Isolation, Characterization, and Expression Analysis of NAC Transcription Factor from Andrographis paniculata (Burm. f.) Nees and Their Role in Andrographolide Production.

Andrographis paniculata (Burm. f.) Nees is an important medicinal plant known for its bioactive compound andrographolide. NAC transcription factors (NAM, ATAF1/2, and CUC2) play a crucial role in secondary metabolite production, stress responses, and plant development through hormonal signaling. In this study, a putative partial transcript of three NAC family genes (ApNAC83, ApNAC21 22 and ApNAC02) was used to isolate full length genes using RACE. Bioinformatics analyses such as protein structure prediction, cis-acting regulatory elements, and gene ontology analysis were performed. Based on in silico predictions, the diterpenoid profiling of the plant's leaves (five-week-old) and the real-time PCR-based expression analysis of isolated NAC genes under abscisic acid (ABA) treatment were performed. Additionally, the expression analysis of isolated NAC genes under MeJA treatment and transient expression in Nicotiana tabacum was performed. Full-length sequences of three members of the NAC transcription factor family, ApNAC83 (1102 bp), ApNAC21 22 (996 bp), and ApNAC02 (1011 bp), were isolated and subjected to the promoter and gene ontology analysis, which indicated their role in transcriptional regulation, DNA binding, ABA-activated signaling, and stress management. It was observed that ABA treatment leads to a higher accumulation of andrographolide and 14-deoxyandrographolide content, along with the upregulation of ApNAC02 (9.6-fold) and the downregulation of ApNAC83 and ApNAC21 22 in the leaves. With methyl jasmonate treatment, ApNAC21 22 expression decreased, while ApNAC02 increased (1.9-fold), with no significant change being observed in ApNAC83. The transient expression of the isolated NAC genes in a heterologous system (Nicotiana benthamiana) demonstrated their functional transcriptional activity, leading to the upregulation of the NtHMGR gene, which is related to the terpene pathway in tobacco. The expression analysis and heterologous expression of ApNAC21 22 and ApNAC02 indicated their role in andrographolide biosynthesis.

Context-aware Multimodal Auditory BCI Classification through Graph Neural Networks.

The prospect of electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) in the presence of topological information of participants is often left unexplored in most of the brain-computer interface (BCI) systems. Additionally, the usage of these modalities together in the field of multimodality analysis to support multiple brain signals toward improving BCI performance is not fully examined. This study first presents a multimodal data fusion framework to exploit and decode the complementary synergistic properties in multimodal neural signals. Moreover, the relations among different subjects and their observations also play critical roles in classifying unknown subjects. We developed a context-aware graph neural network (GNN) model utilizing the pairwise relationship among participants to investigate the performance on an auditory task classification. We explored standard and deviant auditory EEG and fNIRS data where each subject was asked to perform an auditory oddball task and has multiple trials regarded as context-aware nodes in our graph construction. In experiments, our multimodal data fusion strategy showed an improvement up to 8.40% via SVM and 2.02% via GNN, compared to the single-modal EEG or fNIRS. In addition, our context-aware GNN achieved 5.3%, 4.07% and 4.53% higher accuracy for EEG, fNIRS and multimodal data based experiments, compared to the baseline models.

Discovery of Anti-NRLP3 Inflammasome, Immunomodulatory Phytochemicals from the Extract of Habenaria intermediaD. Don: An Unexplored Plant Species.

The present study describes the isolation, identification, and quantification of biomarker compounds in plant extracts of Habenaria intermedia D. Don (Orchidaceae). The isolation of the compounds was carried out from H. intermedia D. Don by repeated column chromatography of petroleum ether and ethanol fractions of extract of tubers. These compounds were characterized by 1H and 13C NMR and mass spectral data. A new quantitative method was established by using high-performance liquid chromatography (HPLC)-PDA. As a result, seven compounds were isolated and characterized. This is the first report of isolation of these compounds from this plant species H. intermedia D.Don. Out of seven isolated compounds, five were used for the quantitative study. A reliable and suitable HPLC method was developed for the well-resolved chromatogram of compounds. The proposed method was applied successfully to the detection and quantification of compounds. This study also represents the immunomodulatory and anti-inflammasome biological studies of isolated natural products. Loroglossol (HBR-4) has been reported to possess immunomodulatory activity. The immunostimulating assay indicated that HBR-4 could significantly promote the cell proliferation, especially via IL-2, TNF-α, and IFN-γ secretion from spleen cells. These results suggested the potential utilization of HBR-4 as an attractive functional health supplement candidate for hypoimmunity population. Additionally, cyclophosphamide-induced immunosuppression was counteracted by treatment with HBR-4, revealing significant increase in hemagglutinating antibody responses and hemolytic antibody responses. The current work revealed the potential anti-inflammasome and immunomodulatory activities of H. intermedia D. Don compounds and validates the usage of this prominent Rasayna plant.

Scoparone chemical modification into semi-synthetic analogues featuring 3-substitution for their anti-inflammatory activity.

Natural products (NPs) continue to serve as a structural model for the development of new bioactive molecules and improve the process of identifying novel medicines. The biological effects of coumarins, one of the most researched compounds among NPs, are currently being thoroughly investigated. In the present investigation, we reported the synthesis of nineteen semi-synthetic 3-substituted scoparone analogues, followed by their characterization using analytical methods such as NMR, HPLC, and HRMS. All compounds screened for in vitro and in vivo study for their ability to reduce inflammation. The SAR study worked effectively for this particular scoparone 3-substitution, as compounds 3, 4, 9, 16, 18, and 20 displayed improved in vitro results for TNF-α than the parent molecule. Similarly, compounds 3, and 17 showed a higher percentage of IL-6 inhibition. Compounds 3, 4, and 12 have also been identified by in vivo studies as promising candidates with higher percent inhibition than the parent scoparone molecule. As evident from all in vitro and in vivo studies, compound 3 showed the most potent anti-inflammatory activity among all.

Dereplication approach for the first time isolation of tatarinowin a and pentadecanoic acid from Acorus calamus L. by using GC-MS.

In the present study, we report herein the isolation of cadinane-type sesquiterpenoid, tatarinowin A (ACH-6), and pentadecanoic acid (ACH-8) from petroleum ether extract of rhizome of Acorus calamus L. (Acoraceae) along with 6 other known compounds in this species. It is pertinent to mention here that this is the first report to stain these compounds in which dereplication approach based on GC-MS was applied to target unknown compounds ACH-6 and ACH-8 in A. calamus L. Derelpication approaches based on GC-MS is very useful technique in the area of drug discovery and have eminence potential to identify known and unknown compounds present in extracts of medicinal important plants. This technique can be used to expedite the process of purification of unknown compounds from different matrixes. The isolated compounds were identified with the help of inbuilt library search which reveals the presence of 17 known and 4 unknown compounds. Further, the structure elucidation of all isolated compounds was done using spectroscopy techniques. Also, the structure of ACH-6 was further confirmed by using the single-crystal X-ray diffraction technique.

Novel alantolactone derivative AL-04 exhibits potential anti-inflammatory activity via modulation of iNOS, COX-2 and NF-κB.

Natural compounds and their synthesized analogues continue to be valuable sources in the discovery and development of novel anti-inflammatory agents. AL-04 is a thiol analogue derived from a natural sesquiterpene alantolactone, that demonstrated potential anti-inflammatory activity in vitro in comparison to its parent compound. However, the anti-inflammatory mechanism of action of AL-04 has not been elucidated. In this context, we investigated the signaling pathway that primarily mediate the anti-inflammatory activity of AL-04 and its effect on principal inflammatory mediators including iNOS, COX-2 and ROS. Furthermore, the anti-inflammatory activity was investigated in vivo in carrageenan induced paw oedema model in addition to the exploration of anti-nociceptive activity and acute toxicity. The results suggested that treatment with AL-04 significantly decreased the LPS-induced upregulation of pro-inflammatory cytokines and mediators in addition to the downregulated transcription of TNF-α and IL-6 in RAW 264.7 cell line. Furthermore, mRNA and the protein expression of COX-2 and iNOS were also significantly attenuated with AL-04 at a concentration of 10 µM. Western blot studies further suggested that AL-04 downregulated LPS-stimulated NF-κB p65 expression. In addition to this the anti-inflammatory activity of AL-04 was demonstrated in carrageenan induced paw oedema model with significant inhibition of oedema in a dose-dependent manner. The anti-inflammatory activity of AL-04 was further demonstrated in balb/c mice by inhibition of leukocyte migration and vascular permeability. Besides, AL-04 also inhibited thermally and chemically induced pain in tail-flick and acetic acid induced writing assays respectively in balb/c mice suggesting the analgesic potential of the compound. Acute toxicity studies further suggested the appreciable safety of AL-04 at high dose of 2000 mg/kg with no indications of toxicity or changes in biochemical and haematological parameters. Overall, the study insinuates the anti-inflammatory potential of AL-04 and paves way for further exploration of the compound as a safer therapeutic anti-inflammatory agent.

Effects of differently incubated cupric oxide nanoparticles on the granulosa cells of caprine ovary in vitro.

In the nanoscience metal and metal oxide, nanoparticles have a prominent place because of their vast applications. Recent finding shows that in addition to size, there are other critical factors governing the biological response of nanoparticles. These factors include surface chemistry and shape that influences solubility, rate of diffusion, drug delivery, melting temperature, and colour of the nanoparticles. It is thus the present study that was aimed to investigate the effect of temperature on the shape and size of nanoparticles and related cytotoxicity of these particles on ovarian granulosa cells. Cupric oxide nanoparticles (CuONPs) were synthesized using a simple, efficient, and reproducible precipitation method involving the reduction of Cu metal salt with sodium hydroxide and then incubation of the precipitates at 70 °C for 5 h. Subsequently, this prepared sample was divided into 3 subsamples and incubated at 3 different temperatures, i.e. 70 °C, 150 °C, and 350 °C for 5 h to study the effect of temperature on the particles. The products were characterized by XRD, FTIR, HRTEM, and FESEM. Characterization of the particles revealed that all particles were monoclinic crystalline in nature and had a size range from 9 to 60 nm. Particles were of different shapes: spherical, needle, and capsule. The toxicity of each particle was determined on granulosa cells by exposing cells for 24 h at 2 different doses. Toxicological results showed the size and shape-related toxicity of nanoparticles where spherical shapes were significantly more toxic than capsule-shaped particles.

Potential Inhibitors Targeting Escherichia coli UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA): An Overview.

Antibiotic resistance is one of the biggest challenges that is escalating and affecting humanity across the globe. To overcome this increasing burden of resistance, discovering novel hits by targeting the enzymes involved in peptidoglycan (murein) biosynthesis has always been considered better in antimicrobial drug discovery. UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) enzyme has been identified as essential for Escherichia coli survival and catalyzes the early-stage step in bacterial cell wall synthesis. The present article gives a brief overview of the role of enzymes in peptidoglycan synthesis and MurA enzyme (previously known as MurZ in E. coli), in particular, including its structural and active site features. This review also provides an insight into the current knowledge of the reported MurA inhibitors, their mechanism of action and drawbacks of these hits that hinder their clinical trials, which would be helpful for synthesis and discovering potent molecules. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12088-021-00988-6.

Dereplication Based Strategy for Rapid Identification and Isolation of a Novel Anti-inflammatory Flavonoid by LCMS/MS from Colebrookea oppositifolia.

Colebrookea oppositifolia is a folkloric medicinal plant, well known for its tremendous medicinal properties such as curing epilepsy, ulcers, and urinary problems. The aim of the present study was to apply the dereplication strategy on the ethanol extract of C. oppositifolia with potent anti-inflammatory activity for the rapid identification and isolation of novel bioactive molecules to aid the drug discovery process. An integrated approach using liquid chromatography-mass spectrometry (LCMS) followed by preparative high-performance liquid chromatography (HPLC) was used for the isolation of potent molecules from the anti-inflammatory extract of C. oppositifolia . Purity of the compounds (>98.5%) was established by HPLC, and identification was carried out by NMR and ESI-MS. 5,6,7-Trihydroxyflavone-3-O-glucuronide methyl ester (compound III) isolated from C. oppositifolia was extensively studied for anti-inflammatory potential in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the mice model. Compound III significantly repressed various proinflammatory mediators and upregulated the release of anti-inflammatory cytokine IL-10. Compound III reduced inflammation when studied for parameters such as the phagocytic index, carrageenan-induced paw edema in mice, and effect on organ weight. It reduced inflammation in a dose-dependent manner both in vitro and in vivo. Further molecular insights into the study revealed that compound III blocks the phosphorylation of I kappa b kinase α/ß (IKKα/ß), IκBα, and nuclear factor kB p65 (NF-κBp65) which is a key controller of inflammation, thereby showing anti-inflammatory potential. Hence, this study permits further investigation to develop compound III as an anti-inflammatory drug.

Prevalence and severity of secondary traumatic stress and optimism in Indian health care professionals during COVID-19 lockdown.

BACKGROUND: The COVID-19 pandemic has brought to light the lacunae in the preparedness of healthcare systems across the globe. This preparedness also includes the safety of healthcare providers (HCPs) at various levels. Sudden spread of COVID-19 infection has created threatening and vulnerable conditions for the HCPs. The current pandemic situation has not only affected physical health of HCPs but also their mental health. OBJECTIVE: This study aims to understand the prevalence and severity of secondary traumatic stress, optimism parameters, along with states of mood experienced by the HCPs, viz., doctors, nurses and allied healthcare professionals (including Physiotherapist, Lab technicians, Phlebotomist, dieticians, administrative staff and clinical pharmacist), during the COVID-19 lockdown in India. METHODOLOGY: The assessment of level of secondary traumatic stress (STS), optimism/pessimism (via Life Orientation Test-Revised) and current mood states experienced by Indian HCPs in the present COVID-19 pandemic situation was done using a primary data of 2,008 HCPs from India during the first lockdown during April-May 2020. Data was collected through snow-ball sampling technique, reaching out to various medical health care professionals through social media platforms. RESULT: Amongst the study sample 88.2% of doctors, 79.2 of nurses and 58.6% of allied HCPs were found to have STS in varying severity. There was a female preponderance in the category of Severe STS. Higher optimism on the LOTR scale was observed among doctors at 39.3% followed by nurses at 26.7% and allied health care professionals 22.8%. The mood visual analogue scale which measures the "mood" during the survey indicated moderate mood states without any gender bias in the study sample. CONCLUSION: The current investigation sheds light on the magnitude of the STSS experienced by the HCPs in the Indian Subcontinent during the pandemic. This hitherto undiagnosed and unaddressed issue, calls for a dire need of creating better and accessible mental health programmes and facilities for the health care providers in India.

Antiarthritic activity of OA-DHZ; a gastroprotective NF-κB/MAPK/COX inhibitor.

Arthritis, a primary autoimmune disorder having a global incidence of 2.03% person/year, is presently being treated by many commercially available drugs that treat symptomatically or improve the disease's clinical state; however, all the therapies pose varying amount of side effects. Therefore, it has become a fundamental need to search for therapeutics that offer better efficacy and safety profile, and the natural or nature-derived products are known for their outstanding performance in this arena. OA-DHZ, known to possess anti-inflammatory and analgesic properties, when explored for its efficacy against arthritis in adjuvant-induced arthritis (AIA) model, was found to inhibit paw edema by 34% and TNF-α, IL-6, and IL-1ß by 67%, 39%, and 45% respectively when compared to diseased control. It was also able to reduce the inflamed spleen size by 45% and successfully normalized biochemical and hematological changes that followed arthritis. In vitro studies revealed that the underlying mechanism for inhibiting arthritis progression might be due to NF-κB /MAPK pathway modulation. OA-DHZ also showed selective inhibition of COX-2 in vitro while showing gastroprotective effects when evaluated for ulcerogenic and antiulcer potential in vivo. In contrast to the results obtained from in vivo experimentation, there is a disparity in the pharmacokinetic profile of OA-DHZ, where it showed low oral exposure and high clearance rate. OA-DHZ being antiarthritic acting via NF-κB /MAPK/ COX inhibition while showing gastroprotective effects, can be a suitable candidate to be in the drug pipeline and further exploration.

Evaluation of analgesic and anti-inflammatory activities and molecular docking analysis of steroidal lactones from Datura stramonium L.

BACKGROUND: Datura stramonium L. is widely used across the world for its therapeutic potential to treat inflammatory disorders. The current work was designed to isolate and identify steroidal lactones from D. stramonium leaves and evaluate their anti-inflammatory and analgesic properties. METHODS: Several compounds were isolated from D. stramonium leaves and characterized by nuclear magnetic resonance and high-resonance electron spray ionization mass spectrometry techniques. Further, anti-inflammatory properties of these compounds were evaluated by in vitro assays, such as release of NO and pro-inflammatory cytokines by lipopolysaccharide (LPS)-activated J774A.1 macrophages. Using in vivo models, anti-inflammatory and analgesic effects were examined by mouse tail-flick, carrageenan-induced inflammation in rat paw model, vascular permeability in rats, and acetic acid-induced writhing in mice. The docking studies were performed for assessing the binding efficiency of the test compounds with cyclooxygenase-1 (COX-1) and COX-2, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), inducible nitric oxide synthases (iNOS) and nuclear factor-κB (NF-κB). RESULTS: Three lactones were isolated and confirmed as daturalactone (D1), 12-deoxywithastramonolide (D23), and daturilin (D27). Further, the isolated compounds showed nitric oxide inhibition and pro-inflammatory cytokines released by LPS-activated J774A.1 macrophages. The in vivo results suggest that D1, D23 and D27 (20 mg/kg) were able to reduce the pain and inflammation in various animal models. The docking analysis showed that these three compounds actively bind with COX-1, COX-2, LOX-1, NF-κB, and iNOS, validating the anti-inflammatory effects of the lactones. CONCLUSION: These findings demonstrate substantial anti-inflammatory and analgesic properties of D. stramonium-derived lactones and their potential as anti-inflammatory agents to treat chronic inflammatory ailments.

Forest-linked livelihoods in a globalized world.

Forests have re-taken centre stage in global conversations about sustainability, climate and biodiversity. Here, we use a horizon scanning approach to identify five large-scale trends that are likely to have substantial medium- and long-term effects on forests and forest livelihoods: forest megadisturbances; changing rural demographics; the rise of the middle-class in low- and middle-income countries; increased availability, access and use of digital technologies; and large-scale infrastructure development. These trends represent human and environmental processes that are exceptionally large in geographical extent and magnitude, and difficult to reverse. They are creating new agricultural and urban frontiers, changing existing rural landscapes and practices, opening spaces for novel conservation priorities and facilitating an unprecedented development of monitoring and evaluation platforms that can be used by local communities, civil society organizations, governments and international donors. Understanding these larger-scale dynamics is key to support not only the critical role of forests in meeting livelihood aspirations locally, but also a range of other sustainability challenges more globally. We argue that a better understanding of these trends and the identification of levers for change requires that the research community not only continue to build on case studies that have dominated research efforts so far, but place a greater emphasis on causality and causal mechanisms, and generate a deeper understanding of how local, national and international geographical scales interact.

Datura stramonium essential oil composition and it's immunostimulatory potential against colon cancer cells.

The current study deals with the investigation of the antioxidant, anti-inflammatory and immunomodulatory properties of the essential oil from Datura stramonium leaves (D. oil). The GC-MS analysis showed that the dominant compounds present in the D. oil were neophytadiene (Phytol acetate) (10.76%), ß-damascenone (9.67%), and ß- eudesmol (7.2%). D. oil exhibited in vitro scavenging potential of free radicals by DPPH and ABTS assays (IC50 values 71.35 ±1.06 µg/ml and 61.01 ± 1.07 µg/ml, respectively). We found that D. oil decreased the nitric oxide production in LPS-stimulated J774A.1 cells by 52.43% without affecting their cell viability. D. oil was found to stimulate the proliferation of human peripheral blood mononuclear cells (PBMC) and, also enhanced the secretion of IL-2, IFN-γ and TNF-α. Furthermore, D. oil treatment of PBMC induced the expression of CD3, CD8, and CD56 and intracellular granulysin levels in the immune cells. The treatment of human lymphocytes by D. oil enhanced their ability to kill colon cancer cells HCT-116 (51.09 ± 7.5%) and SW620 (48.57 ± 8.08%) at 20:1 (effector: target ratio). Moreover, these activated lymphocytes cause target cell death by reactive oxygen species and by damaging mitochondrial membrane potential of these cells. Taken together, the current findings showed D. oil as immunotherapeutic agent which can be used for colon cancer treatment.

Wernicke's Encephalopathy: Typical Disease with an Atypical Clinicoradiological Manifestation.

Wernicke's encephalopathy is an acute neurological disorder caused due to thiamine deficiency. It is characterized by a triad of confusion, ataxia, and ophthalmoplegia. Wernicke's encephalopathy can present with atypical clinical manifestations, particularly in setting of nonalcoholic background. Our patient manifested with clinical complaints of acute drowsiness, speech difficulty, and ataxia. Magnetic resonance imaging of the brain revealed T2 hyperintensity in bilateral medial thalami, globus pallidus, periaqueductal gray matter, dorsal pons, and dorsal medulla. The diagnosis of Wernicke's encephalopathy was entertained and he well responded to parental thiamine therapy. The clinician should be aware about atypical presentation of Wernicke's encephalopathy.

Anti-inflammatory and analgesic potential of OA-DHZ; a novel semisynthetic derivative of dehydrozingerone.

Despite various advances in the arena of the current system of medicine, there are numerous side effects associated with the therapeutics which essentially demand research on the development of safer therapeutics. One way is to explore the bioactive plant secondary metabolites and their semisynthetic derivatives. In context to this, we analyzed OA-DHZ, a dehydrozingerone derivative as the later has been reported to show anti-inflammatory and analgesic properties. OA-DHZ was found to be having promising anti-inflammatory and analgesic potential. OA-DHZ was found to inhibit the carrageenan-induced edema and leukocyte migration, acetic acid-induced increase in vascular permeability and lipopolysaccharide-induced pro-inflammatory cytokines like TNF-α, IL-6, and IL-1ß. Meanwhile, it was also found to potentially inhibit thermally as well as chemically induced pain signifying its analgesic/nociceptive potential. Further, safety pharmacology studies using in vivo animal models for the central nervous system, gastrointestinal tract, the cardio-respiratory system suggest that optimum functioning of vital organ systems does not get altered after single oral administration. Also, the acute toxicity study revealed its nontoxic nature up to 2000 mg/kg. This study paves the way for future exploration and development of OA-DHZ based on its potent activity and nontoxic nature.

Tumefactive Demyelination Associated with Bilateral Optic Neuritis in Neuromyelitis Optica Spectrum Disorders.

Tumefactive demyelination is an uncommon neurological disorder mimicking tumors. It is one of the rare varieties of demyelinating disorders, often causing diagnostic dilemma among neuroscientists. The literature tells us about approaching these patients added by peculiar neuroimaging findings. Neuromyelitis optica is an immune mediated inflammatory clinical disorder, typically involving optic nerves bilaterally and longitudinally extensive transverse myelitis. With the revelation of aquaporin four channels, its distribution in the brain and related antibody, the concept of neuromyelitis optica spectra disorders has been evolved. In this case report, our intention is to present a young female who presented with bilateral vision loss with tumor-like mass lesion in cerebral cortex. Such an association of bilateral optic neuropathy involving chiasmatic region, suggestive of neuromyelitis optica spectrum disorder (NMOSD) with tumefactive demyelination is rarely reported in the literature.

Evaluating the effects of consolidation on intrusion and retraction using temporary anchorage devices-a FEM study.

BACKGROUND: Extraction of premolars and retracting the anterior teeth using mini-implants and anterior retraction hooks became advent now a day. In such treatments, consolidation of arches is not done in regular practice. So, the present study is concentrated on effects of consolidation in two implant and three implant combinations of retraction and intrusion. METHODS: A three-dimensional FEM model of maxillary teeth and periodontal ligament housed in the alveolar bone with the first premolars extracted is generated with appropriate number of elements and nodes. The models were broadly divided into two groups according to the no. of implants. Mini-implants were placed bilaterally between the second premolar and molar at varying heights (7, 10, 13 mm) in group I, and along with bilateral implants, an additional mid-implant is placed between the central incisors as group II. Brackets with 0.022 slot were placed on the teeth, 19 × 25 SS wire is placed in the brackets, an anterior retraction hook was placed at 9 mm height, and analysis was done to evaluate the stresses and displacement patterns in consolidation and non-consolidation models. RESULTS: The results showed that consolidation of the anterior teeth during intrusion and retraction shows various advantages such as less stresses on the bone, PDL, implant, teeth, and no labial flaring of the anterior teeth and three implant system, i.e., two bilateral implant at 10 mm and a mid-implant at 12 mm between the centrals has shown to be better than other models as bodily movement is observed. CONCLUSION: Consolidation is better than non consolidation during enmasse retraction and intrusion.

Alkyne-azide cycloaddition analogues of dehydrozingerone as potential anti-prostate cancer inhibitors via the PI3K/Akt/NF-kB pathway.

Herein, we report the isolation and synthetic modification of dehydrozingerone (DHZ, 1), a secondary metabolite present in the rhizome of Zingiber officinale. We synthesized O-propargylated dehydrozingerone, which was subsequently coupled by alkyne-azide cycloaddition (3-20) using click chemistry. The compounds (1-20) were evaluated for their in vitro cytotoxic activity in a panel of three cancer cell lines. Among all the DHZ derivatives, 3, 6, 7, 8, 9 and 15 displayed potent cytotoxic potential with an IC50 value ranging from 1.8-3.0 µM in MCF-7, PC-3 and HCT-116 cell lines. Furthermore, compound 7 has proven to be the most potent cytotoxic compound in all the three distinct cancer cell lines and also demonstrated significant anti-invasive potential in prostate cancer. The mechanistic study of compound 7 showed that it not only suppressed the AKT/mTOR signalling which regulates nuclear transcription factor-NF-kB but also augmented the expression of anti-invasive markers E-cadherin and TIMP. Compound 7 significantly decreased the expression of pro-invasive markers vimentin, MMP-2 and MMP-9, respectively. This study underscores an efficient synthetic approach employed to evaluate the structure-activity relationship of dehydrozingerone (1) in search of potential new anticancer agents.