Ayurvedic herbal formulations Haridra Khanda and Manjisthadi Kwath (brihat) in the management of allergic rhinitis: A pharmacological study.

This study aims to pharmacologically validate Haridra Khanda (HK) and Manjishthadi Kwatham (brihat) (MMK) in allergy management using invivo and invitro studies to rationalize the prescription of these two ayurvedic polyherbal drug formulations, which are currently used in Indian government hospitals. Experimental animals received HK and MMK orally from day 0 to day 14 and histamine (1 mg/kg b.w/i.v) and 1 % evans blue (EB) (0.1 mL) via tail vein on day 14. The compound 48/80 (intracutaneous) challenged mice model followed the same technique. The former mimicked acute anaphylaxis and the latter mast cell degranulation. For both models, EB dye leakage was quantified spectrophotometrically to determine vascular permeability. Plasma histamine was measured in Compound 48/80-induced animals using LC-ESI-MS/MS. The guineapig received HK and MMK p.o. and 0.6 % histamine sprayed in a histamine chamber to simulate allergic rhinitis. Blood eosinophil count and sneeze rate were measured in histamine-challenged guineapigs. Goat R.B.C. membrane stability assay (mammalian cell membrane toxicity) and intracellular histamine-induced cytosolic Ca2+ release assay in Chinese hamster ovary (CHO) cells were performed in vitro. For both histamine and Compound 48/80 challenged animals, HK (22.81 % and 14.58 %) and MMK (19.71 % and 22.40 %) significantly reduced EB dye leakage (p < 0.05). Both formulations, HK and MMK considerably (p < 0.05) decreased plasma histamine (29.62 % and 25.37 % respectively) in mice and eosinophilic count (11.56 % and 9.94 % respectively) and sneeze rate (42.58 % and 29.03 % respectively) in guinea pigs. In membrane stability experiment, HK and MMK reduced RBC lysis. Both HK and MMK raw/dialysate blocked CHO cell cytosolic Ca2+ release. HK and MMK activities mimic mast cell stabilization with possible H1 receptor inactivation seen by decreased Ca2+ efflux and thus indicate potential for allergic rhinitis management. The combination of activities is usually related with curative and prophylactic therapy and might lead future clinical trials and therapies.

Prospective Evaluation of Fractional Carbon Dioxide Laser Treatment of Mature Burn Scars, Post-traumatic Scars, and Post-acne Scars.

BACKGROUND: Annually, around 100 million patients worldwide acquire scars, some of which can cause significant problems. Various treatment interventions, such as topical scar creams, steroids, laser therapy, and surgery, have been developed to manage these scars. This study was conducted to evaluate the effectiveness of fractional CO2 laser treatment by assessing outcomes using the Patient Observer Scar Assessment Scale (POSAS) and clinical photographs. MATERIALS AND METHODS: A total of 47 patients were included in the study, divided into three groups: a post-acne scar group with 14 patients, a post-burn scar group with 17 patients, and a post-traumatic scar group with 16 patients. Detailed histories were taken, and clinical examinations were performed and recorded on a prepared proforma. Aesthetic outcomes were evaluated based on clinical photographs, and total patient and observer scores were recorded using POSAS at baseline, and after one and three months. POSAS comprises two components: the observer scale (POSAS-O) and the patient scale (POSAS-P). Fractional CO2 laser treatments were performed in each group, with sessions repeated every four weeks for three consecutive sessions. Data were analyzed using the paired t-test for before-and-after comparisons in each study group. Welch's ANOVA test was used for comparisons among the three groups at a significance level of p=0.05, using MS Excel (Microsoft Corporation, Redmond, Washington) and IBM SPSS Statistics for Windows, Version 20 (Released 2011; IBM Corp., Armonk, New York). RESULTS: The mean age for men was 26.38 ± 8.19 years and for women 22.21 ± 6.38 years. The study comprised 34 female patients (72.34%) and 13 male patients (27.66%). The mean POSAS observer and patient scales were recorded and compared for all three types of scars from baseline to three months. The mean percentage change in POSAS-O and POSAS-P (total score) in relation to different scar sites was recorded. The most significant difference in mean percentage change, statistically significant (p-value < 0.05), was observed for facial scars, followed by scars on the neck, and was minimal for scars on the hand, in both observer and patient groups. Even a single session of fractional CO2 laser therapy had profound effects on the overall quality of scars. CONCLUSION: Fractional carbon dioxide laser therapy improves the quality of scars and produces significant improvements in skin texture, with better effects on post-traumatic scars than on post-burn and post-acne scars. Future studies are needed to better understand the mechanism of action and to optimize the doses and timing of therapy.

Significance of TRAIL/Apo-2 ligand and its death receptors in apoptosis and necroptosis signalling: Implications for cancer-targeted therapeutics.

The human immune defensesystem routinely expresses the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which is the most prevalent element for antitumor immunity. TRAIL associates with its death receptors (DRs), DR4 (TRAIL-R1), and DR5 (TRAIL-R2), in cancer cells to initiate the intracellular apoptosis cascade. Accordingly, numerous academic institutions and pharmaceutical companies havetried to exploreTRAIL's capacity to kill tumourcells by producing recombinant versions of it (rhTRAIL) or TRAIL receptor agonists (TRAs) [monoclonal antibody (mAb), synthetic and natural compounds, etc.] and molecules that sensitize TRAIL signalling pathway for therapeutic applications. Recently, several microRNAs (miRs) have been found to activate or inhibit death receptor signalling. Therefore, pharmacological regulation of these miRs may activate or resensitize the TRAIL DRs signal, and this is a novel approach for developing anticancer therapeutics. In this article, we will discuss TRAIL and its receptors and molecular pathways by which it induces various cell death events. We will unravel potential innovative applications of TRAIL-based therapeutics, and other investigated therapeutics targeting TRAIL-DRs and summarize the current preclinical pharmacological studies and clinical trials. Moreover, we will also emphasizea few situations where future efforts may be addressed to modulate the TRAIL signalling pathway.

ICON-P - A double-blind evaluation of quality improvements with individualized CONstraints from low-cost knowledge-based radiation therapy planning in prostate cancer.

Purpose: /Objective(S)A low-cost, prior knowledge-based individualized dose-constraint generator for organs-at-risk has been developed for prostate cancer radiation therapy (RT) planning. In this study, we aimed to evaluate the feasibility and improvements in organs-at-risk (OAR) doses in prostate cancer RT planning using this tool served on a web application. Materials And Methods: A set of previously treated prostate cancer cases planned and treated with generic constraints were replanned using individualized dose constraints derived from a library of cases with similar volumes of target, OAR, and overlap regions and served on the web-based application. The goal was to assess the reduction in mean dose, specified dose volumes (V59Gy, V56Gy, V53Gy, V47Gy, and V40Gy), and generalized equivalent uniform dose (gEUD) to the rectum and bladder. Planners and assessors were blinded to the initial achieved doses and penalties. Sample size estimation was based on improvement in V53Gy for the rectum and bladder with a paired evaluation. Results: Twenty-four patients were replanned. All the plans had a PTV D95 of at least 97% of the prescribed dose. The individualized OAR constraints could be met for 87.5% of patients for all dose levels. The mean dose, V59Gy, V53Gy, and V47Gy for the bladder was reduced by 7.5 Gy, 1.12%, 5.51%, and 10.53% respectively. Similarly for the rectum, the mean dose, V59Gy, V53Gy, V47Gy and was reduced by 5.5 Gy, 4.34%, 6.97%, and 11.61% respectively. All dose reductions were statistically significant. The gEUD of the bladder was reduced by 2.47 Gy (p < 0.001) and the rectum by 3.21 Gy (p < 0.001). Conclusion: Treatment planning based on individualized dose constraints served on a web application is feasible and leads to improvement at clinically important dose volumes in prostate cancer RT planning. This application can be served publicly for improvements in RT plan quality.

Therapeutic advancements in targeting BCL-2 family proteins by epigenetic regulators, natural, and synthetic agents in cancer.

Cancer is amongst the deadliest and most disruptive disorders, having a much higher death rate than other diseases worldwide. Human cancer rates continue to rise, thereby posing the most significant concerns for medical health professionals. In the last two decades, researchers have gone past several milestones in tackling cancer while gaining insight into the role of apoptosis in cancer or targeting various biomarker tools for prognosis and diagnosis. Apoptosis which is still a topic full of complexities, can be controlled considerably by B-cell lymphoma 2 (BCL-2) and its family members. Therefore, targeting proteins of this family to prevent tumorigenesis, is essential to focus on the pharmacological features of the anti-apoptotic and pro-apoptotic members, which will help to develop and manage this disorder. This review deals with the advancements of various epigenetic regulators to target BCL-2 family proteins, including the mechanism of several microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Similarly, a rise in natural and synthetic molecules' research over the last two decades has allowed us to acquire insights into understanding and managing the transcriptional alterations that have led to apoptosis and treating various neoplastic diseases. Furthermore, several inhibitors targeting anti-apoptotic proteins and inducers or activators targeting pro-apoptotic proteins in preclinical and clinical stages have been summarized. Overall, agonistic and antagonistic mechanisms of BCL-2 family proteins conciliated by epigenetic regulators, natural and synthetic agents have proven to be an excellent choice in developing cancer therapeutics.

Oroxylum indicum Stem Bark Extract Reduces Tumor Progression by Inhibiting the EGFR-PI3K-AKT Pathway in an In Vivo 4NQO-Induced Oral Cancer Model.

OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the predominant type of oral cancer. Its incidence is high in certain geographic regions, and it is correlated with chewing tobacco. Epidermal growth factor receptor (EGFR), induced by tobacco carcinogens, is overexpressed in OSCC, leading to poor prognosis. Thus, EGFR inhibitors are promising agents against OSCC. High cost and toxicity of existing EGFR inhibitors necessitate alternative EGFR-targeted therapy. Here, we tested the antitumor potential of ethyl acetate fraction of an ethnomedicinal tree, Oroxylum indicum stem bark extract (OIEA) in a 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis model. METHODS: OIEA was prepared by solvent extraction method, and subsequently its in vitro radical scavenging activities were measured. High-performance liquid chromatography (HPLC) analysis of OIEA was done to identify the constituent active compounds. Hemolytic, trypan blue exclusion, and MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] assays were performed in normal and cancer cells to select an optimum dose of OIEA for antitumor activity study in 4NQO-induced oral cancer in F344 rats. Measurement of tumor volume, weight, and cell count was followed by tumor cell cycle analysis and comet and annexin V/Propidium Iodide (PI) assay. Pro-apoptotic markers were detected by western blot testing. Molecular docking was done to predict the interaction between OIEA active component and EGFR or phosphatidylinositol-3-kinase (PI3K), which was further validated biologically. Finally, hepatic and renal function testing and histopathology were performed. RESULTS: OIEA reduced tumor burden and increased survivability of the tumor-bearing rats significantly as compared to untreated tumor bearers. HPLC revealed oroxylin A as the predominant bioactive component in OIEA. Molecular docking predicted significant binding between oroxylin A and EGFR as well as PI3K, which was confirmed by western blot analysis of in vivo samples. OIEA also ameliorated hepato-, renal- and myelotoxicity induced by 4NQO. CONCLUSION: OIEA reduces 4NQO-induced OSCC by modulating the EGFR/PI3K/AKT signaling cascade and also ameliorated toxicity in tumor bearers.

Investigating In Vitro and In Vivo Anti-Tumor Activity of Curvularia-Based Platinum Nanoparticles.

The use of platinum (Pt)-based anticancer drugs, although widespread in clinical practice, is severely limited due to toxic side-effects. One of the strategies for making Pt-based chemotherapy more effective is the synthesis and use of Pt nanoparticles (PtNPs). However, increasing evidence suggestD that nanoplatinum also pose potential risk to human health. This study examined the toxicity and anticancer activity of mycosynthesized PtNPs against sarcoma-180 (S-180) cells in vitro and in vivo. Curvularia affinis Boedijn, a phyto-pathogenic fungi isolated from rice, was used to synthesize PtNPs (named as CaPtNP). Well dispersed, mostly spherical CaPtNPs, with sizes ranging from 3-9 nm were characterized by Transmission electron microscopy (TEM), field emission scanning electron microscopy, X-ray diffraction, atomic force microscopy, and Fourier transform infrared spectrometry. Two concentrations of the CaPtNPs (2.31 and 4.63 ng/mL) were selected based on in vitro cytotoxicity assay on erythrocytes and peripheral blood mononuclear cells. The selected doses were found to induce significant in vitro and in vivo anti-proliferative and pro-apoptotic activity in S-180 cells. Elevated levels of pro-apoptotic markers (p53, Bax/Bcl2 ratio, Cyt c, caspase-3, cleaved PARP) and reduced BrdU incorporation validated the anticancer activity of CaPtNPs. The antitumor activity was further confirmed in S-180 transplanted tumor bearing mice. Moreover, examination of the impact of sub-chronic exposure (three months) of CaPtNPs on the ultra-structural features of renal and hepatic tissue by TEM revealed no significant toxicological manifestation in these organs. The CaPtNPs were also found to reduce oxidative stress and improve liver function in tumor bearing mice compared with untreated controls. Thus, this green CaPtNPs was well tolerated in mice and displayed significant antitumor property.

Eucalyptol targets PI3K/Akt/mTOR pathway to inhibit skin cancer metastasis.

Eucalyptol (EU) is a monoterpenoid found as an active compound of many plants such as bay leaves, cardamom and is also found as a major constituent in eucalyptus oil. Although the anticancer activity of eucalyptol (EU) has been reported in a few cancer cell lines, its effect on tumor metastasis has not been studied so far. Here, we have shown that the EU has anti-metastatic activity against skin cancer cells in vitro and in vivo. EU decreases migration and invasion of skin cancer cells. Further, it reduces the expression of mesenchymal markers vimentin, snail, slug, twist, and induces the expression of epithelial marker, E-cadherin which indicates that it reverses the epithelial to mesenchymal transition. Gelatin zymography shows that the EU reduces the activity of MMP2 and MMP9. Furthermore signaling study by molecular docking and western blotting shows that EU modulates PI3K/Akt/mTOR signaling pathway. The reduction in the expression of PI3K/Akt/mTOR was enhanced by the use of the PI3K inhibitor, LY294002. In vivo, the anti-metastatic potential of EU was confirmed in C57BL/6 mouse. In conclusion, the EU inhibits migration and invasion of skin cancer by modulating PI3K/Akt/mTOR pathway both in in vitro and in vivo and might provide a new therapeutic approach in skin cancer.

Evaluation of Mollugo oppositifolia Linn. as cholinesterase and ß-secretase enzymes inhibitor.

Mollugo oppositifolia Linn. is traditionally used in neurological complications. The study aimed to investigate in-vitro neuroprotective effect of the plant extracts through testing against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-secretase linked to Alzheimer's disease (AD). To understand the safety aspects, the extracts were tested for CYP450 isozymes and human hepatocellular carcinoma cell (HepG2) inhibitory potential. The heavy metal contents were estimated using atomic absorption spectroscopy (AAS). Further, the antioxidant capacities as well as total phenolic content and total flavonoid content (TFC) were measured spectrophotometrically. UPLC-QTOF-MS/MS analysis was employed to identify phytometabolites present in the extract. The interactions of the ligands with the target proteins (AChE, BChE, and BACE-1) were studied using AutoDockTools 1.5.6. The results showed that M. oppositifolia extract has more selectivity towards BChE (IC50 = 278.23 ± 1.89 µg/ml) as compared to AChE (IC50 = 322.87 ± 2.05 µg/ml). The IC50 value against ß-secretase was 173.93 µg/ml. The extract showed a CC50 value of 965.45 ± 3.07 µg/ml against HepG2 cells and the AAS analysis showed traces of lead 0.02 ± 0.001 which was found to be within the WHO prescribed limits. Moreover, the IC50 values against CYP3A4 (477.03 ± 2.01 µg/ml) and CYP2D6 (249.65 ± 2.46 µg/ml) isozymes justify the safety aspects of the extract. The in silico molecular docking analysis of the target enzymes showed that the compound menthoside was found to be the most stable and showed a good docking score among all the identified metabolites. Keeping in mind the multi-targeted drug approach, the present findings suggested that M. oppositifolia extract have anti-Alzheimer's potential.

Synthetic and computational efforts towards the development of peptidomimetics and small-molecule SARS-CoV 3CLpro inhibitors.

Severe Acute Respiratory Syndrome (SARS) is a severe febrile respiratory disease caused by the beta genus of human coronavirus, known as SARS-CoV. Last year, 2019-n-CoV (COVID-19) was a global threat for everyone caused by the outbreak of SARS-CoV-2. 3CLpro, chymotrypsin-like protease, is a major cysteine protease that substantially contributes throughout the viral life cycle of SARS-CoV and SARS-CoV-2. It is a prospective target for the development of SARS-CoV inhibitors by applying a repurposing strategy. This review focuses on a detailed overview of the chemical synthesis and computational chemistry perspectives of peptidomimetic inhibitors (PIs) and small-molecule inhibitors (SMIs) targeting viral proteinase discovered from 2004 to 2020. The PIs and SMIs are one of the primary therapeutic inventions for SARS-CoV. The journey of different analogues towards the evolution of SARS-CoV 3CLpro inhibitors and complete synthetic preparation of nineteen derivatives of PIs and ten derivatives of SMIs and their computational chemistry perspectives were reviewed. From each class of derivatives, we have identified and highlighted the most compelling PIs and SMIs for SARS-CoV 3CLpro. The protein-ligand interaction of 29 inhibitors were also studied that involved with the 3CLpro inhibition, and the frequent amino acid residues of the protease were also analyzed that are responsible for the interactions with the inhibitors. This work will provide an initiative to encourage further research for the development of effective and drug-like 3CLpro inhibitors against coronaviruses in the near future.

Understanding stem cells and its pivotal role in regenerative medicine.

Stem cells (SCs) are clonogenic cells that develop into the specialized cells which later responsible for making up various types of tissue in the human body. SCs are not only the appropriate source of information for cell division, molecular and cellular processes, and tissue homeostasis but also one of the major putative biological aids to diagnose and cure various degenerative diseases. This study emphasises on various research outputs that occurred in the past two decades. This will give brief information on classification, differentiation, detection, and various isolation techniques of SCs. Here, the various signalling pathways which includes WNT, Sonic hedgehog, Notch, BMI1 and C-met pathways and how does it effect on the regeneration of various classes of SCs and factors that regulates the potency of the SCs are also been discussed. We also focused on the application of SCs in the area of regenerative medicine along with the cellular markers that are useful as salient diagnostic or curative tools or in both, by the process of reprogramming, which includes diabetes, cancer, cardiovascular disorders and neurological disorders. The biomarkers that are mentioned in various literatures and experiments include PDX1, FOXA2, HNF6, and NKX6-1 (for diabetes); CD33, CD24, CD133 (for cancer); c-Kit, SCA-1, Wilm's tumor 1 (for cardiovascular disorders); and OCT4, SOX2, c-MYC, EN1, DAT and VMAT2 (for neurological disorders). In this review, we come to know the advancements and scopes of potential SC-based therapies, its diverse applications in clinical fields that can be helpful in the near future.

Rapid determination of erythrocyte sedimentation rate (ESR) by an electrically driven blood droplet biosensor.

In healthcare practice, the sedimentation rate of red blood cells (erythrocytes) is a widely used clinical parameter for screening of several ailments such as stroke, infectious diseases, and malignancy. In a traditional pathological setting, the total time taken for evaluating this parameter varies typically from 1 to 2 h. Furthermore, the volume of human blood to be drawn for each test, following a gold standard laboratory technique (alternatively known as the Westergren method), varies from 4 to 5 ml. Circumventing the above constraints, here we propose a rapid (∼1 min) and highly energy efficient method for the simultaneous determination of hematocrit and erythrocyte sedimentation rate (ESR) on a microfluidic chip, deploying electrically driven spreading of a tiny drop of blood sample (∼8 µl). Our unique approach estimates these parameters by correlating the same with the time taken by the droplet to spread over a given radius, reproducing the results from more elaborate laboratory settings to a satisfactory extent. Our novel methodology is equally applicable for determining higher ranges of ESR such as high concentration of bilirubin and samples corresponding to patients with anemia and patients with some severe inflammation. Furthermore, the minimal fabrication steps involved in the process, along with the rapidity and inexpensiveness of the test, render the suitability of the strategy in extreme point-of-care settings.

Eugenol and capsaicin exhibit anti-metastatic activity via modulating TGF-ß signaling in gastric carcinoma.

The transforming growth factor-ß (TGF-ß) signaling is considered to be a key player in gastric cancer metastasis, and the inhibition of the TGF-ß/SMAD4 signaling pathway may be a novel strategy for therapeutic interventions in cancer. Here, the anti-metastatic activity of two phytochemicals, eugenol and capsaicin, has been studied, and their potential to antagonize TGF-ß has been investigated in gastric cancer cells. Both the phytochemicals exhibited anti-metastatic activity by inhibiting the TGF-ß signaling pathway independent of P21 or P53, with capsaicin proving to be more potent than eugenol. However, unlike eugenol, the inhibitory effect of capsaicin on the TGF-ß signaling pathway and metastasis was found to be dependent on SMAD4, which was validated in SMAD4-knocked down AGS cell and SMAD4-null SW620 cell line. Furthermore, the use of recombinant TGF-ß and TGF-ß receptor inhibitor LY2109761 confirmed that the anti-metastatic activity of eugenol is partially and that of capsaicin is principally mediated through the TGF-ß signaling pathway. Identifying phytochemicals with the potential to inhibit cancer metastasis by targeting the TGF-ß signaling pathway has immense scope for developing a therapeutic strategy against cancer metastasis.

TGFß mediated LINC00273 upregulation sponges mir200a-3p and promotes invasion and metastasis by activating ZEB1.

Transforming growth factor ß (TGFß) is a prominent cytokine that promotes tumor progression by activating epithelial-to-mesenchymal transition (EMT). This study indicated that TGFß exerted metastasis by inducing zinc finger E-box binding homeobox 1 (ZEB1) and a long noncoding RNA, LINC00273, expressions in A549 cells. Knocking down LINC00273 diminished TGFß induced ZEB1 expression as well as metastasis. Mechanistically, LINC00273 acted as a molecular sponge of microRNA (miR)-200a-3p which liberate ZEB1 to perform its prometastatic functions. LINC00273 knockdown and miR200a3p mimic transfection of A549 cells were used for validating the link between TGFß and LINC00273 induced metastasis. RNA pulldown and luciferase assay were performed to establish mir200a-3p-LINC00273 interaction. High expressions of LINC00273, TGFß, and ZEB1 with concurrent low miR200a-3p expression had been verified in vivo and in patient samples. Overall, LINC00273 promoted TGFß-induced lung cancer EMT through miR-200a-3p/ZEB1 feedback loop and may serve as a potential target for therapeutic intervention in lung cancer metastasis.

A Lysosome-Targetable Fluorescence Sensor for Ultrasensitive Detection of Hg2+ in Living Cells and Real Samples.

A new lysosome-targetable fluorescence sensor, Lyso-HGP, was designed and synthesized based on 4-methyl-2,6-diformylphenol as a fluorophore. Lyso-HGP displays highly sensitive fluorescent detection of Hg2+ in HEPES buffer solution (10 mM, DMSO 1%) of pH 7.0 at 37 °C due to the formation of highly fluorescent formyl-functionalized derivative Lyso-HGP-CHO. The sensor triggered a "turn-on" fluorescence response to Hg2+ with a simultaneous increase of fluorescence intensity by 180-fold just after 10 min. The response is very selective over a variety of biologically relevant cations, anions, molecules, and competitive toxic heavy metal cations. The limit of detection (LOD) was calculated as low as 6.82 nM. So, it can be utilized to detect this toxic heavy metal in biology and environmental samples in an aqueous buffer medium. Also, the sensor is able to monitor the subcellular distribution of Hg2+ specifically localized in the lysosome's compartment in the MCF7 human breast cancer cell line by fluorescence microscopy.

The inhibition of hypoxia-induced angiogenesis and metastasis by cinnamaldehyde is mediated by decreasing HIF-1α protein synthesis via PI3K/Akt pathway.

Tumor hypoxia is positively correlated with tumor aggressiveness and hence is a negative prognostic factor in cancer. As normal cells usually do not experience such low oxygen levels, hypoxic cell signaling has attracted significant attention for the development of tumor-selective treatment strategies. In response to hypoxia, the master transcriptional regulator, HIF-1α plays central role in cellular adaptation by transactivating several crucial downstream target genes, which are involved in angiogenesis, metastasis, and EMT. In this study, we investigated the effect of cinnamaldehyde (CA), the main active ingredient of Cinnamon cassia bark extract, on hypoxia-induced angiogenesis and metastasis. The study in vitro comprised two cell lines, viz, sarcoma 180 and B16F10 melanoma, which were further confirmed in their respective transplantable in vivo models. Results show that CA administration inhibited tumor angiogenesis, EMT, and metastasis. At the molecular level, this was accompanied by a reduction in VEGF secretion, VEGF receptor (FLK) phosphorylation, matrix metalloproteinase (MMP) expression, and activity as well as a reduction in the EMT-related factors TWIST and ZEB1. Next, we focused our study particularly on the modulation of HIF-1 α by CA, which revealed that CA decreased HIF-1 α protein level by inhibiting its synthesis without affecting its proteasomal degradation. Furthermore, the PI3/Akt/mTOR pathway, which plays an important role in HIF-1α transcription and translation, was also inhibited by CA both in vitro and in vivo. Thus, it can be concluded that CA decreased angiogenesis and metastasis in tumor cells by inhibiting HIF-1α protein accumulation probably by targeting the PI3/Akt/mTOR pathway. © 2019 BioFactors, 45(3):401-415, 2019.

Example of two novel thiocyanato bridged copper (II) complexes derived from substituted thiosemicarbazone ligand: structural elucidation, DNA/albumin binding, biological profile analysis, and molecular docking study.

Two novel copper (II) substituted thiosemicarbazone Schiff base complexes [Cu(L1)(µ-SCN)]n(NO3)2 (1) and [Cu2(µ-SCN)(SCN)(L2)2](NO3) (2) have been synthesized by condensing substituted thiosemicarbazides like 4-methyl-3-thiosemicarbazide or 4-ethyl-3-thiosemicarbazide with 2-acetylpyridine. Both the metal complexes 1 and 2 are characterized using different spectroscopic techniques like IR, UV-Vis, ESR spectroscopy followed by elemental analysis, cyclic voltammetric measurement and single crystal X-ray structure analysis. X-ray crystal structure analysis reveal that complex 1 is polymeric while complex 2 is dimeric in nature. The coordination geometry around Cu(II) are square pyramidal in which thiosemicarbazone Schiff base ligand coordinate to the central Cu(II) atom in tridentate fashion. The prominent interaction patterns of 1 and 2 with CT-DNA were examined by employing electronic absorption and emission spectral titrations, cyclic voltammetry and viscosity measurements. All the results show that CT-DNA binds with both copper (II) complexes 1 and 2. Furthermore, protein binding ability in vitro of complexes 1 and 2 with both BSA and HSA were carried out using multispectroscopic techniques and a static quenching pattern was observed in both cases. Molecular docking study was employed to ascertain the exact mechanism of action of 1 and 2 with DNA and protein molecules (BSA and HSA). In vitro cytotoxicity activity of complexes 1 and 2 toward AGS and A549 was evaluated using MTT assay which demonstrates that both complexes 1 and 2 have superior prospectus to act as anticancer agents. Communicated by Ramaswamy H. Sarma.

Evaluating the antimicrobial, apoptotic, and cancer cell gene delivery properties of protein-capped gold nanoparticles synthesized from the edible mycorrhizal fungus Tricholoma crassum.

Biosynthesis of gold nanoparticles of distinct geometric shapes with highly functional protein coats without additional capping steps is rarely reported. This study describes green synthesis of protein-coated gold nanoparticles for the first time from the edible, mycorrhizal fungus Tricholoma crassum (Berk.) Sacc. The nanoparticles were of the size range 5-25 nm and of different shapes. Spectroscopic analysis showed red shift of the absorption maxima with longer reaction period during production and blue shift with increase in pH. These were characterized with spectroscopy, SEM, TEM, AFM, XRD, and DLS. The particle size could be altered by changing synthesis parameters. These had potent antimicrobial activity against bacteria, fungi, and multi-drug-resistant pathogenic bacteria. These also had inhibitory effect on the growth kinetics of bacteria and germination of fungal spores. These showed apoptotic properties on eukaryotic cells when tested with comet assays. Moreover, the particles are capped with a natural 40 kDa protein which was utilized as attachment sites for genes to be delivered into sarcoma cancer cells. The present work also attempted at optimizing safe dosage of these nanoparticles using hemolysis assays, for application in therapy. Large-scale production of the nanoparticles in fermentors and other possible applications of the particles have been discussed.

Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study.

AIMS: The TITRATION trial investigated two strategies to initiate and up-titrate sacubitril/valsartan (LCZ696) to the same target dose, over a condensed (3-week) or conservative (6-week) period, in patients with heart failure with reduced ejection fraction (HFrEF) and systolic blood pressure (SBP) of ≥100 mmHg. This post hoc analysis examined the relationship between baseline SBP at screening and achievement of the target dose of sacubitril/valsartan of 97 mg/103 mg (also termed 'LCZ696 200 mg') twice per day during the study. METHODS AND RESULTS: Patients (n = 498) were categorized in four groups based on SBP at screening: 100-110 mmHg (n = 70); 111-120 mmHg (n = 93); 121-139 mmHg (n = 168) and ≥140 mmHg (n = 167). Overall, 72.7%, 76.1%, 85.6% and 82.9%, respectively, of patients in these SBP categories achieved and maintained the target dose of sacubitril/valsartan without down-titration/dose interruption over 12 weeks ('treatment success'). Compared with patients with SBP of 100-110 mmHg, rates of treatment success among patients in the higher SBP groups [111-120 mmHg (P = 0.96); 121-139 mmHg (P = 0.06) and ≥140 mmHg (P = 0.25)] did not differ significantly. A higher percentage of patients with lower SBP (100-110 mmHg) achieved treatment success with gradual up-titration (6 weeks) (∼80%) than with rapid up-titration (∼69%). Similar findings were observed with regard to 'tolerability success' (maintenance of the target dose for at least the final 2 weeks prior to study completion). Hypotension occurred more frequently in patients with lower SBP. CONCLUSIONS: The majority of patients (>80%) with SBP of ≥100 mmHg achieved and maintained the target dose of sacubitril/valsartan if the treatment was titrated gradually. These findings suggest that low SBP should not prevent clinicians from considering the initiation of sacubitril/valsartan.

LINCRNA00273 promotes cancer metastasis and its G-Quadruplex promoter can serve as a novel target to inhibit cancer invasiveness.

Discovery of anti-metastatic drugs is of immense clinical significance as metastasis is responsible for 90% of all cancer deaths. Here we report the inhibitory effect of a bis schiff base (M2) on cancer cell migration and invasion in vitro and in vivo. M2 has shown good solubility and permeability across the intestinal cell wall and hence can be classified as BCS (Biopharmaceutical classification system) class I. Microarray studies identified a long non coding intergenic RNA, LINC00273 as a novel molecular target of M2. We report that LINC00273 harbors a unique (4n-1) parallel G-Quadruplex structure in its promoter as validated by DMS footprint. M2 is proposed to stabilize this G-quadruplex structure resulting in the down-regulation of LINC00273 expression. Dual Luciferase reporter assay also suggests inhibition of LINC00273 promoter activity by M2. Involvement of this linc in metastasis is proven by siRNA and shRNA mediated knock down of LINC00273 in vitro and in vivo in nude mice which significantly decelerates cancer cell migration and invasion and also makes the cells unresponsive to TGF-ß's pro-metastatic effects. Furthermore, the real time expression of LINC00273 in thirty seven human clinical samples is found to be positively correlated with the histopathological staging of metastasis.