Newly discovered clouting interplay between matrix metalloproteinases structures and novel quaternary Ammonium K21: computational and in-vivo testing.

AIMS AND OBJECTIVES: To analyze anti-MMP mode of action of Quaternary Ammonium Silane (QAS, codenamed as k21) by binding onto specific MMP site using computational molecular simulation and Anti-Sortase A (SrtA) mode of action by binding onto specific site using computational molecular simulation. MATERIALS AND METHODS: In silico Molecular Dynamics (MD) was used to determine the interactions of K21 inside the pocket of the targeted protein (crystal structure of fibroblast collagenase-1 complexed to a diphenyl-ether sulphone based hydroxamic acid; PDB ID: 966C; Crystal structure of MMP-2 active site mutant in complex with APP-derived decapeptide inhibitor. MD simulations were accomplished with the Desmond package in Schrödinger Drug Discovery Suite. Blood samples (~ 0.5 mL) collected into K2EDTA were immediately transferred for further processing using the Litron MicroFlow® PLUS micronucleus analysis kit for mouse blood according to the manufacturer's instructions. Bacterial Reverse Mutation Test of K21 Molecule was performed to evaluate K21 and any possible metabolites for their potential to induce point mutations in amino acid-requiring strains of Escherichia coli (E. coli) (WP2 uvrA (tryptophan-deficient)). RESULTS: Molecular Simulation depicted that K21 has a specific pocket binding on various MMPs and SrtA surfaces producing a classical clouting effect. K21 did not induce micronuclei, which are the result of chromosomal damage or damage to the mitotic apparatus, in the peripheral blood reticulocytes of male and female CD-1 mice when administered by oral gavage up to the maximum recommended dose of 2000 mg/kg. The test item, K21, was not mutagenic to Salmonella typhimurium (S. typhimurium) strains TA98, TA100, TA1535 and TA1537 and E. coli strain WP2 uvrA in the absence and presence of metabolic activation when tested up to the limit of cytotoxicity or solubility under the conditions of the test. CONCLUSION: K21 could serve as a potent protease inhibitor maintaining the physical and biochemical properties of dental structures.

Antimicrobial FiteBac® K21 promotes antimicrobial Potency and wound healing.

Objectives: Successful root canal therapy is dependent on the efficacy of complete instrumentation and adequate use of chemical irrigant to eliminate the biofilm from dentin surface. The aim of the study was to examine antibiofilm and antimicrobial effectiveness of newly formulated Quaternary ammonium silane (QAS/also codenamed K21; against Fusobacterium nucleatum (F. nucleatum) and Enterococcus faecalis (E. faecalis) biofilm on radicular dentin with evaluation of the anti-inflammatory consequence in vivo. Methods: Fourier Transform Infrared Spectroscopy (FTIR) was performed after complete hydrolysis of K21 solution. Human teeth were inoculated with biofilms for 7-days followed by treatment with various irrigants. The irrigant groups were Sodium hypochlorite [NaOCl (6%)], Chlorhexidine [CHX (2%)], K21 (0.5%), K21 (1%) and Saline. Scanning electron microscopy (SEM) was performed for biofilm and resin-dentin penetration. Transmission Electron Microscopy (TEM) of biofilms was done to evaluate application of K21. For in vivo evaluation, Albino wistar rats were injected subcutaneously and sections were stained with haematoxylin/eosin. Macrophage, M1/M2 expression were evaluated along with molecular simulation. Raman measurements were done on dried biofilms. Results: FTIR K21 specimens demonstrated presence of ethanol/silanol groups. Raman band at 1359 cm-1 resemble to -CH2- wagging displaying 29Si atoms in Nuclear Magnetic Resonance (NMR). 0.5%K21 showed cells exhibiting folded membranes. SEM showed staggering amount of resin tags with 0.5% K21 group. TEM showed membrane disruption in K21-groups. K21 groups were initially irritant, which subsided completely afterwards showing increased CD68. K21 and MMP/collagen complex was thermodynamically favourable. Conclusion: K21 root canal irrigant was able to penetrate bacterial wall and can serve as a potential irrigant for therapeutic benefits. Expression of M2 polarized subsets showed K21 can serve in resolving inflammation and potentiate tissue repair.

Advancements in dextran-based nanocarriers for treatment and imaging of breast cancer.

Breast cancer is the most prevalent type of cancer worldwide,particularly among women, with substantial side effects after therapy. Despite the availability of numerous therapeutic approaches, particularly chemotherapy, the survival rates for breast cancer have declined over time. The therapies currently utilized for breast cancer treatment do not specifically target cancerous cells, resulting in significant adverse effects and potential harm to healthy cells alongside the cancer cells. As a result, nanoparticle-based drug delivery systems have emerged. Among various types of nanoparticles, natural polysaccharide-based nanoparticles have gained significant attention due to their ability to precisely control the drug release and achieve targeted drug delivery. Moreover, polysaccharides are biocompatible, biodegradable, easily modifiable, and renewable, which makes them a unique material for nanoformulation. In recent years, dextran and its derivatives have gained much interest in the field of breast cancer therapy. Dextran is a hydrophilic polysaccharide composed of a main chain formed by α-1,6 linked glucopyranoside residues and a side chain composed of residues linked in α-1,2/3/4 positions. Different dextran-antitumor medication conjugates enhancethe efficacy of anticancer agents. With this context, the present review provides brief insights into dextran and its modification. Further, it meticulously discusses the role of dextran-based nanoparticles in breast cancer therapy and imaging, followed by snippets on their toxicity. Lastly, it presents clinical trials and future perspectives of dextran-based nanoparticles in breast cancer treatment.

Swietenine Alleviates Nonalcoholic Fatty Liver Disease in Diabetic Mice via Lipogenesis Inhibition and Antioxidant Mechanisms.

Our previous studies have reported the effect of swietenine (a major bioactive component of Swietenia macrophylla seeds) in reversing and potentiating the effect of metformin in hyperglycemia and hyperlipidaemia in diabetic rats. Moreover, we reported that the anti-inflammatory effect of swietenine is mediated via the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). This study evaluated the effect of swietenine and its mechanisms in nonalcoholic fatty liver disease (NAFLD) in high-fat diet/streptozotocin-induced diabetic mice. The effect was assessed by determining blood biochemical parameters (glucose, cholesterol, triglycerides, alanine transaminase (ALT), asparate transaminase (AST), alkaline phosphatase (ALP), glutathione (GSH), total antioxidant capacity (TAC), and malondialdehyde (MDA)) and liver biochemical parameters (liver index, cholesterol, and triglycerides). Hepatic lipid accumulation (initial causative factor in NAFLD) was determined by oil-O-red staining. Gene expression (qPCR) and immunohistochemical studies were performed to elucidate the mechanism of swietenine's effect in NAFLD. The critical regulators (genes and proteins) involved in lipogenesis (ACLY, ACC1, FASN, SREBP1c, and ChREBPß) and oxidative stress (Nrf2, NQO-1 and HO-1) pathways were determined. In mice fed with a high-fat diet followed by streptozotocin injection, the liver cholesterol, triglycerides, and lipids were elevated. These increases were reversed by the oral administration of swietenine, 80 mg/kg body weight, on alternate days for eight weeks. Gene expression and immunohistochemical studies showed that swietenine reversed the elevated levels of crucial enzymes of lipogenesis (ACLY, ACC1 and FASN) and their master transcription factors (SREBP1c and ChREBPß). Furthermore, swietenine activated the Nrf2 antioxidant defense mechanism, as evidenced by the upregulated levels of Nrf2, NQO-1, and HO-1. It is concluded that swietenine shows beneficial effects in diabetes-induced NAFLD via inhibiting lipogenesis and activating the Nrf2 pathway.

In-vitro evaluation of the effectiveness of polyphenols based strawberry extracts for dental bleaching.

To formulate a dental bleaching agent with strawberry extract that has potent bleaching properties and antimicrobial efficacy. Enamel specimens (3 × 3 × 2 mm3) were prepared. Quaternary Ammonium Silane (CaC2 enriched) was homogenized with fresh strawberries: Group 1: supernatant strawberry (10 g) extract < Group 2: supernatant strawberry (10 g) extract + 15%HA (Hydroxyapatite) < Group 3: supernatant strawberry (10 g) extract + 15% (HA-2%k21) < Group 4: supernatant strawberry (20 g) extract only (20 g strawberries) < Group 5: supernatant strawberry (20 g) extract + 15% HA < Group 6: supernatant strawberry (20 g) extract + 15% (HA-2%K21) < Group 7: In-office Opalescence Boost 35%. Single-colony lactobacillus was examined using confocal microscopy identifying bacterial growth and inhibition in presence of bleaching agents using 300 µL aliquot of each bacterial culture. Images were analysed by illuminating with a 488 nm argon/helium laser beam. Colour difference (∆E00) was calculated using an Excel spreadsheet implementation of the CIEDE2000 colour difference formula and colour change measured between after staining and after bleaching. Scanning electron microscope was used to image specimens. Raman spectra were collected, and enamel slices were used for STEM/TEM analysis. HPLC was used for strawberry extract analysis. Nano-indentation was performed and X-ray photoelectron spectroscopy. Antioxidant activity was determined along with molecular simulation. hDPSCs were expanded for Alamar Blue Analysis and SEM. Mean colour change was significantly reduced in group 1 compared to other groups (p < 0.05). CLSM showed detrimental effects of different strawberry extracts on bioflms, especially with antimicrobial (p < 0.05). Groups 1, 2 and 3 showed flatter/irregular surfaces with condensation of anti-microbial in group 3. In strawberry specimens, bands predominate at 960 cm-1. HPLC determined the strawberry extracts content. Molecular simulation verified interaction between calcium and polyphenol components. XPS peak-fitted high-resolution corresponding results of Ca2p3/2 and Ca2p1/2 for all k21 groups. Combination of 10 g strawberry extract supernatant and 15% (hydroxyapatite 2%k21) improved the whiteness and provided additional antimicrobial potential. The novel strawberry extract and antimicrobial based dental formulation had immediate bleaching effect without promoting significant changes in enamel morphology.

Synthesis of New Shogaol Analogues as NRF2 Activators and Evaluation of Their Anti-Inflammatory Activity, Modes of Action and Metabolic Stability.

6-shogaol is a natural and the most potent bioactive vanilloid in dried Zingiber officinale rhizomes. Many scientific studies have reported the diverse biological activities of 6-shogaol. However, the major drawback of 6-shogaol is its instability at room temperature. We synthesised new shogaol thiophene compounds (STCs) by replacing the pentyl group in the sidechain with thiophene derivatives. The STCs were tested for their nuclear factor erythroid 2-related factor 2 (NRF2) activation ability in murine hepatoma cells (Hepa1c1c-7) by determining their NAD(P)H quinone oxidoreductase 1 (NQO1) inducing ability and expression of NRF2-associated antioxidant genes. The anti-inflammatory activity of STCs was determined in Escherichia coli lipopolysaccharide (LPSEc)-stimulated NR2-proficient and -silenced mouse microglial cells (BV-2) by measuring the inflammatory markers, cytokines, and mediators. The modes of action (interacting with the Kelch domain of KEAP1, covalent bonding with cysteines of KEAP1, and inhibition of GSK-3ß enzyme activity) of NRF2 activation by STCs were determined using commercially available kits. The in vitro metabolic stability of the STCs in liver microsomes (humans, rats, and mice) was also investigated. The molecular docking and molecular dynamics studies were conducted to identify the binding poses, stability, and molecular interactions of the STCs in the binding pockets of Kelch and BTB domains of KEAP1 and GSK-3ß enzyme. The new STCs were synthesised in good yields of > 85%, with a purity of about 95%, using a novel synthesis method by employing a reusable proline-proline dipeptide catalyst. The STCs are more potent than 6-shogaol in activating NRF2 and reducing inflammation. The nature of substituents on thiophene has a profound influence on the bioactivity of the STCs. Phenylthiophene STC (STC5) is the most potent, while thiophenes containing electron-withdrawing groups showed weaker bioactivity. The bioactivity of 6-shogaol is in the micromolar range, whereas STC5 showed bioactivity in the sub micromolar range. The STCs showed anti-inflammatory effects via NRF2-dependent and NRF2-independent mechanisms. The STCs improved NRF2 activity through multiple (KEAP1-independent and -dependent) mechanisms. The STCs showed decreased reactivity with thiols than 6-shogaol and thus may possess fewer side-effects than 6-shogaol. The STCs were more metabolically stable than 6-shogaol.

Effect of Sustained Systemic Administration of Ginger (Z officinale) Rhizome Extracts on Salivary Flow in Mice.

OBJECTIVE: This study aimed to evaluate the effect of methanol (70% v/v), ethanol (80% v/v), dimethyl sulfoxide (DMSO; 100% v/v) extracts of ginger rhizome (GR), and 6-shogaol on the pilocarpine-stimulated salivary flow rate in C57BL/6 mice. METHODS: Three extracts of ginger (Zingiber officinale) rhizome prepared by maceration using the respective solvents and 6-shogoal were reconstituted in normal saline with 0.2% DMSO. Thirty C57BL/6 15-week-old mice were divided into 5 groups: Group 1, saline; Group 2, 70% methanol extract; Group 3, 80% ethanol extract; Group 4, 100% DMSO extract; and Group 5, 6-shogaol. The baseline pilocarpine-stimulated salivary flow rate was measured at the age of 15 weeks (15th week), and treatment solutions were administered by intraperitoneal injection from the 16th to 18th week. The stimulated salivary flow rate during treatment weeks was recorded for each group, and its difference with baseline was analysed using paired-sample t test. The change in salivary flow rate between the treatment groups and the control group was analysed using one-way analysis of variance. RESULTS: Groups 2, 3, 4, and 5 showed a significant increase in salivary flow rate when compared to baseline (P < .05). The increase in salivary flow rate in all 4 treatment groups was significant when compared to the control group (P < .05). Group 4 produced the highest increase in salivary flow rate; however, the differences amongst the treatment groups did not reach statistical significance (P > .05). CONCLUSIONS: All GR extracts (70% methanol, 80% ethanol, 100% DMSO) and 6-shogaol were equally effective in increasing the pilocarpine-stimulated salivary flow rate in C57BL/6 mice when administered systemically as a sustained dose for 3 weeks.

Quercetin and metformin synergistically reverse endothelial dysfunction in the isolated aorta of streptozotocin-nicotinamide- induced diabetic rats.

The antidiabetic effects of quercetin and metformin are well known. However, their synergistic effect in reversing the symptoms of diabetes-induced endothelial dysfunction remains unknown. In this study, we have investigated their synergistic effect in streptozotocin (STZ)-nicotinamide induced diabetic rats. Seventy-five rats were divided into five groups; normal control, diabetic control, treatment groups (10 mg/kg quercetin, 180 mg/kg metformin, and combined). The plasma glucose and lipid levels, liver enzymes, ex-vivo studies on aortic rings, histology of liver, kidney, pancreas, abdominal aorta and thoracic aorta, and immunohistochemical studies were carried out. The findings revealed that the combination of quercetin and metformin showed a greater antidiabetic effect than either drug, and rendered protection to the endothelium. The combination effectively reversed the hyperglycemia-induced endothelial dysfunction in diabetic rats. Furthermore, it also reversed the dysregulated expression of eNOS, 3-nitrotyrosine, VCAM-1, CD31 and SIRT-1. Overall, the present study's findings demonstrate that quercetin potentiates the activity of metformin to control the complications associated with diabetes.

Synthesis and Anti-Inflammatory Activity of 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-Derived NRF2 Activators.

This is the first study investigating the nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity of compounds containing a new scaffold, tetrahydrobenzo[b]thiophene. Eighteen compounds were synthesised and confirmed their NRF2 activation through NQO1 enzymatic activity and mRNA expression of NQO1 and HO-1 in Hepa-1c1c7 cells. The compounds disrupted the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and NRF2 via interfering with the KEAP1's Kelch domain. The compounds exhibited anti-inflammatory activity in Escherichia coli Lipopolysaccharide (LPSEc )-stimulated RAW 264.7 cells. The anti-inflammatory activity of the compounds was associated with their ability to activate NRF2. The compounds reversed the elevated levels of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, and IFN-γ) and inflammatory mediators (PGE2, COX-2, and NF-κB). The compounds were metabolically stable in human, rat, and mouse liver microsomes and showed optimum half-life (T1/2 ) and intrinsic clearance (Clint ). The binding mode of the compounds and physicochemical properties were predicted via in silico studies.

Anti-Inflammatory Effects of Auranamide and Patriscabratine-Mechanisms and In Silico Studies.

Auranamide and patriscabratine are amides from Melastoma malabathricum (L.) Smith. Their anti-inflammatory activity and nuclear factor erythroid 2-related factor 2 (NRF2) activation ability were evaluated using Escherichia coli lipopolysaccharide (LPSEc)-stimulated murine macrophages (RAW264.7) and murine hepatoma (Hepa-1c1c7) cells, respectively. The cytotoxicity of the compounds was assessed using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. The anti-inflammatory activity was determined by measuring the nitric oxide (NO) production and pro-inflammatory cytokines (Interleukin (IL)-1ß, Interferon (IFN)-γ, tumour necrosis factor (TNF)-α, and IL-6) and mediators (NF-κB and COX-2). NRF2 activation was determined by measuring the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) quinone oxidoreductase 1 (NQO1), nuclear NRF2 and hemeoxygenase (HO)-1. In vitro metabolic stability was assessed using the mouse, rat, and human liver microsomes. The compounds were non-toxic to the cells at 10 µM. Both compounds showed dose-dependent effects in downregulating NO production and pro-inflammatory cytokines and mediators. The compounds also showed upregulation of NQO1 activity and nuclear NRF2 and HO-1 levels. The compounds were metabolically stable in mouse, rat and human liver microsomes. The possible molecular targets of NRF2 activation by these two compounds were predicted using molecular docking studies and it was found that the compounds might inhibit the Kelch domain of KEAP1 and GSK-3ß activity. The physicochemical and drug-like properties of the test compounds were predicted using Schrodinger small molecule drug discovery suite (v.2022-2).

Light-responsive polyurethanes: classification of light-responsive moieties, light-responsive reactions, and their applications.

Stimuli responsiveness has been an attractive feature of smart material design, wherein the chemical and physical properties of the material can be varied in response to small environmental change. Polyurethane (PU), a widely used synthetic polymer can be upgraded into a light-responsive smart polymer by introducing a light-sensitive moiety into the polymer matrix. For instance, azobenzene, spiropyran, and coumarin result in reversible light-induced reactions, while o-nitrobenzyl can result in irreversible light-induced reactions. These variations of light-stimulus properties endow PU with wide ranges of physical, mechanical, and chemical changes upon exposure to different wavelengths of light. PU responsiveness has rarely been reviewed even though it is known to be one of the most versatile polymers with diverse ranges of applications in household, automotive, electronic, construction, medical, and biomedical industries. This review focuses on the classes of light-responsive moieties used in PU systems, their synthesis, and the response mechanism of light-responsive PU-based materials, which also include dual- or multi-responsive light-responsive PU systems. The advantages and limitations of light-responsive PU are reviewed and challenges in the development of light-responsive PU are discussed.

PH Responsive Polyurethane for the Advancement of Biomedical and Drug Delivery.

Due to the specific physiological pH throughout the human body, pH-responsive polymers have been considered for aiding drug delivery systems. Depending on the surrounding pH conditions, the polymers can undergo swelling or contraction behaviors, and a degradation mechanism can release incorporated substances. Additionally, polyurethane, a highly versatile polymer, has been reported for its biocompatibility properties, in which it demonstrates good biological response and sustainability in biomedical applications. In this review, we focus on summarizing the applications of pH-responsive polyurethane in the biomedical and drug delivery fields in recent years. In recent studies, there have been great developments in pH-responsive polyurethanes used as controlled drug delivery systems for oral administration, intravaginal administration, and targeted drug delivery systems for chemotherapy treatment. Other applications such as surface biomaterials, sensors, and optical imaging probes are also discussed in this review.

Microarray Analysis of the Genomic Effect of Eugenol on Methicillin-Resistant Staphylococcus aureus.

Staphylococcus aureus is a highly adaptive human pathogen responsible for serious hospital- and community-acquired infectious diseases, ranging from skin and soft tissue infections, to complicated and life-threatening conditions such as endocarditis and toxic shock syndrome (TSS). The rapid development of resistance of this organism to available antibiotics over the last few decades has necessitated a constant search for more efficacious antibacterial agents. Eugenol (4-allyl-2-methoxyphenol) belongs to the class of chemical compounds called phenylpropanoids. It is a pure-to-pale yellow, oily liquid substance, mostly extracted as an essential oil from natural products such as clove, cinnamon, nutmeg, basil, and bay leaf. Eugenol has previously been shown to have antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). However, the mechanism of action of eugenol against MRSA has not, as yet, been elucidated; hence, the necessity of this study. Global gene expression patterns in response to challenge from subinhibitory concentrations of eugenol were analysed using the Agilent DNA microarray system to identify genes that can be used as drug targets-most importantly, essential genes involved in unique metabolic pathways elicited for bacterial survival. Transcriptomic analysis of fluctuating genes revealed those involved in amino acid metabolism, fatty acid metabolism, translational, and ribosomal pathways. In amino acid metabolism, for instance, the argC gene encodes for N-acetyl-gamma-glutamyl-phosphate reductase. The argC gene plays an important role in the biosynthesis of arginine from glutamate in the amino acid metabolic pathway. It is the enzyme that catalyses the third step in the latter reaction, and without this process the production of N-acetylglutamate 5-semialdehyde cannot be completed from the NADP-dependent reduction of N-acetyl-5-glutamyl phosphate, which is essential for the survival of some microorganisms and plants. This study enables us to examine complete global transcriptomic responses in MRSA when challenged with eugenol. It reveals novel information with the potential to further benefit the exploratory quest for novel targets against this pathogen, with a view to the development of efficacious antimicrobial agents for the treatment of associated infections.

Biochemical changes and macrophage polarization of a silane-based endodontic irrigant in an animal model.

Silane-based/fully hydrolyzed, endodontic irrigant exhibiting antimicrobial properties, is prepared, and is hypothesized to control macrophage polarization for tissue repair. Albino wistar rats were injected with 0.1 ml root canal irrigant, and bone marrow cells procured. Cellular mitochondria were stained with MitoTracker green along with Transmission Electron Microscopy (TEM) performed for macrophage extracellular vesicle. Bone marrow stromal cells (BMSCs) were induced for M1 and M2 polarization and Raman spectroscopy with scratch assay performed. Cell counting was used to measure cytotoxicity, and fluorescence microscopy performed for CD163. Scanning Electron Microscopy (SEM) was used to investigate interaction of irrigants with Enterococcus faecalis. K21 specimens exhibited reduction in epithelium thickness and more mitochondrial mass. EVs showed differences between all groups with decrease and increase in IL-6 and IL-10 respectively. 0.5%k21 enhanced wound healing with more fibroblastic growth inside scratch analysis along with increased inflammation-related genes (ICAM-1, CXCL10, CXCL11, VCAM-1, CCL2, and CXCL8; tissue remodelling-related genes, collagen 1, EGFR and TIMP-2 in q-PCR analysis. Sharp bands at 1643 cm-1 existed in all with variable intensities. 0.5%k21 had a survival rate of BMSCs comparable to control group. Bacteria treated with 0.5%k21/1%k21, displayed damage. Antimicrobial and reparative efficacy of k21 disinfectant is a proof of concept for enhanced killing of bacteria across root dentin acquiring functional type M2 polarization for ethnopharmacological effects.

Zingiber officinale var. rubrum: Red Ginger's Medicinal Uses.

Zingiber officinale var. rubrum (red ginger) is widely used in traditional medicine in Asia. Unlike other gingers, it is not used as a spice in cuisines. To date, a total of 169 chemical constituents have been reported from red ginger. The constituents include vanilloids, monoterpenes, sesquiterpenes, diterpenes, flavonoids, amino acids, etc. Red ginger has many therapeutic roles in various diseases, including inflammatory diseases, vomiting, rubella, atherosclerosis, tuberculosis, growth disorders, and cancer. Scientific evidence suggests that red ginger exhibits immunomodulatory, antihypertensive, antihyperlipidemic, antihyperuricemic, antimicrobial, and cytotoxic activities. These biological activities are the underlying causes of red ginger's therapeutic benefits. In addition, there have been few reports on adverse side effects of red ginger. This review aims to provide insights in terms the bioactive constituents and their biosynthesis, biological activities, molecular mechanisms, pharmacokinetics, and qualitative and quantitative analysis of red ginger.

Success stories of AI in drug discovery - where do things stand?

INTRODUCTION: Artificial intelligence (AI) in drug discovery and development (DDD) has gained more traction in the past few years. Many scientific reviews have already been made available in this area. Thus, in this review, the authors have focused on the success stories of AI-driven drug candidates and the scientometric analysis of the literature in this field. AREA COVERED: The authors explore the literature to compile the success stories of AI-driven drug candidates that are currently being assessed in clinical trials or have investigational new drug (IND) status. The authors also provide the reader with their expert perspectives for future developments and their opinions on the field. EXPERT OPINION: Partnerships between AI companies and the pharma industry are booming. The early signs of the impact of AI on DDD are encouraging, and the pharma industry is hoping for breakthroughs. AI can be a promising technology to unveil the greatest successes, but it has yet to be proven as AI is still at the embryonic stage.

The role of DMPK science in improving pharmaceutical research and development efficiency.

The successful regulatory authority approval rate of drug candidates in the drug development pipeline is crucial for determining pharmaceutical research and development (R&D) efficiency. Regulatory authorities include the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceutical and Food Safety Bureau Japan (PFSB), among others. Optimal drug metabolism and pharmacokinetics (DMPK) properties influence the progression of a drug candidate from the preclinical to the clinical phase. In this review, we provide a comprehensive assessment of essential concepts, methods, improvements, and challenges in DMPK science and its significance in drug development. This information provides insights into the association of DMPK science with pharmaceutical R&D efficiency.

Synthesis and Incorporation of Quaternary Ammonium Silane Antimicrobial into Self-Crosslinked Type I Collagen Scaffold: A Hybrid Formulation for 3D Printing.

Novel 3D-biomaterial scaffold is constructed having a combination of a new quaternary ammonium silane (k21) antimicrobial impregnated in 3D collagen printed scaffolds cross linked with Riboflavin in presence of d-alpha-tocopheryl poly(ethyleneglycol)-1000-succinate. Groups of "0.1% and 0.2% k21", and "0.1% and 0.2% Chlorhexidine (CHX)" are prepared. k21/CHX with neutralized collagen is printed with BioX. Riboflavin is photo-activated and examined using epifluorescence for Aggregatibacter actinomycetemcomitans (7-days). Collagen is examined using TEM and measured for porosity, and shape-fitting. Raman and tandem mass/solid-state are performed with molecular-docking and circular-dichroism. X-ray diffractions, rheological tests, contact angle, and ninhydrin assay are conducted. k21 samples demonstrated collagen aggregates while 0.1% CHX and 0.2% CHX showed irregularities. Porosity of control and "0.1% and 0.2% k21" scaffolds show no differences. Low contact angle, improved elastic-modulus, rigidity, and smaller strain in k21 groups are seen. Bacteria are reduced and strong organic intensities are seen in k21 scaffolds. Simulation shows hydrophobicity/electrostatic interaction. Crosslinking is observed in 0.2% CHX/79% and 0.2% k21/80%. Circular dichroism for k21 are suggestive of triple helix. XRD patterns appear at d = 5.97, 3.03, 2.78, 2.1, and 2.90 A°. 3D-printing of collagen impregnated with quaternary ammonium silane produces a promising scaffold with antimicrobial potency and structural stability.

Concentration-Dependent Multi-Potentiality of L-Arginine: Antimicrobial Effect, Hydroxyapatite Stability, and MMPs Inhibition.

This study's objective was to examine L-arginine (L-arg) supplementation's effect on mono-species biofilm (Streptococcus mutans/Streptococcus sanguinis) growth and underlying enamel substrates. The experimental groups were 1%, 2%, and 4% arg, and 0.9% NaCl was used as the vehicle control. Sterilised enamel blocks were subjected to 7-day treatment with test solutions and S. mutans/S. sanguinis inoculum in BHI. Post-treatment, the treated biofilms stained for live/dead bacterial cells were analysed using confocal microscopy. The enamel specimens were analysed using X-ray diffraction crystallography (XRD), Raman spectroscopy (RS), and transmission electron microscopy (TEM). The molecular interactions between arg and MMP-2/MMP-9 were determined by computational molecular docking and MMP assays. With increasing arg concentrations, bacterial survival significantly decreased (p < 0.05). The XRD peak intensity with 1%/2% arg was significantly higher than with 4% arg and the control (p < 0.05). The bands associated with the mineral phase by RS were significantly accentuated in the 1%/2% arg specimens compared to in other groups (p < 0.05). The TEM analysis revealed that 4% arg exhibited an ill-defined shape of enamel crystals. Docking of arg molecules to MMPs appears feasible, with arg inhibiting MMP-2/MMP-9 (p < 0.05). L-arginine supplementation has an antimicrobial effect on mono-species biofilm. L-arginine treatment at lower (1%/2%) concentrations exhibits enamel hydroxyapatite stability, while the molecule has the potential to inhibit MMP-2/MMP-9.

In vitro methods used for discovering plant derived products as wound healing agents - An update on the cell types and rationale.

Wounds still pose a huge burden on human health and healthcare systems in many parts of the world. Phytomedicines are being used to heal the wounds since ancient times. Now-a-days also many researchers are exploring the wound healing activity of phytomedicines. Wound healing is a complex process thus, it is always a question mark regarding the best test model (in vivo, ex vivo and in vitro) model to assess the wound healing activity of phytomedicines. In general, the researchers would opt for in vivo model - probably because of closer physiological relevance to human wounds. However, in vivo experimental models are not suitable for high throughput screening and not ethical in terms of initial screening of the phytomedicines. The in vivo models are associated with difficulties in obtaining the ethical approvals, requires huge budget, and resources. We argue that judicious selection of cell types would serve the purpose of developing a physiologically relevant in vitro experimental model. A lot of progress has been made in molecular biology techniques to bridge the gap between in vitro models and their physiological relevance. The in vitro models are the best suited for high throughput screening and to elucidate the molecular mechanisms. The main aim of this review is to provide insights on selection of the cell types for developing physiologically relevant in vitro wound healing assays, which can be used to improve the value of phytomedicines further.