A quinoline derived Schiff base as highly selective 'turn-on' probe for fluorogenic recognition of Al3+ ion.

A quinoline-derived Schiff base QnSb has been synthesized for fluorescent and colorimetric recognition of Al3+ ions in a semi-aqueous medium. The compound QnSb has been characterized by elemental analysis, FT-IR, 1H/13C NMR, UV-Vis and fluorescence spectral techniques. The crystal structure of the QnSb was confirmed by single crystal X-ray diffraction (SC-XRD) analysis. Notably, almost non-fluorescent QnSb served as a 'turn on' responsive probe for Al3+ by inducing a remarkable fluorescence enhancement at 422 nm when excited at 310 nm. The probe QnSb exhibited high selectivity for Al3+ in CH3CN/H2O (4:1, v/v) solution over several competing metal ions (e.g., Mg2+, Pb2+, Zn2+, Cd2+, Co2+, Cu2+, Ca2+, Ni2+, Fe3+/2+, Cr3+, Mn2+, Sn2+, and Hg2+). The limit of detection (LoD) was computed as low as 15.8 nM which is significantly lower than the permissible limit set by WHO for Al3+ ions in drinking water. A 1:1 binding stoichiometry of complex QnSb-Al3+ was established with the help of Job's plot, ESI-MS, NMR and DFT analyses. Based on its remarkable sensing ability, the probe QnSb was utilized to establish molecular logic gates, and the fluorescence detection of Al3+ could clearly be demonstrated on the filter paper test strips.

Targeting neuroblastoma by small-molecule inhibitors of human ALYREF protein: mechanistic insights using molecular dynamics simulations.

Neuroblastoma is a tumour of the sympathetic nervous system mainly prevalent in children. Many strategies have been employed to target several drug-targetable proteins for the clinical management of neuroblastoma. However, the heterogeneous nature of neuroblastoma presents serious challenges in drug development for its treatment. Albeit numerous medications have been developed to target various signalling pathways in neuroblastoma, the redundant nature of the tumour pathways makes its suppression unsuccessful. Recently, the quest for neuroblastoma therapy resulted in the identification of human ALYREF, a nuclear protein that plays an essential role in tumour growth and progression. Therefore, this study used the structure-based drug discovery method to identify the putative inhibitors targeting ALYREF for the Neuroblastoma treatment. Herein, a library of 119 blood-brain barrier crossing small molecules from the ChEMBL database was downloaded and docked against the predicted binding pocket of the human ALYREF protein. Based on docking scores, the top four compounds were considered for intermolecular interactions and molecular dynamics simulation analysis, which revealed CHEMBL3752986 and CHEMBL3753744 with substantial affinity and stability with the ALYREF. These results were further supported by binding free energies and essential dynamics analysis of the respective complexes. Hence, this study advocates the sorted compounds targeting ALYREF for further in vitro and in vivo assessment to develop a drug against neuroblastoma.Communicated by Ramaswamy H. Sarma.

Turn-on detection of Al3+ and Zn2+ ions by a NSN donor probe: reversibility, logic gates and DFT calculations.

An efficient dual functional naphthalene-derived Schiff base NpSb probe has been synthesised and evaluated for its fluorescence and chromogenic response towards metal ions. The NpSb probe was capable of selectively recognising Al3+ and Zn2+ ions when they were excited at the same wavelength in an aqueous organic solvent system. Almost non-fluorescent NpSb displayed a 'turn-on' fluorescence response when treated with Zn2+ (λem = 416 nm) and Al3+ (λem = 469 nm) ions due to the chelation-enhanced fluorescence (CHEF) effect. The limit of detection (LoD) values for Al3+ and Zn2+ have been determined to be 38.0 nM and 43.0 nM, respectively. The binding constants for Al3+ and Zn2+ were found to be 1.18 × 106 M-1 and 3.5 × 105 M-1, respectively. The NpSb also acted as a colorimetric sensor for Al3+ as the colour of the probe's solution turned to pale green from colourless upon Al3+ addition. The binding mechanism between NpSb and Zn2+/Al3+ was supported by the ESI-MS, Job's plot, NMR, and DFT studies. The reversibility experiments were carried out with an F- ion and EDTA with the development of corresponding logic gates. Moreover, NpSb could be applied to detect Al3+ ions in real samples such as tap water, distilled water and soil samples.

In vivo antiangiogenic effect of nimbolide, trans-chalcone and piperine for use against glioblastoma.

BACKGROUND: Angiogenesis is an important hallmark of Glioblastoma (GBM) marked by elevated vascular endothelial growth factor-A (VEGF-A) and its receptor 2 (VEGFR-2). As previously reported nimbolide (NBL), trans-chalcone (TC) and piperine (PPR) possess promising antiangiogenic activity in several cancers however, their comparative efficacy and mechanism of antiangiogenic activity in GBM against VEGFR-2 has not been elucidated. METHODS: 2D and 3D spheroids cultures of U87 (Uppsala 87 Malignant Glioma) were used for evaluation of non-cytotxoic dose for anti-angiogenic activity. The antiangiogenic effect was investigated by the GBM U87 cell line bearing chick CAM model. Excised U87 xenografts were histologically examined for blood vascular density by histochemistry. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the presence of avian and human VEGF-A and VEGFR-2 mRNA transcripts. RESULTS: Using 2D and 3D spheroid models, the non-cytotoxic dose of NBL, TC and PPR was ≤ 11 µM. We found NBL, TC and PPR inhibit U87-induced neoangiogenesis in a dose-dependent manner in the CAM stand-alone model as well as in CAM U87 xenograft model. The results also indicate that these natural compounds inhibit the expression of notable angiogenic factors, VEGF-A and VEGFR-2. A positive correlation was found between blood vascular density and VEGF-A as well as VEGFR-2 transcripts. CONCLUSION: Taken together, NBL, TC and PPR can suppress U87-induced neoangiogenesis via a reduction in VEGF-A and its receptor VEGFR-2 transcript expression at noncytotoxic concentrations. These phytochemicals showed their utility as adjuvants to GBM therapy, with Piperine demonstrating superior effectiveness among them all.

Fluorescent and chromogenic organic probes to detect group 10 metal ions: design strategies and sensing applications.

Group 10 metals including Ni, Pd and Pt have been extensively applied in various essential aspects of human social life, material science, industrial manufactures, medicines and biology. The ionic forms of these metals are involved in several biologically important processes due to their strong binding capability towards different biomolecules. However, the mishandling or overuse of such metals has been linked to serious contamination of our ecological system, more specifically in soil and water bodies with acute consequences. Therefore, the detection of group 10 metal ions in biological as well as environmental samples is of huge significance from the human health point of view. Related to this, considerable efforts are underway to develop adequately efficient and facile methods to achieve their selective detection. Optical sensing of metal ions has gained increasing attention of researchers, particularly in the environmental and biological settings. Innovatively designed optical probes (fluorescent or colorimetric) are usually comprised of three basic components: an explicitly tailored receptor unit, a signalling unit and a clearly defined reporter unit. This review deals with the recent progress in the design and fabrication of fluorescent or colorimetric organic sensors for the detection of group 10 metal ions (Ni(II), Pd(II) and Pt(II)), with attention to the general aspects for design of such sensors.

Prospective Use of Probiotics to Maintain Astronaut Health during Spaceflight.

Maintaining an astronaut's health during space travel is crucial. Multiple studies have observed various changes in the gut microbiome and physiological health. Astronauts on board the International Space Station (ISS) had changes in the microbial communities in their gut, nose, and skin. Additionally, immune system cell alterations have been observed in astronauts with changes in neutrophils, monocytes, and T-cells. Probiotics help tackle these health issues caused during spaceflight by inhibiting pathogen adherence, enhancing epithelial barrier function by reducing permeability, and producing an anti-inflammatory effect. When exposed to microgravity, probiotics demonstrated a shorter lag phase, faster growth, improved acid tolerance, and bile resistance. A freeze-dried Lactobacillus casei strain Shirota capsule was tested for its stability on ISS for a month and has been shown to enhance innate immunity and balance intestinal microbiota. The usage of freeze-dried spores of B. subtilis proves to be advantageous to long-term spaceflight because it qualifies for all the aspects tested for commercial probiotics under simulated conditions. These results demonstrate a need to further study the effect of probiotics in simulated microgravity and spaceflight conditions and to apply them to overcome the effects caused by gut microbiome dysbiosis and issues that might occur during spaceflight.

Intranasal (2R, 6R)-hydroxynorketamine for acute pain: Behavioural and neurophysiological safety analysis in mice.

Ketamine is known for its antinociceptive effect and is also used for treatment-resistant depression. However, the efficacy and safety of (2R, 6R)-hydroxynorketamine (HNK), a ketamine metabolite has been sparingly investigated for acute pain management. The current study aims at investigating the antinociceptive effect of intranasal (2R, 6R)-HNK using pre-clinical models of acute pain. Additionally, the behavioural and neurophysiological safety analyses were carried out for the effective time window. Antinociceptive efficacy of (2R, 6R)-HNK was evaluated using the hot plate test and Hargreaves' plantar test. The formalin test was carried out in both the acute and tonic phases. The neurophysiological and behavioural safety analyses were carried out separately for the haemodynamic function, cortical electroencephalography (EEG), and spontaneous behavioural functions. Analgesic effect of (2R, 6R)-HNK was evident by a significant increase in paw-withdrawal latency in both Hargreaves' and hot plate tests. Additionally, the (2R, 6R)-HNK showed a significant ameliorative effect on pain-related behaviour in the second phase of the formalin test. (2R, 6R)-HNK exhibited an anxiolytic effect without causing any significant changes in locomotor activity and haemodynamic parameters. Power spectral density (PSD) analysis of electroencephalogram revealed no significant changes except a comparative increase in the gamma band range. Both the locomotor functions in the open field test and the PSD value of delta wave indicated no sedative effect at the given dose of (2R, 6R)-HNK. The results demonstrated the pain-alleviating effect of (2R, 6R)-HNK without compromising the neurophysiological and behavioural function. Therefore, intranasal (2R, 6R)-HNK is suggested as a safe candidate for further clinical study in the management of acute pain.

Serum biomarkers based neurotrauma severity scale: a study in the mice model of fluid percussion injury.

The study aimed to investigate the significance of serum biomarkers in the severity grading of traumatic brain injury (TBI). For this purpose, mice underwent fluid percussion injury (FPI) at three discrete severity levels, mild, moderate, and severe. The severity of trauma was verified by the qualitative and quantitative histopathology of the brain. The serum samples were analyzed for the potential changes in ubiquitin C­terminal hydrolase­1 (UCHL­1), S100ß, interleukin­6 (IL­6), corticosterone, and ß­endorphin at 24 and 72 h post injury. A multifold increase in the values of UCHL­1 was reported at all severity extents of FPI. However, TBI severity­dependent increase in UCHL­1 was reported on 72 h following FPI but not at 24 h. S100ß values were significantly augmented in the mild and moderate group at both the time point but not in the severe group. Serum level of IL­6 was significantly increased in the mild injury group at 24 h but not in the moderate and severe. At 72 h, IL­6 showed a reverse trend. ß­endorphin and corticosterone were sensitive at an early stage only. Such unique dynamics of each biomarker enable us to propose TBI severity scale in the term of biomarkers codes to predict the extent of neurotrauma. Our preclinical study presents a predictive model for further clinical validation.

In vitro & in vivo evaluations of PLGA nanoparticle based combinatorial drug therapy for baclofen and lamotrigine for neuropathic pain management.

AIM: Baclofen and Lamotrigine via PLGA nanoparticles were developed for nose-to-brain delivery for the treatment of Neuropathic pain. METHODS: Nanoparticles were prepared using the modified nano-precipitation method. The prepared NPs were characterised and further in vitro and in vivo studies were performed. RESULTS: The Bcf-Ltg-PLGA-NPs were ∼177.7 nm with >75%(w/w) drugs encapsulated. In vitro dissolution studies suggested zero-order release profiles following the Korsmeyer-Peppas model. In vitro cytotoxicity and staining studies on mammalian cells showed dose dependant cytotoxicity where nanoparticles were significantly less toxic (>95% cell-viability). ELISA studies on RAW-macrophages showed Bcf-Ltg-PLGA-NPs as a potential pro-inflammatory-cytokines inhibitor. In vivo gamma-scintigraphy studies on rats showed intra-nasal administration of 99mTc-Bcf-Ltg-PLGA-NPs showed Cmax 3.6%/g at Tmax = 1.5h with DTE% as 191.23% and DTP% = 38.61% in brain. Pharmacodynamics evaluations on C57BL/6J mice showed a significant reduction in licks/bites during inflammation-induced phase II pain. CONCLUSION: The findings concluded that the combination of these drugs into a single nanoparticle-based formulation has potential for pain management.

Baclofen and Lamotrigine loaded PLGA nanoparticles were prepared with a size of 177.7nm, PDI 0.057 and Zeta Potential −15.8 mVIn vitro cell lines based studies showed dose dependant cytotoxicity and Bcf-Ltg-PLGA-NPs were found to be pro-inflammatory cytokines inhibitorsIn vivo Pharmacokinetic studies showed C_max 3.6%/g at T_max = 1.5 h with Drug Targeting Efficiency 191.23% and Drug Target Organ Transport 38.61% in the brain for prepared nanoparticlesIn vivo pharmacodynamics studies showed a significant reduction in licks/bites during inflammation-induced phase II pain.

Intranasal Ketamine for Acute Pain: Behavioral and Neurophysiological Safety Analysis in Mice.

BACKGROUND: Subanesthetic ketamine has been used for treatment-resistant depression and is popular as an opioid-sparing agent. OBJECTIVE: The present study aimed to investigate the dose-dependent antinociceptive effect of intranasal ketamine (INK) along with behavioral and neurophysiological safety in mice. METHODS: Antinociceptive efficacy was evaluated in the terms of thermal nociceptive response and formalin test. The safety studies were carried out separately in healthy mice using telemetry-based cortical electroencephalography, hemodynamic changes, and spontaneous behavioral functions, including anxiety, stereotypic movement, and locomotor functions. RESULTS: INK administration significantly augmented the thermal nociceptive threshold and alleviated the pain response in the tonic phase of the formalin test. The results showed the dose-independent effectiveness of ketamine for thermal nociceptive responses because there were no significant differences among different INK dose groups. Behavioral safety analysis using the open field exploratory test revealed no significant effect of INK on anxiety-like functions in healthy mice. However, INK mice showed significantly more stereotypic movement but slower locomotor activities. The electroencephalography signal power spectrum density analysis revealed no significant changes by INK administration except a lower value in the α range. No significant changes were reported in heart rate, diastolic blood pressure, or systolic blood pressure at the higher dose equivalent used in the pain model. CONCLUSIONS: The study demonstrated the behavioral and neurophysiological safety of INK, although it had a mild sedative effect. Therefore, INK is suggested as a potentially safe candidate for the management of acute pain. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX)© 2021 Elsevier HS Journals, Inc.

A rare case of acute abdomen: spontaneous rupture of degenerated fibroid.

A 29-year-old nulliparous woman presented with an acute abdomen. She had a large uterus with multiple fibroids and was on the waiting list for elective surgery. An urgent CT scan demonstrated an extensive intraperitoneal fluid collection suspicious for fibroid rupture. She required an emergency laparotomy which identified a rupture of the largest degenerative fibroid. There was 2 Litres of pus in the peritoneal cavity. This case was a rare presentation of spontaneous fibroid rupture due to degeneration and necrosis, and acute abdomen from peritoneal irritation. Imaging was vital in making the diagnosis, and urgent surgical intervention was essential to reduce morbidity and mortality.

Clinical relevance of chronic neuropathic pain phenotypes in mice: A comprehensive behavioral analysis.

Despite a large number of preclinical studies performed each year, the safe and effective therapeutic interventions for chronic pain are scant. Therefore, it appears that pre-clinical modeling requires a systematically organized behavioral test paradigm to quantify the response of animals for a specific pain state. The present study, therefore, conceptualized a test battery to evaluate the behavioral changes in mice following neuropathic pain. We employed sciatic nerve chronic constriction injury (CCI) in C57BL/6 J mice to model chronic pain state. Mice were monitored for thermal hyperalgesia and grip strength for 30 days. Subsequently, mice underwent a behavioral test battery consisting of the nociceptive threshold, the affective and cognitive functions and motor coordination, and strength. Our results showed that CCI mice are insensitive to thermal stimuli. However, nerve-injured mice showed significant changes in neuromuscular coordination, basal anxiety, and hedonic state. Such impaired neuromuscular coordination is indicative of disability rather than the actual pain phenotype. While using the digital gait analysis, our study revealed rationales for the insensitivity of CCI mice to thermal stimuli. Our results suggest that the predictive validity of the CCI model necessitates a comprehensive behavioral test battery to select the clinically relevant and measurable phenotype to quantify chronic neuropathic pain.

Low-pressure fluid percussion minimally adds to the sham craniectomy-induced neurobehavioral changes: Implication for experimental traumatic brain injury model.

Modeling experimental traumatic brain injury (TBI) in rodents is necessarily required to understand the pathophysiological and neurobehavioral consequences of neurotrauma. Numerous models have been developed to study experimental TBI. Fluid percussion injury (FPI) is the most extensively used model to represent clinical phenotypes. Nevertheless, the surgical 'sham' procedure (craniectomy), a prerequisite of FPI, is the impeding factor in experimental TBI. We hypothesized that if craniectomy causes substantial structural and functional changes in the brain, it might mimic the mild FPI-induced neurobehavioral dysfunctions. To understand the hypothesis, C57BL/6 mice were exposed to lateral FPI at 1.2 atm pressure and changes in the neuronal architecture, hippocampal neurogenesis, neuroinflammation, and behavioral functions were compared to the sham (craniectomy) and control mice at day 7 post-FPI. We observed that both the craniectomy and FPI significantly augmented the ipsilateral hippocampal neurogenesis as evaluated by DCX and Beta-III tubulin immunoreactivity. Similarly, a significant increase in GFAP and TMEM immunoreactivity in CA1 and CA3 regions showed that craniectomy mimics FPI-induced neuroinflammation. The additive damaging effect of craniectomy with FPI was also reported in the term of axonal and dendritic fragmentation, swelling and neuronal death using silver staining, Fluoro-jade, and MAP-2 immunoreactivity. Sham-exposed mice showed a significant functional decrease in grip strength. Our results indicate that sham craniectomy itself is enough to cause TBI like characteristics, and thus fluid percussion at mild pressure is minimally additive with craniectomy. Considering the method as a mixed (focal & diffused) injury model, the 'net neurotrauma severity' should be compared with naïve control instead of the sham as it is an outcome of cumulative damage due to fluid pressure and craniectomy. Nevertheless, to understand the long term consequences of neurotrauma, the extent of recovery in surgical sham may separately be quantified.

Fluoride contamination in drinking water in rural habitations of northern Rajasthan, India.

This study was carried out to assess the fluoride concentration in groundwater in some villages of northern Rajasthan, India, where groundwater is the main source of drinking water. Water samples collected form deep aquifer based hand-pumps were analysed for fluoride content. Fluoride in presently studied sites was recorded in the ranges of 4.78 and 1.01 mg/l. The average fluoride concentration for this region was recorded 2.82 mg/l. As per the desirable and maximum permissible limit for fluoride in drinking water, determined by WHO or by Bureau of Indian Standards, the groundwater of about 95 of the studied sites is unfit for drinking purposes. Due to the higher fluoride level in drinking water several cases of dental and skeletal fluorosis have appeared at alarming rate in this region. The middle and eastern parts of the Hanumangarh, a northern most district of the state, can be classified as higher risk area for fluorosis; due to relatively high concentrations of fluoride (3-4 mg/l) in groundwater of this region. After evaluating the data of this study it is concluded that there is an instant need to take ameliorative steps in this region to prevent the population from fluorosis.