

Full-thickness diabetic wounds are chronic injuries characterized by bleeding, excessive exude, and prolonged inflammation. Single-layer dressings fail to address their disturbed pathophysiology. Therefore, bilayer dressings with structural and compositional differences in each layer have gained attention. We hypothesized that natural polymer (alginate, curdlan, and agarose) based bilayer dressings with inherent healing properties could effectively resolve these issues. Hence, bilayer dressings were fabricated by electrospinning curdlan/agarose/ polyvinyl alcohol blend (top layer) on an alginate/agarose/polyvinyl alcohol-based lyophilized porous (bottom) layer. Ciprofloxacin was incorporated in both layers as a potential antibacterial drug. The bilayer dressing exhibited high swelling (~1300 %), biocompatibility (>90 % with NIH 3T3 and L929 mouse fibroblasts), and hemocompatibility (hemolysis <5 %). In vitro, scratch assay revealed a faster wound closure (~ 95-100 %) than control. Inhibition zone assay revealed antibacterial activity against Staphylococcus aureus and Escherichia coli. Real-time (in vitro) gene expression experiments performed using human THP-1 macrophages exhibited a significant increase in anti-inflammatory cytokines (4.51 fold in IL-10) and a decrease in pro-inflammatory cytokines (1.42 fold in IL-6) in comparison to lipopolysaccharide. Thus, fabricated dressings with high swelling, hemostatic, immunomodulatory, and antibacterial characteristics can serve as potential multifunctional and sustainable templates for healing full-thickness diabetic wounds.

Microbial Interactions in Oral Biofilm: Evaluating Therapeutic Interventions and the Emergence of Resistance: A Narrative Review.

The oral cavity comprises numerous anatomical surfaces that are inhabited by a diverse array of bacteria, collectively forming a bacterial biofilm. Within this complex microbial community, certain bacterial species are etiologically linked to the development of common oral pathologies, such as dental caries and periodontitis, which stand as prominent instances of bacterial infections frequently encountered in clinical settings. Most biofilms are believed to be multispecies consortia. While single-species biofilms have been well-researched, mixed-species biofilms and their interactions amongst themselves have not drawn interest. The aim of the current review was to assess the various interactions of dual-species microorganisms in oral biofilm formation. Farnesol given exogenously for the treatment of biofilm can enhance or inhibit the growth of certain organisms, as seen in Candida albicans. In the age of antibiotic resistance, it is imperative to develop and uncover drugs capable of simultaneously targeting multiple species in order to mitigate antimicrobial resistance.

Biomimetic Approach to Counter Streptococcus mutans Biofilm: An In Vitro Study on Seashells.

Aim This study aimed to investigate the anti-adherent property of the seashell surface and periostracum to prevent the formation of Streptococcus mutans biofilm. Materials and methods The seashells were initially collected from the natural urban beach, and an antibiofilm assay of the shells with and without periostracum was performed against Streptococcus mutans. Furthermore, the seashells were analyzed with a stylus profilometer (Mitutoyo Surftest SJ-301, Mitutoyo America Corporation, Illinois, USA), atomic force microscope (AFM; Nanosurf Easyscan 2, Nanosurf Inc., USA), contact angle assessment, Fourier-transform infrared (FTIR) spectroscopy analysis, and scanning electron microscopy (SEM; JEOL USA, Inc., FE-SEM IT800, Massachusetts, USA) analysis. The ability of seashells to prevent the attachment of Streptococcus mutans and form a biofilm with and without periostracum was studied by crystal violet assay. Results The results revealed that shells without periostracum promoted higher biofilm formation when compared to those having intact periostracum (by 15%, p<0.001). Shell 1 showed the highest biofilm formation, whereas shell 3 showed the least biofilm formation due to the differences in their surface morphologies. The remaining shells (4, 2, 6, and 5) showed interspersed biofilm formation. Conclusion In summary, our study was able to correlate the topologies of the shell surface with the biofilm formed by Streptococcus mutans with the wetting behavior of those shell surfaces and their roughness. More hydrophobic surfaces (with intact periostracum) were observed to lead to less attachment (correlation coefficient=-0.67). This study can pave the way for designing such biomimetic surfaces to prevent bacterial attachment.

Ferroptosis Mediated Novel Drug Design Approach in the Treatment of Oral Squamous Cell Carcinoma.

BACKGROUND: Globally, Oral Squamous Cell Carcinoma (OSCC) is the highest prevalent type of oral cancer. Implementing a successful treatment plan for the aforementioned tumor has always been a primary concern. There are numerous targeted therapies of which Ferroptosis has been receiving increasing attention in the recent decade. A novel form of controlled cell death "Ferroptosis' is caused by iron-dependent lipid peroxidation. A well-known mechanism for controlling ferroptosis is the Cysteine/GSH/GPX4 axis, in which System X͞c is crucial. System X͞c inhibitors have been proven earlier to improve chemotherapy sensitivity. MATERIALS AND METHODS: Five System X͞c inhibitors were selected from the literature. The structure of these molecules from Zinc15 and the protein sequence of the target from Protein Data Bank were obtained. Twenty new molecules were identified following pharmacophore modeling and were docked with the target protein using SwissDock. The binding energies of the new molecules with the target were compared with that of the reported molecules. RESULT: The molecular docking study showed that two new molecules (ZINC89362298 and ZINC1730544) resulted in the highest binding pattern (-8.64) than that of the reported molecules (-7.75). CONCLUSION: The present study concluded that ZINC89362298 and ZINC1730544 had better binding efficiencies than that of the reported System xc- inhibitors. Hence these two molecules could be used in targeted drug therapy and could be a promising lead in the management of oral cancer in the future.

Perspectives of nanofibrous wound dressings based on glucans and galactans - A review.

Wound healing is a complex and dynamic process that needs an appropriate environment to overcome infection and inflammation to progress well. Wounds lead to morbidity, mortality, and a significant economic burden, often due to the non-availability of suitable treatments. Hence, this field has lured the attention of researchers and pharmaceutical industries for decades. As a result, the global wound care market is expected to be 27.8 billion USD by 2026 from 19.3 billion USD in 2021, at a compound annual growth rate (CAGR) of 7.6 %. Wound dressings have emerged as an effective treatment to maintain moisture, protect from pathogens, and impede wound healing. However, synthetic polymer-based dressings fail to comprehensively address optimal and quick regeneration requirements. Natural polymers like glucan and galactan-based carbohydrate dressings have received much attention due to their inherent biocompatibility, biodegradability, inexpensiveness, and natural abundance. Also, nanofibrous mesh supports better proliferation and migration of fibroblasts because of their large surface area and similarity to the extracellular matrix (ECM). Thus, nanostructured dressings derived from glucans and galactans (i.e., chitosan, agar/agarose, pullulan, curdlan, carrageenan, etc.) can overcome the limitations associated with traditional wound dressings. However, they require further development pertaining to the wireless determination of wound bed status and its clinical assessment. The present review intends to provide insight into such carbohydrate-based nanofibrous dressings and their prospects, along with some clinical case studies.

Fabrication of injectable antibiotic-loaded apatitic bone cements with prolonged drug delivery for treating post-surgery infections.

Antibiotic-loaded bioactive bone substitutes are widely used for treating various orthopedic diseases and prophylactically to avoid post implantation infection. Calcium deficient hydroxyapatite (also known as apatitic bone cement) is a potential bioactive bone substitute in orthopedics due to its chemical composition similar to that of natural bone minerals. In this study, fabrication of mannitol (a solid porogen) incorporated injectable synthetic (Syn) and eggshell derived (ESD) apatitic bone cements loaded with antibiotics (gentamicin/meropenem/ rifampicin/vancomycin) was investigated. The release kinetics of the antibiotics were studied by fitting them with different kinetic models. All the antibiotics-loaded apatitic bone cements set within clinically accepted setting time (20 ± 2 min) and with good injectability (>70%). The antibiotics released from these bone cements were found to be controlled and sustained throughout the study time. Weibull and Gompertz (applies in least initial burst and sustain drug release rate models) were the best models to predict the release behavior. They cements had acceptable compressive strength (6-10 MPa; in the range of trabecular bone) and were biodegradable (21%-27% within 12 weeks of incubation) in vitro in simulated body fluids at physiological conditions. These bone cements showed excellent antibacterial activity from day 1 onwards and no bacterial colony was found from day 3 onwards. The viability of MG63 cells in vitro after 72 h was significantly higher after 24 h (i.e., ~110%). The cells were well attached and spread over the surface of the cements with extended morphology. The ESD antibiotic-loaded apatitic bone cements showed better injectability, degradation and cytocompatibility compared when compared to Syn antibiotic-loaded apatitic bone cements. Thus, we believe that the ESD antibiotic-loaded apatitic bone cements are suitable as potential injectable bone substitutes to avoid post-operative implant associated and other acute or chronic bone infections.

Fabrication and evaluation of agarose-curdlan blend derived multifunctional nanofibrous mats for diabetic wounds.

Diabetic wounds with complex pathophysiology significantly burden the wound care industry and require novel management strategies. In the present study, we hypothesized that agarose-curdlan based nanofibrous dressings could be an effective biomaterial for addressing diabetic wounds due to their inherent healing properties. Hence, agarose/curdlan/polyvinyl alcohol based nanofibrous mats loaded with ciprofloxacin (0, 1, 3, and 5 wt%) were fabricated using an electrospinning technique with water and formic acid. In vitro evaluation revealed the average diameter of the fabricated nanofibers between 115 and 146 nm with high swelling (~450-500 %) properties. They exhibited enhanced mechanical strength (7.46 ± 0.80 MPa -7.79 ± 0.007 MPa) and significant biocompatibility (~90-98 %) with L929 and NIH 3T3 mouse fibroblasts. In vitro scratch assay showed higher proliferation and migration of fibroblasts (~90-100 % wound closure) compared to electrospun PVA and control. Significant antibacterial activity was observed against Escherichia coli and Staphylococcus aureus. In vitro real-time gene expression studies with human THP-1 cell line revealed a significant downregulation of pro-inflammatory cytokines (8.64 fold decrease for TNF-α) and upregulation of anti-inflammatory cytokines (6.83 fold increase for IL-10) compared to lipopolysaccharide. In brief, the results advocate agarose-curdlan mat as a potential multifunctional, bioactive, and eco-friendly dressing for healing diabetic wounds.

In-vivo studies on Transitmycin, a potent Mycobacterium tuberculosis inhibitor.

This study involves the in-vitro and in-vivo anti-TB potency and in-vivo safety of Transitmycin (TR) (PubChem CID:90659753)- identified to be a novel secondary metabolite derived from Streptomyces sp (R2). TR was tested in-vitro against drug resistant TB clinical isolates (n = 49). 94% of DR-TB strains (n = 49) were inhibited by TR at 10µg ml-1. In-vivo safety and efficacy studies showed that 0.005mg kg-1 of TR is toxic to mice, rats and guinea pigs, while 0.001mg kg-1 is safe, infection load did not reduce. TR is a potent DNA intercalator and also targets RecA and methionine aminopeptidases of Mycobacterium. Analogue 47 of TR was designed using in-silico based molecule detoxification approaches and SAR analysis. The multiple targeting nature of the TR brightens the chances of the analogues of TR to be a potent TB therapeutic molecule even though the parental compound is toxic. Analog 47 of TR is proposed to have non-DNA intercalating property and lesser in-vivo toxicity with high functional potency. This study attempts to develop a novel anti-TB molecule from microbial sources. Though the parental compound is toxic, its analogs are designed to be safe through in-silico approaches. However, further laboratory validations on this claim need to be carried out before labelling it as a promising anti-TB molecule.

Controlled Synthesis of Dendrite-like Polyglycerols Using Aluminum Complex for Biomedical Applications.

This work describes a one-pot synthesis of dendrite-like hyperbranched polyglycerols (HPGs) via a ring-opening multibranching polymerization (ROMBP) process using a bis(5,7-dichloro-2-methyl-8-quinolinolato)methyl aluminum complex (1) as a catalyst and 1,1,1-tris(hydroxymethyl)propane/trimethylol propane (TMP) as an initiator. Single-crystal X-ray diffraction (XRD) analysis was used to elucidate the molecular structure of complex 1. Inverse-gated (IG)13C NMR analysis of HPGs showed degree of branching between 0.50 and 0.57. Gel permeation chromatography (GPC) analysis of the HPG polymers provided low, medium, and high-molecular weight (M n) polymers ranging from 14 to 73 kDa and molecular weight distributions (M w/M n) between 1.16 and 1.35. The obtained HPGs exhibited high wettability with water contact angle between 18 and 21° and T g ranging between -39 and -55 °C. Notably, ancillary ligand-supported aluminum complexes as catalysts for HPG polymerization reactions have not been reported to date. The obtained HPG polymers in the presence of the aluminum complex (1) can be used for various biomedical applications. Here, nanocomposite electrospun fibers were fabricated with synthesized HPG polymer. The nanofibers were subjected to cell culture experiments to evaluate cytocompatibility behavior with L929 and MG63 cells. The cytocompatibility studies of HPG polymer and nanocomposite scaffold showed high cell viability and spreading. The study results concluded, synthesized HPG polymers and composite nanofibers can be used for various biomedical applications.

An in silico study on pulmonary fibrosis inhibitors from Tinospora cordifolia and Curcuma longa targeting TGF-ß RI.

Pulmonary fibrosis is characterized by damage to the epithelial cells and alveolar-capillary basement membrane. The increased expression levels of transforming growth factor ß (TGF-ß) and TGF-ß-receptor-1 induced differentiation of lung fibroblasts to myofibroblasts, an alarming sign and considered the hallmark event development of pulmonary fibrosis. In the current study, the stability of phytochemicals of Curcuma longa and Tinospora cordifolia as inhibitors of transforming growth factor ß RI (TGF-ß RI) were evaluated using molecular docking and molecular dynamics studies. A total of 108 Curcuma longa and 16 Tinospora cordifolia constituents were screened against TGF-ß RI as the target. Further, their ADMET properties were evaluated using the pkCSM online server. The compounds tembetarine, magnoflorine from T. cordiolia, and 2-(Hydroxymethyl) anthraquinone and quercetin in C. longa showed significant binding affinities bonding interactions with the target, TGF-ß RI, and the study was compared with the known inhibitors from the literature. The MD simulations study also supported that the selected compounds show a close affinity with the binding site and maintained stable behavior throughout the simulation time. The pharmacophore feature analysis of the selected compounds and inhibitors were analyzed using the pharmagist web server, and the common features like H-bond donor and aromatic ring were mapped.Communicated by Ramaswamy H. Sarma.

Fabrication of macroporous apatite bone cements for non-load bearing orthopedic applications.

Calcium deficient hydroxyapatite (CDHA)-based apatite forming bone cements are well known for their bioactivity and bioresorbability. The formulation of CDHA-based cements with improved macroporosity, injectability, and resorbability has been investigated. The solid phase consists of nanocrystalline hydroxyapatite (HA) and tricalcium phosphate (ß-TCP). The liquid phase is diluted acetic acid with disodium hydrogen phosphate as binding accelerator along with gelatin and chitosan to improve the injectability. A porogen agent either mannitol (as solid porogen) or polysorbate (as liquid porogen) is also used to improve the porosity. All combined in fine-tuned composition results in optimal bone cements. The cement sets within the clinically preferred setting time (≤20 min) and injectability (>70%) and also stable at physiological pH (i.e., ~7.3-7.4). The XRD and FT-IR analysis confirmed the formation of CDHA phase on day 7 when the after-set cement immersed under phosphate buffer solution (PBS) at physiological conditions. The cements were found to have acceptable compressive strength for trabecular bone substitute. The cements were macroporous in nature with average pore size between 50 and 150 µm and were interconnected as confirmed by SEM, micro-CT and MIP analysis. The prepared cements are degradable up to 22% and 19% in simulated body fluid and PBS respectively within 10 weeks of immersion at physiological conditions. The cements exhibit higher viability (%) (>110%) with L929 and MG63 cells compared to the control after 3 days of incubation. They also show increased proliferation, well spreading and extended filopodia with MG63 cells. Overall, the developed apatite forming bone cements seems to be suitable for low or non-load bearing orthopedic applications.

Significant perspectives on various viral infections targeted antiviral drugs and vaccines including COVID-19 pandemicity.

A virus enters a living organism and recruits host metabolism to reproduce its own genome and proteins. The viral infections are intricate and cannot be completely removed through existing antiviral drugs. For example, the herpes, influenza, hepatitis and human immunodeficiency viruses are a few dreadful ones amongst them. Significant studies are needed to understand the viral entry and their growth in host cells to design effective antivirals. This review emphasizes the range of therapeutical antiviral drugs, inhibitors along with vaccines to fight against viral pathogens, especially for combating COVID-19. Moreover, we have provided the basic and in depth information about viral targets, drugs availability, their mechanisms of action, method of prevention of viral diseases and highlighted the significances of anticoagulants, convalescent plasma for COVID-19 treatment, scientific details of airborne transmission, characteristics of antiviral drug delivery using nanoparticles/carriers, nanoemulsions, nanogels, metal based nanoparticles, alike the future nanosystems through nanobubbles, nanofibers, nanodiamonds, nanotraps, nanorobots and eventually, the therapeutic applications of micro- and nanoparticulates, current status for clinical development against COVID-19 together with environmental implications of antivirals, gene therapy etc., which may be useful for repurposing and designing of novel antiviral drugs against various dreadful diseases, especially the SARS-CoV-2 and other associated variants.

Molecular docking analysis reveals the functional inhibitory effect of Genistein and Quercetin on TMPRSS2: SARS-COV-2 cell entry facilitator spike protein.

BACKGROUND: The Transmembrane Serine Protease 2 (TMPRSS2) of human cell plays a significant role in proteolytic cleavage of SARS-Cov-2 coronavirus spike protein and subsequent priming to the receptor ACE2. Approaching TMPRSS2 as a therapeutic target for the inhibition of SARS-Cov-2 infection is highly promising. Hence, in the present study, we docked the binding efficacy of ten naturally available phyto compounds with known anti-viral potential with TMPRSS2. The aim is to identify the best phyto compound with a high functional affinity towards the active site of the TMPRSS2 with the aid of two different docking software. Molecular Dynamic Simulations were performed to analyse the conformational space of the binding pocket of the target protein with selected molecules. RESULTS: Docking analysis using PyRx version 0.8 along with AutoDockVina reveals that among the screened phyto compounds, Genistein shows the maximum binding affinity towards the hydrophobic substrate-binding site of TMPRSS2 with three hydrogen bonds interaction ( - 7.5 kcal/mol). On the other hand, molecular docking analysis using Schrodinger identified Quercetin as the most potent phyto compound with a maximum binding affinity towards the hydrophilic catalytic site of TMPRSS2 ( - 7.847 kcal/mol) with three hydrogen bonds interaction. The molecular dynamics simulation reveals that the Quercetin-TMPRSS complex is stable until 50 ns and forms stable interaction with the protein ( - 22.37 kcal/mol of MM-PBSA binding free energy). Genistein creates a weak interaction with the loop residues and hence has an unstable binding and exits from the binding pocket. CONCLUSION: The compounds, Quercetin and Genistein, can inhibit the TMPRSS2 guided priming of the spike protein. The compounds could reduce the interaction of the host cell with the type I transmembrane glycoprotein to prevent the entry of the virus. The critical finding is that compared to Genistein, Quercetin exhibits higher binding affinity with the catalytic unit of TMPRSS2 and forms a stable complex with the target. Thus, enhancing our innate immunity by consuming foods rich in Quercetin and Genistein or developing a novel drug in the combination of Quercetin and Genistein could be the brilliant choices to prevent SARS-Cov-2 infection when we consider the present chaos associated with vaccines and anti-viral medicines.