Investigating the role of axonal ion channel cooperativity in action potential dynamics: Studies on Hodgkin-Huxley's model.

Voltage-gated ion channels play an important role in generating action potential in neurons. These ion channels are found to be in localized cluster form on the axonal membrane surface and behave cooperatively. However, in Hodgkin & Huxley's model of action potential the ion channels are considered to function independently. According to some recent reports, the activity of an ion channel is influenced by the neighboring ion channels' activities. We have modified the Hodgkin-Huxley's model based on our previous studies on cooperativity among ion channels. Computational analysis of the proposed model shows that the initiation of the action potential, amplitude and hyperpolarization are affected significantly by the cooperative interactions among the voltage-gated ion channels present on the axonal membrane surface. These results are qualitatively supported by the existing experimental facts.

In vitro and Bioimaging Studies of Mesoporous Silica Nanocomposites Encapsulated Iron-oxide and Loaded Doxorubicin Drug (DOX/IO@Silica) as Magnetically Guided Drug Delivery System.

BACKGROUND: In recent years, the delivery of drugs by nanocomposites has emerged as an exciting field of research for bio-imaging tools and targeted cancer treatment. The large surface area and porous volume of mesoporous silica nanocomposites (MSN's) have gained a lot of interest for their application in the delivery of drugs and the magnetic properties of iron oxide (IO) nanocomposites play a key role in the targeted delivery system. METHODS: In this study, mesoporous silica encapsulated IO nanocomposites loaded with doxorubicin (DOX) were synthesized for the magnetically guided delivery of anticancer drugs. The synthesis of IO nanocomposites was done through the precipitation method, and then silica encapsulation and drug loading were done by the StÖber method. RESULTS: The magnetically driven delivery of the drug is produced by the encapsulation of magnetically active IO in the mesoporous silica shell. The controlled release of DOX is possible because of the MSN's. TEM images show that the nanocomposites have a spherical morphology and average diameter in the range of 120 nm. Power-XRD data confirm the crystalline nature of nanocomposites. The strong absorption peak was observed in UV-Visible spectroscopy at 490 nm and quenching in fluorescence spectra confirms the encapsulation of DOX in the mesoporous silica shell. VSM data showed the magnetic nature of nanocomposites, with large magnetic susceptibility (74.88 emu/g). The use of DOX/IO@Silica nanocomposites as a sustainable drug release and targeted drug delivery vehicle has been reported here. The pH dependent release of DOX was studied and significant release was observed at lower pH. In-vitro cell viability assay and fluorescence imaging assay have demonstrated that these nanocomposites show significant dose-dependent toxicity to cancer cells in the presence of a magnetic field. CONCLUSION: In-vitro studies via the MTT assay showed that these synthesized nanocomposites in culture are non-toxic to healthy cells compared to DOX-induced cytotoxicity due its controlled release and can be further strengthened by magnetic guidance. Therefore, due to its optical properties and potential for guided delivery of drug to the targeted site, these nanocomposites are ideal as an anticancer agent and bio-imaging prob.

Biosynthesis of anticancer phytochemical compounds and their chemistry.

Cancer is a severe health issue, and cancer cases are rising yearly. New anticancer drugs have been developed as our understanding of the molecular mechanisms behind diverse solid tumors, and metastatic malignancies have increased. Plant-derived phytochemical compounds target different oncogenes, tumor suppressor genes, protein channels, immune cells, protein channels, and pumps, which have attracted much attention for treating cancer in preclinical studies. Despite the anticancer capabilities of these phytochemical compounds, systemic toxicity, medication resistance, and limited absorption remain more significant obstacles in clinical trials. Therefore, drug combinations of new phytochemical compounds, phytonanomedicine, semi-synthetic, and synthetic analogs should be considered to supplement the existing cancer therapies. It is also crucial to consider different strategies for increased production of phytochemical bioactive substances. The primary goal of this review is to highlight several bioactive anticancer phytochemical compounds found in plants, preclinical research, their synthetic and semi-synthetic analogs, and clinical trials. Additionally, biotechnological and metabolic engineering strategies are explored to enhance the production of bioactive phytochemical compounds. Ligands and their interactions with their putative targets are also explored through molecular docking studies. Therefore, emphasis is given to gathering comprehensive data regarding modern biotechnology, metabolic engineering, molecular biology, and in silico tools.

Use of Intraoperative C-Arm Fluoroscopy in Open Reduction and Internal Fixation of Mandibular Condyle Fracture - A Case Report.

The Rationale: Condyle fractures are a common type of mandibular fracture that can result in malocclusion. Open reduction and internal fixation (ORIF) in condylar fracture is considered as the most acceptable treatment modality. Patient Concerns: The patient complained of pain and difficulty in the jaw while chewing. Diagnosis: An orthopantomogram and reverse Towne's view can lead to diagnosis of the condylar fracture. Treatment: Open reduction and internal fixation using intraoperative real-time visualisation of subcondylar fracture reduction utilising the C-arm fluoroscopic approach were used to allow for adequate anatomical repositioning and fast restoration of function to meet the patient's concerns. Outcomes: We were able to achieve correct reduction of the fracture fragments with restoration of function and occlusion. Take-away Lessons: When this procedure is used to treat condylar fractures, surgeons can get a better view of the fracture segments while eliminating the need for postoperative intermaxillary fixation and also reduces the complications from inappropriate reduction and fixation.

Use of Foley's catheter as a tourniquet for the management of vascular lesion of lip in Mowat-Wilson syndrome.

BACKGROUND: Vascular malformation of lower lip is a very rare anomaly. The lesion leads to facial asymmetry, difficulty in speech and eating and drooling of saliva. Treatment goals include symmetrical reconstruction of the lip with minimal scarring, provide adequate bulk for the reconstruction of vermillion, in toto removal of the lesion and prevent recurrence. The most common complication during surgical removal of these lesions includes blood loss and profuse bleeding which leads to poor visibility, increased operation time and postoperative requirement of blood transfusion. Therefore, the use of sclerosing agent is recommended before surgical removal. This may help in decreasing bleeding during surgery but not in all cases. CASE REPORT: Here, we report the use of Foley's catheter for the management of a high flow lesion of lower lip in a 12-year-old patient diagnosed with Mowat-Wilson syndrome. This technique helped in providing bloodless field which lead to minimal blood loss and good visibility intraoperatively.

Glandular Odontogenic Cyst of Anterior Maxilla - A Rare Case Report.

Rationale: Glandular odontogenic cyst (GOC) is a rare type of cyst of the jaws, which shares histological features with that of lateral periodontal cyst, botryoid cyst, radicular cyst with mucous metaplasia, or low-grade mucoepidermoid carcinoma, making it difficult to come to a definitive diagnosis. Not many cases of GOC have been reported in the literature. Patient Concerns: A 40-year-old male patient presented with pain in the upper right front tooth region. Mild extraoral swelling, obliterating the right nasolabial fold, was present. Tenderness on percussion was present in involved teeth. Diagnosis: On histopathological examination, GOC was confirmed featuring pseudostratified columnar cells with cilia, goblet cells, and mucous cells. Treatment: Complete enucleation of the cyst was done. Outcomes: No recurrence was noted on 1-year follow-up. Take-away Lessons: Due to high recurrence rate and aggressive nature of the cyst, it is important to plan proper management and long-term follow-up.

Delving into the Antiurolithiatic Potential of Tribulus terrestris Extract Through -In Vivo Efficacy and Preclinical Safety Investigations in Wistar Rats.

Modern treatment interventions for kidney stones are wrought with side-effects, hence the need for alternative therapies such as plant-based medicines. We have previously documented through in vitro studies that statistically optimized aqueous extract of Tribulus terrestris (Zygophyllaceae family) possesses antiurolithic and antioxidant potential. This provides strong scientific foundation to conduct in vivo efficacy and preclinical safety studies to corroborate and lend further proof to its ability to prevent and cure kidney stones. The preventive and curative urolithiatic efficacy in experimentally induced nephrolithiatic Wistar rats, along with preclinical toxicity was evaluated following oral administration of statistically optimized aqueous extract of T. terrestris. Treatment showed augmented renal function, restoration of normal renal architecture and increase in body weight. Microscopic analysis of urine revealed excretion of small sized urinary crystals, demonstrating that treatment potentially modulated the morphology of renal stones. Tissue enzymatic estimation affirmed the antioxidant efficacy of treatment with reduced free radical generation. Significant upregulation of p38MAPK at both the gene and protein level was noted in hyperoxaluric group and interestingly treatment reversed it. Acute oral toxicity study established the Median Lethal Dose (LD50) to be greater than 2000 mg/kg body weight (b.wt.) No observed adverse effect level (NOAEL) by repeated oral toxicity for 28 days at 750 mg/kg b.wt. was noted. This study lends scientific evidence to the safe, preventive and curative potential of statistically optimized aqueous extract of T. terrestris at a dose of 750 mg/kg b.wt. and suggests that the extract shows promise as a therapeutic antiurolithic agent.

Increase in Electrical Conductivity of MOF to Billion-Fold upon Filling the Nanochannels with Conducting Polymer.

Redox-active pyrrole (Py) monomers were intercalated into 1D nanochannels of [Cd(NDC)0.5(PCA)]·Gx (H2NDC = 2,6-napthalenedicarboxylic acid, HPCA = 4-pyridinecarboxylic acid, G = guest molecules) (1) - a fluorescent 3D MOF (λem = 385 nm). Subsequent activation of 1⊃Py upon immersing into iodine (I2) solution resulted in an increment of the bulk electrical conductivity by ∼9 orders of magnitude. The unusual increase in conductivity was attributed to the formation of highly oriented and conducting polypyrrole (PPy) chains inside 1D nanochannels and specific host-guest interaction in 1⊃PPy thereof. The Hall-effect measurements suggested 1⊃PPy to be an n-type semiconductor material with remarkably high-carrier density (η) of ∼1.5 × 10(17) cm(-3) and mobility (µ) of ∼8.15 cm(2) V(-1) s(-1). The fluorescence property of 1 was almost retained in 1⊃PPy with concomitant exciplex-type emission at higher wavelength (λem = 520 nm). The here-presented results on [MOF⊃Conducting Polymer] systems in general will serve as a prototype experiment toward rational design for the development of highly conductive yet fluorescent MOF-based materials for various optoelectronic applications.

Glucose-dependent insulinotropic polypeptide (GIP) and GIP receptor (GIPR) genes: An association analysis of polymorphisms and bone in young and elderly women.

INTRODUCTION: The gastro-intestinal hormone glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-induced insulin secretion, with bone anabolic effects through GIP receptor (GIPR) in animal models. We explore its potential in humans by analyzing association between polymorphisms (SNPs) in the GIP and GIPR genes with bone phenotypes in young and elderly women. METHODS: Association between GIP (rs2291725) and GIPR (rs10423928) and BMD, bone mineral content (BMC), bone microarchitecture, fracture and body composition was analyzed in the OPRA (75y, n = 1044) and PEAK-25 (25y; n = 1061) cohorts and serum-GIP in OPRA. RESULTS: The GIP receptor AA-genotype was associated with lower ultrasound values in young women (BUA p = 0.011; SI p = 0.030), with no association to bone phenotypes in the elderly. In the elderly, the GIP was associated with lower ultrasound (GG vs. AA; SOS padj = 0.021) and lower femoral neck BMD and BMC after adjusting for fat mass (padj = 0.016 and padj = 0.03). In young women, neither GIPR nor GIP associated with other bone phenotypes including spine trabecular bone score. In the elderly, neither SNP associated with fracture. GIP was associated with body composition only in Peak-25; GIPR was not associated with body composition in either cohort. Serum-GIP levels (in elderly) were not associated with bone phenotypes, however lower levels were associated with the GIPR A-allele (ß = - 6.93; padj = 0.03). CONCLUSIONS: This first exploratory association study between polymorphisms in GIP and GIPR in relation to bone phenotypes and serum-GIP in women at different ages indicates a possible, albeit complex link between glucose metabolism genes and bone, while recognizing that further studies are warranted.

Magnetic removal of Entamoeba cysts from water using chitosan oligosaccharide-coated iron oxide nanoparticles.

Amebiasis, a major health problem in developing countries, is the second most common cause of death due to parasitic infection. Amebiasis is usually transmitted by the ingestion of Entamoeba histolytica cysts through oral-fecal route. Herein, we report on the use of chitosan oligosaccharide-functionalized iron oxide nanoparticles for efficient capture and removal of pathogenic protozoan cysts under the influence of an external magnetic field. These nanoparticles were synthesized through a chemical synthesis process. The synthesized particles were characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, and zeta potential analysis. The particles were found to be well dispersed and uniform in size. The capture and removal of pathogenic cysts were demonstrated by fluorescent microscopy, transmission electron microscopy, and scanning electron microscopy (SEM). Three-dimensional modeling of various biochemical components of cyst walls, and thereafter, flexible docking studies demonstrate the probable interaction mechanism of nanoparticles with various components of E. histolytica cyst walls. Results of the present study suggest that E. histolytica cysts can be efficiently captured and removed from contaminated aqueous systems through the application of synthesized nanoparticles.

Influence of persistent organic pollutants on oxidative stress in population-based samples.

Persistent organic pollutants (POPs) are a large group of chemicals widely used and produced in various industrial applications. Many cell culture/animal studies have shown that POPs can induce oxidative stress. Since such data is lacking in humans, we conducted a large population-based study to analyze associations between POPs and oxidative stress markers. We measured following POPs; 16 polychlorinated biphenyls (PCBs), 5 organochlorine (OC) pesticides, octachlorinated dibenzo-p-dioxin, and polybrominated diphenyl ether 47, and oxidative stress markers; homocysteine, reduced [GSH] and oxidized glutathione [GSSG], glutathione ratio [GSSG/GSH], total glutathione, oxidized low-density lipoprotein [ox-LDL], ox-LDL antibodies, conjugated dienes, baseline conjugated dienes of LDL, and total anti-oxidative capacity in plasma samples collected from 992 70-year old individuals (50% women) from the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Linear regression analyses were performed to study the associations between oxidative stress markers and summary measures of POPs including the total toxic equivalence (TEQ), sums of PCBs and OC pesticides (main exposures) while adjusting for potential confounders. In multivariable-adjusted analyses, sum of PCBs showed strong associations with ox-LDL (ß=0.94; P=2.9*10(-6)). Further, sum of PCBs showed association with glutathione-related markers (GSSG: ß=-0.01; P=6.0*10(-7); GSSG/GSH: ß=-0.002; P=9.7*10(-10)), although in reverse direction. Other summary measures did not show any significant association with these markers. In our study of elderly individuals from the general population, we show that plasma levels of POPs are associated with markers of increased oxidative stress thereby suggesting that even low dose background exposure to POPs may be involved in oxidative stress.

Persistent organic pollutants and inflammatory markers in a cross-sectional study of elderly Swedish people: the PIVUS cohort.

BACKGROUND: Persistent organic pollutants (POPs) are compounds that are generated through various industrial activities and released in the surrounding environment. Different animal studies have shown effects of different POPs on various inflammatory markers. OBJECTIVE: Because very few studies have been conducted in humans, we assessed the associations between different POPs and inflammatory markers in a large population-based sample of elderly men and women (all 70 years of age) from Sweden. METHODS: This cross-sectional study investigated the concentrations of several polychlorinated biphenyls (PCBs), organochlorine pesticides, polychlorinated dibenzo-p-dioxin, and brominated diphenyl ether congeners and their association with a number of inflammatory markers [vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, C-reactive protein (CRP), total leucocyte count, tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1 (MCP-1), and interleukin 6 (IL-6)] in 992 individuals. These individuals were recruited from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. We used a total toxic equivalency (TEQ) value that measures toxicological effects with the relative potencies of various POPs. RESULTS: Following adjustment for potential confounders, the TEQ value (driven mainly by PCB-126) was significantly associated with levels of ICAM-1 (p < 10-5). A similar trend was also observed between sum of PCBs and VCAM-1 (p < 0.001). No significant associations were observed between levels of POPs and other inflammatory markers. CONCLUSIONS: TEQ values were associated with levels of ICAM-1, to a lesser degree also with VCAM-1, but not with CRP and several other inflammatory markers. These findings suggest an activation of vascular adhesion molecules by POPs, and particularly by PCB-126.

Structural and functional analysis of cathepsin S of Heterodera spp: a promising candidate for its control.

Cysteine proteinases are required for a wide range of physiological processes in all living organisms. In parasitic nematodes, they are particularly crucial for the digestion of host tissues and evasion of host immune responses. Therefore, in general, these are identified as primary targets for the control of parasitic nematodes. Herein, cathepsin S-like cysteine proteinase of Heterodera avenae (Hacp-s) has been cloned and analysed for the first time. The predicted protein is 298 amino acids long and showed significant similarity with cathepsin S of Heterodera glycines (Hgcp-s). The sequence of cathepsin S contains a signal peptide of 30 amino acids which suggests its role in extracellular functions. Multiple sequence alignment revealed the presence of ERFNIN motif and conserved catalytic residues. Three dimensional structure (3D) of Hgcp-s was modelled using homology modelling. In order to illustrate the plausible mode of interaction of cathepsin S (Hgcp-s), docking analysis was performed with E-64 cysteine proteinase inhibitor. Docking studies revealed the hydrogen bonding of E-64 with Gln153, His299 and Gly203 as well as close interaction with catalytic residues Cys159 and Asn320 Expression analysis of Hacp-s using qRT-PCR showed high expression of cathepsin S in pre parasitic J2s and female stages suggesting its significant role in both pre-parasitic and parasitic stages of the nematode life cycle.

Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1.

Primary astrocytomas of grade 3 or 4 according to the classification system of the World Health Organization (high-grade astrocytomas or HGAs) are preponderant among adults and are almost invariably fatal despite the use of multimodal therapy. Here we show that the juvenile brain has an endogenous defense mechanism against HGAs. Neural precursor cells (NPCs) migrate to HGAs, reduce glioma expansion and prolong survival time by releasing endovanilloids that activate the vanilloid receptor (transient receptor potential vanilloid subfamily member-1 or TRPV1) on HGA cells. TRPV1 is highly expressed in tumor and weakly expressed in tumor-free brain. TRPV1 stimulation triggers tumor cell death through the branch of the endoplasmic reticulum stress pathway that is controlled by activating transcription factor-3 (ATF3). The antitumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid arvanil, suggesting that TRPV1 agonists have potential as new HGA therapeutics.

Osteocalcin gene polymorphisms influence concentration of serum osteocalcin and enhance fracture identification.

Osteoporosis is a major health problem affecting more than 75 million people throughout Europe, the United States, and Japan. Epidemiologic studies have determined that both genetic and environmental factors contribute to the pathogenesis of osteoporosis. We have investigated the association between polymorphisms at the osteocalcin locus and variables linked to bone health. Osteocalcin provides a link between bone and energy metabolism, hence its potential importance as an osteoporosis candidate gene. In this study, we included a total of 996 women (all aged 75 years) from the Osteoporosis Prospective Risk Assessment (OPRA) cohort. We sequenced the osteocalcin gene along with flanking regions to search for novel coding polymorphisms. We also analyzed four polymorphisms selected from within and flanking regions of the osteocalcin gene to study their association with serum total osteocalcin levels (S-TotalOC), total-body (TB) bone mineral density (BMD), fracture, TB fat mass, and body mass index (BMI). The promoter polymorphism rs1800247 was significantly associated with S-TotalOC (p = .012) after controlling for BMI and TB BMD. The polymorphism rs1543297 was significantly associated with prospectively occurring fractures (p = .008). In a model taking into account rs1543297 and rs1800247, along with TB BMD, BMI, smoking, and S-TotalOC, the polymorphisms together were able to identify an additional 6% of women who sustained a fracture (p = .02). We found no association between the polymorphisms and TB BMD, BMI, or TB fat mass. In conclusion, polymorphisms in and around the osteocalcin locus are significantly associated with S-TotalOC and fracture. Genotyping at the osteocalcin locus could add valuable information in the identification of women at risk of osteoporosis.

Cystathionine beta-synthase 844Ins68 polymorphism is not associated with the levels of homocysteine and cysteine in an Indian population.

Cystathionine beta-synthase (CBS) is a key enzyme that plays a critical role in homocysteine metabolism and intracellular redox balance. We have analysed the association of the CBS 844Ins68 polymorphism alone and in combination with methylenetetrahydrofolate reductase (MTHFR C677T) and choline dehydrogenase (CHDH A119C) polymorphisms (the two polymorphisms recently shown to be associated with levels of homocysteine) with homocysteine, cysteine, folate and vitamin B(12) in 817 individuals (397 patients with coronary artery disease and 420 controls). The CBS 844Ins68 polymorphism alone or in combination with MTHFR C677T and CHDH A119C polymorphisms was not significantly associated with any of the biochemical variables studied.

Vitamin B12 deficiency is associated with coronary artery disease in an Indian population.

BACKGROUND: The incidence of coronary artery disease (CAD) is increasing at an alarming rate, especially in developing countries, such as India. It is often advocated that a vegetarian lifestyle could reduce the burden of CAD. However, in spite of a majority of Indians being vegetarians, the incidence of CAD is highest in this population. This may be due to deficiency of vitamin B12, a micronutrient, sourced only from animal products. METHODS: Herein, we assessed the effect of vitamin B12 with respect to CAD in 816 individuals (368 CAD patients and 448 controls) recruited from a tertiary care center in New Delhi, India. RESULTS: We found that vitamin B12 levels were significantly lower in CAD patients than in controls (p<0.0001). Also, vegetarians were found to have significantly lower vitamin B12 concentrations (p=0.0001) and higher incidence of CAD (p=0.01). Interestingly, elevated homocysteine levels, a hallmark of vitamin B12 deficiency, was not associated with CAD. In contrast, cysteine levels were significantly higher in CAD patients than in controls (p=0.004). CONCLUSIONS: We believe that, when vitamin B12 is deficient, homocysteine is rapidly metabolized via the transsulfuration pathway leading to increased cysteine levels.

Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian population.

An elevated level of homocysteine is an independent risk factor for cardiovascular diseases and is associated with other complex disorders. Homocysteine levels can be elevated due to dietary and/or genetic factors. A majority of Indian population have a low level of vitamin B12 (presumably due to vegetarian diet)--a critical nutritional factor, deficiency of which results in hyperhomocysteinemia. Hence, polymorphisms in the genes responsible for homocysteine metabolism can be perceived to have a greater impact in relation to hyperhomocysteinemia in Indian population. For this reason, the effects of diet and/or methylenetetrahydrofolate reductase (MTHFR) polymorphism were assessed in 200 individuals having varying homocysteine levels. Homocysteine levels were significantly elevated in individuals adhering to a vegetarian diet (P = 0.019) or having MTHFR A1298C polymorphism (P = 0.006). The minor allele frequency (MAF) of MTHFR C677T and A1298C was 0.15 and 0.44 respectively in this cohort. Since the MAF of these polymorphisms differed considerably from Caucasian and other Asian populations, frequencies of these polymorphisms were also determined in more than 400 individuals from different ethnic populations, selected from the entire country based on their geographical location and linguistic lineage, and was found to be similar to that of our cohort. The fact that MTHFR A1298C polymorphism is significantly associated with homocysteine levels, and that the CC genotype is present at a higher frequency in the Indian population, makes it extremely relevant in terms of its potential impact on hyperhomocysteinemia.