Advanced Overview of Biomarkers and Techniques for Early Diagnosis of Alzheimer's Disease.

The development of early non-invasive diagnosis methods and identification of novel biomarkers are necessary for managing Alzheimer's disease (AD) and facilitating effective prognosis and treatment. AD has multi-factorial nature and involves complex molecular mechanism, which causes neuronal degeneration. The primary challenges in early AD detection include patient heterogeneity and lack of precise diagnosis at the preclinical stage. Several cerebrospinal fluid (CSF) and blood biomarkers have been proposed to show excellent diagnosis ability by identifying tau pathology and cerebral amyloid beta (Aß) for AD. Intense research endeavors are being made to develop ultrasensitive detection techniques and find potent biomarkers for early AD diagnosis. To mitigate AD worldwide, understanding various CSF biomarkers, blood biomarkers, and techniques that can be used for early diagnosis is imperative. This review attempts to provide information regarding AD pathophysiology, genetic and non-genetic factors associated with AD, several potential blood and CSF biomarkers, like neurofilament light, neurogranin, Aß, and tau, along with biomarkers under development for AD detection. Besides, numerous techniques, such as neuroimaging, spectroscopic techniques, biosensors, and neuroproteomics, which are being explored to aid early AD detection, have been discussed. The insights thus gained would help in finding potential biomarkers and suitable techniques for the accurate diagnosis of early AD before cognitive dysfunction.

Global trends in pesticides: A looming threat and viable alternatives.

Pesticides are widely used chemical compounds in agriculture to destroy insects, pests and weeds. In modern era, they form an indispensable part of agricultural and health practices. Globally, nearly 3 billion kg of pesticides are used every year with a budget of ~40 billion USD. This extensive usage has increased the crop yield as well as led to significant reduction in harvest losses and thereby, enhanced food availability. On the other hand, indiscriminate usage of these chemicals has led to several environmental implications and caused adverse effects on human health. Epidemiological evidences have revealed the harmful effects of pesticides exposure on various organs including liver, brain, lungs and colon. Recent investigations have shown that pesticides can also lead to fatal consequences such as cancer among individuals. These chemicals enter ecosystem, thus hampering the sensitive environmental equilibrium through bio-accumulation. Due to their non-biodegradable nature, they can persist in nature for years and are regarded as potent biohazard. Worldwide, very few surveillance methods have been considered, which can bring awareness among the individuals, therefore the present review is an attempt to delineate consequences induced by various types of pesticide exposure on the environment. Further, the prospective of biopesticides use could facilitate the increase of crop production without compromising human health.

Neuro-protective potential of quercetin during chlorpyrifos induced neurotoxicity in rats.

Chlorpyrifos (CPF) has been considered as one of the most potent organophosphates and is linked to several neurological disorders. On the other hand, Quercetin is a vital plant flavanoid and has been reported to regulate a number of physiological processes in the central nervous system. The present study was conducted to investigate the protective potential of quercetin during chlorpyrifos induced neurotoxicity. Female Wistar rats weighing 150-200 g were divided into four different groups viz: Normal control, CPF treated (13.5 mg/kg.b.wt. every alternate day), Quercetin treated (50 mg/kg.b.wt./day) and combined CPF and quercetin-treated. All the treatments were carried out for a total duration of eight weeks. Chlorpyrifos treatment showed significant alterations in the cognitive behavior and motor activities of rats, which were appreciably improved upon simultaneous supplementation with quercetin. Further, CPF treatment caused a significant inhibition in the enzyme activities of acetylcholinesterase and choline acetyltransferase, but caused an increase in the levels of acetylcholine in the brain. Further, chlorpyrifos exposure significantly elevated the levels of lipid peroxidation and protein carbonyl contents as well as the activities of catalase, superoxide dismutase, which were interestingly found to be decreased following co-treatment with quercetin. In contrast, CPF treatment decreased the activities of glutathione reductase, transferase, as well as levels of reduced and total glutathione in both the cerebrum and cerebellum but co-administration of quercetin, increased these levels. Chlorpyrifos treatment altered the neuro-histoarchitecture, which showed improvement upon quercetin supplementation. Hence, this study suggests that quercetin can be used as a prophylactic intervention to prevent CPF induced neurotoxicity.

A concept of radiation hormesis: stimulation of antioxidant machinery in rats by low dose ionizing radiation.

OBJECTIVE: The concept of radiation hormesis has been the matter of discussion with regard to beneficial effects to biological systems from low doses of ionizing radiations. However, its molecular basis is not well understood till now and the present study is a step forward to elucidate how low levels of ionizing radiation prove beneficial for functioning of biological systems. MATERIAL AND METHODS: Female Wistar rats weighing 100-120g were divided into four different groups. Each group consisted of eight animals. The animals in Group I served as normal controls for Group II animals which were subjected to whole body X-rays exposure of 20rads and were sacrificed 6 hours following exposure. Group III animals served as normal controls for group IV animals which were given whole body X-rays radiation of 20rads and were sacrificed 24 hours following exposure. RESULTS: The levels of reduced glutathione (GSH), total glutathione (TG) were increased in liver, kidney, brain and blood after 6hrs as well as 24hrs following X-rays exposure. On the contrary, no significant change in the oxidized glutathione (GSSG) content was observed following X-rays irradiation in any of the organs. Further, the low dose of X-rays resulted in a significant decrease in the lipid peroxidation (LPO) in liver, kidney and brain, whereas it caused an increase in LPO levels in blood. The enzyme activities of catalase (CAT) as well as glutathione-S-transferase (GST) were also increased in different organs after X-rays exposure. Furthermore, low dose irradiation with X-rays caused a significant increase in the counts of total leukocytes, lymphocytes and eosinophils, whereas it decreased the counts of neutrophils as well as monocytes. Hence, our results clearly indicate that low dose X-rays radiation exposure stimulates endogenous antioxidant defense machinery and also causes an increase in whole blood lymphocytes and eosinophils responsible for providing key defenses. CONCLUSION: Low doses of X-rays exposure may afford radiation hormesis by providing protection to organs from oxidative injury and support immune reaction.

Low dose X-irradiation mitigates diazepam induced depression in rat brain.

Depression is considered as one of the most prevalent health ailments. Various anti-depressant drugs have been used to provide succour to this ailment, but with little success and rather have resulted in many side effects. On the other hand, low dose of ionizing radiations are reported to exhibit many beneficial effects on human body by stimulating various biological processes. The present study was conducted to investigate the beneficial effects of low doses of X-rays, if any, during diazepam induced depression in rats. Female Sprague Dawley rats were segregated into four different groups viz: Normal control, Diazepam treated, X-irradiated and Diazepam + X-irradiated. Depression model was created in rats by subjecting them to diazepam treatment at a dosage of 2 mg/kg b.wt./day for 3 weeks. The skulls of animals belonging to X-irradiated and Diazepam + X-irradiated rats were X-irradiated with a single fraction of 0.5 Gy, given twice a day for 3 days, thereby delivered dose of 3 Gy. Diazepam treated animals showed significant alterations in the neurobehavior and neuro-histoarchitecture, which were improved after X-irradiation. Further, diazepam exposure significantly decreased the levels of neurotransmitters and acetylcholinesterase activity, but increased the monoamine oxidase activity in brain. Interestingly, X-rays exposure to diazepam treated rats increased the levels of neurotransmitters, acetylcholinesterase activity and decreased the monoamine oxidase activity. Further, depressed rats also showed increased oxidative stress with altered antioxidant parameters, which were normalized on X-rays exposure. The present study, suggests that low dose of ionizing radiations, shall prove to be an effective intervention and a novel therapy in controlling depression and possibly other brain related disorders.

Modulation of (14) C-labeled glucose metabolism by zinc during aluminium induced neurodegeneration.

Aluminium (Al) is one of the most prominent metals in the environment and is responsible for causing several neurological disorders, including Alzheimer's disease. On the other hand, zinc (Zn) is an essential micronutrient that is involved in regulating brain development and function. The present study investigates the protective potential of Zn in the uptake of (14) C-labeled amino acids and glucose and their turnover in rat brain slices during Al intoxication. Male Sprague Dawley rats (140-160 g) were divided into four different groups: normal control, Al treated (100 mg/kg body weight/day via oral gavage), Zn treated (227 mg/liter in drinking water), and Al + Zn treated. Radiorespirometric assay revealed an increase in glucose turnover after Al exposure that was attenuated after Zn treatment. Furthermore, the uptake of (14) C-labeled glucose was increased after Al treatment but was appreciably decreased upon Zn supplementation. In addition, the uptakes of (14) C-lysine, (14) C-leucine, and (14) C-aspartic acid were also found to be elevated following Al exposure but were decreased after Zn treatment. Al treatment also caused alterations in the neurohistoarchitecture of the brain, which were improved after Zn coadministration. Therefore, the present study suggests that Zn provides protection against Al-induced neurotoxicity by regulating glucose and amino acid uptake in rats, indicating that Zn could be a potential candidate for the treatment of various neurodegenerative disorders.

Zinc down regulates Apaf-1-dependent Bax/Bcl-2 mediated caspases activation during aluminium induced neurotoxicity.

Aluminium (Al), a ubiquitous element in nature is associated with the onset of Alzheimer's disease. On the other hand, zinc (Zn) is an essential trace element that regulates large number of physiological processes in the human body. The present study was conducted to explore the role of zinc, if any, in regulating apoptotic machinery during Al induced neurodegeneration in rat. Male sprague dawley rats weighing 140-160 g were divided into four different groups viz: Normal control, Al treated (100 mg/kg b.wt./day), Zn treated (227 mg/l) and combined Al and Zn treated. All the treatments were carried out for a total duration of 8 weeks. Al treatment resulted in a significant increase in the protein expressions of cytochrome c, Bax, Apaf-1, caspase 9, caspase 3 (p17), caspase 8, caspase 6, caspase 7 but decreased the Bcl-2 in both the cerebrum and cerebellum. However, Zn supplementation to Al treated rats resulted in a reduction in the protein expressions of cytochrome c, Bax, Apaf-1, caspase 9, caspase 3 (p17), caspase 8, caspase 6 and caspase 7 whereas it elevated the Bcl-2 in both the regions. Further, gene expressions of caspase 3 and caspase 9 were also found to be elevated after Al treatment, which however were reduced following Zn co-treatment. The electron-microscopic analysis of brain revealed that Al intoxication resulted in a number of degenerative signs at ultrastructural level, which were appreciably improved upon Zn supplementation. The present study suggests that Zn provides protection against Al induced neurotoxicity by triggering anti-apoptotic machinery.

Influence of zinc on the biokinetics of (65)Zn in brain and whole body and its bio-distribution in aluminium-intoxicated rats.

The present study was designed to understand the influence of zinc (Zn) if any, on the biokinetics of (65)Zn in brain as well as whole body and its bio-distribution following aluminium (Al) treatment to rats. Male Sprague-Dawley rats weighing 140-160 g were divided into four different groups viz: normal control, aluminium treated (100 mg/kg b.wt./day via oral gavage), zinc treated (227 mg/L in drinking water) and combined aluminium and zinc treated. All the treatments were carried out for a total duration of 8 weeks. Al treatment showed a significant increase in fast component (Tb1) but revealed a significant decrease in slow component (Tb2) of biological half-life in brain as well as in whole body. However, Zn supplementation to Al-treated rats reversed the trend in both brain and whole body, which indicates a significant decrease in Tb1 component while the Tb2 component was significantly increased. Further, Al treatment showed an increased percent uptake value of (65)Zn in cerebrum, cerebellum, heart, liver and lungs whereas a decrease in uptake was found only in blood. On the other hand, there was a significant decline in (65)Zn activity in nuclear and mitochondrial fractions of brain of Al-treated rats. However, Zn treatment reversed the altered (65)Zn uptake values in different organs as well as in various subcellular fractions. The study demonstrates that Zn shall prove to be effective in regulating the biokinetics of (65)Zn in brain and whole body and its distribution at the tissue and subcellular levels in Al-treated rats.

Association of 24 bp duplication of human CHIT1 gene with asthma in a heterozygous population of north India: a case-control study.

PURPOSE: CHIT1 is expressed by pulmonary macrophages, which is typically the site of entry for many environmental fungi that may increase the risk of pulmonary fungal infection and lead to hypersensitivity. The conserved expression of this gene in humans suggests its physiological importance in the mammalian lung. METHODS: The present study was conducted with a total of 964 subjects, including 483 healthy controls and 481 asthma patients. DNA samples were extracted from blood, and the genotyping was done using polymerase chain reaction method. RESULTS: Statistical analysis revealed that the 24 bp duplication in CHIT1 gene polymorphism shows highly significant association in heterozygous (wild/dup) genotype with OR 1.74, 95 % CI (1.29-2.36), and p = 0.000. However, the homozygous mutant genotype (dup/dup) was found to be non-significant with OR 1.06, 95% CI (0.69-1.63), and p = 0.786. The combination of both wild/dup and dup/dup was also found to be highly significant with OR 1.57, 95% CI (1.18-2.11), and p = 0.002. CONCLUSIONS: This is the first study conducted in India which reports a significant association between 24 bp duplication in CHIT1 gene polymorphism and asthma in the studied North Indian population.

Protective role of zinc during aluminum-induced hepatotoxicity.

The study was carried out to assess the role of zinc (Zn) in mitigating the biochemical alterations induced by aluminum (Al) in rat liver. Rats were divided into four groups: normal control, Al treated (AlCl3, 100 mg/kg b.wt./day), Zn treated (ZnSO4, 227 mg/L drinking water), and combined Al + Zn treated. Al and zinc treatments were given for a total duration of 2 months. Al treatment caused a significant increase in the activity of alkaline phosphatase (ALP), but decreased aspartate aminotransferase (AST) and alanine aminotranferase (ALT) activities, which showed the reverse trend following Zn supplementation. Levels of lipid peroxidation (LPx) and activities of catalase and glutathione-S-transferase (GST) were significantly decreased following Al treatment, which, however, were increased significantly in Zn co-treated rats. Further Al exposure showed a significant increase in reduced glutathione (GSH) content as well as activities, of superoxide dismutase (SOD) and glutathione reductase (GR). However, Zn supplementation to Al-treated rats brought down the raised levels of reduced (GSH) and SOD to within normal limits, but caused no effect on GR activity. Furthermore, Al treatment also resulted in alterations in liver histoarchitecture with disruption of hepatic cords and increased vacuolization, which were close to normal following Zn supplementation. The present study reveals that Zn is effective in attenuating the liver damage inflicted by Al toxicity.

Comparison of the effect of zirconia and titanium abutments on peri-implant hard and soft tissues.

AIM: The primary objective of this research was to assess and compare the impact of customized zirconia (Zr) and titanium (Ti) abutments, placed on early loaded dental implants, on both hard tissue (as measured crestal bone level) and soft tissue (as assessed by sulcular bleeding index [SBI], probing depth [PD], and Pink Esthetic Score [PES]), through clinical and radiographic evaluation. SETTINGS AND DESIGN: This research involved a sample of 15 patients who had partially dentulous mandibular arch. Within this group, a total of 30 implants were surgically placed. Specifically, each patient received two implants in the posterior region of the mandible, and the bone density in this area was classified as D2 type. In each patient, one implant was loaded with Zr abutment and the other was loaded with Ti abutment. The bone quality in the area of implant placement was Type D2. Two groups were created for this research. Each group consisted of 15 early loaded dental implants with customized Zr abutments and customized Ti abutments respectively. MATERIALS AND METHODS: Hard- and soft-tissue changes were evaluated in both the groups. Evaluation of crestal bone loss (CBL) with cone beam computed tomography and SBI, PD and PESs were evaluated by various indices at 2, 4, and 6 months postloading. STATISTICAL ANALYSIS USED: After obtaining the readings, data were subjected to statistical analysis and comparison of quantitative data was done, paired t-test was used. RESULTS: The mean CBL in the Ti abutment is higher; the difference between the two groups was not statistically significant. SBI and PD for Zr were higher, but there was no statistically significant difference between the two groups. Zr had a higher PES than Ti abutment and the difference between the two groups was statistically significant. In the literature till date, the PES of Zr abutments were proven better for provisional restorations in implant prosthesis, but very few literatures support the same for the final implant restorations. CONCLUSION: The study did not reveal a clear advantage of either Ti or Zr abutments over the other. Nevertheless, Zr abutments tended to produce a more favorable color response in the peri-implant mucosa and led to superior esthetic outcomes as measured by the PES.

Use of electroconvulsive therapy in the presence of arachnoid cyst: a case report and review of existing literature.

A caution is advised for the use of electroconvulsive therapy (ECT) in patients with space-occupying intracranial lesions. The use of ECT in the presence of arachnoid cyst has been reported only in 10 cases in the literature. Here, we report a case of severe depression with psychotic symptoms who was found to have an arachnoid cyst of 3.4 × 1.6 cm in the left temporal region. The patient received a course of 12 ECT treatments without any complications and had significant improvement in symptoms. Magnetic resonance imaging after completion of ECT did not reveal any change in size of the arachnoid cyst.

Exposure to Tetrabutylammonium Bromide Impairs Cranial Neural Crest Specification, Neurogenic Program, and Brain Morphogenesis.

Tetrabutylammonium bromide (TBAB) is a widely used industrial reagent and is commonly found in our aquatic ecosystem as an industrial byproduct. In humans, the ingestion of TBAB causes severe neurological impairments and disorders such as vertigo, hallucinations, and delirium. Yet, the extent of environmental risk and TBAB toxicity to human health is poorly understood. In this study, we aim to determine the developmental toxicity of TBAB using zebrafish embryos as a model and provide novel insights into the mechanism of action of such chemicals on neurodevelopment and the overall embryonic program. Our results show that exposure to TBAB results in impaired development of the brain, inner ear, and pharyngeal skeletal elements in the zebrafish embryo. TBAB treatment resulted in aberrations in the specification of the neural crest precursors, hindbrain segmentation, and otic neurogenesis. TBAB treatment also induced a surge in apoptosis in the head, tail, and trunk regions of the developing embryo. Long-term TBAB exposure resulted in cardiac edema and craniofacial defects. Further, in silico molecular docking analysis indicated that TBAB binds to AMPA receptors and modulates neural developmental genes such as olfactomedin and acetylcholinesterase in the embryonic brain. To summarize, our study highlights the novel effects of TBAB on embryonic brain formation and segmentation, ear morphogenesis, and craniofacial skeletal development.

In Vivo Acute Toxicity and Therapeutic Potential of a Synthetic Peptide, DP1 in a Staphylococcus aureus Infected Murine Wound Excision Model.

Bacterial infections at the surgical sites are one of the most prevalent skin infections that impair the healing mechanism. They account for about 20% of all types of infections and lead to approximately 75% of surgical-site infection-associated mortality. Several antibiotics, such as cephalosporins, fluoroquinolones, quinolones, penicillin, sulfonamides, etc., that are used to treat such wound infections not only counter infections but also disrupt the normal flora. Moreover, antibiotics, when used for a prolonged duration, may impair the formation of new blood vessels, delay collagen production, or inhibit the migration of certain cells involved in wound repair, leading to an impaired healing process. Therefore, there is a dire need for alternate therapeutic approaches against such infections. Antimicrobial peptides have gained considerable attention as a promising strategy to counter these pathogens and prevent the spread of infection. Recently, we have reported a designed peptide, DP1, and its broad-spectrum in vitro antimicrobial activity against Gram-positive and Gram-negative bacteria. In the present study, in vivo acute toxicity of DP1 was evaluated and even at a high dose (20 mg/kg body weight) of DP1, a 100% survival of mice was observed. Subsequently, a Staphylococcus aureus-infected murine wound excision model was established to assess the wound healing efficacy of DP1. The study revealed significant wound healing vis-a-vis attenuated S. aureus bioburden at the wound site and also controlled the oxidative stress depicting anti-oxidant activity as well. Healing of the infected wounds was also verified by histopathological examination. Based on the results of this study, it can be concluded that DP1 improves wound resolution despite infections and promotes the healing mechanism. Hence, DP1 holds compelling potential as a novel antimicrobial drug that requires further explorations in clinical platforms.

Regulatory role of zinc during aluminium-induced altered carbohydrate metabolism in rat brain.

Aluminium is considered an environmental neurotoxicant and causes many neurological disorders, whereas zinc is vital for many biological functions. The present study was carried out to investigate the role of Zn, if any, in mitigating the adverse effects inflicted by Al on carbohydrate metabolism in rat brain. Male Sprague-Dawley rats weighing 140-160 g were divided into four different groups: normal control, Al-treated (100 mg/kg b.w./day in drinking water via oral gavage), Zn-treated (227mg/liter in drinking water), and combined Al- and Zn-treated rats. All the treatments were continued for 2 months, and their effects on carbohydrate-metabolizing enzymes were studied. Additionally, expressions of the proteins glycogen synthase kinase-3 (GSK3) and protein phosphatase (PP1), which help in regulating carbohydrate energy metabolism, were also studied. Al treatment resulted in increased activities of the glucose-6-phosphatase (G6P), glucose-6-isomerase (G6I), and lactate dehydrogenase (LDH), whereas the activities of hexokinase and succinate dehydrogenase (SDH) and glycogen content were decreased. Moreover, no significant change was observed in the biochemical parameters upon Zn supplementation alone. However, Zn supplementation to Al-treated rats was able to reduce significantly the Al-induced increased activities of G6P, G6I, and LDH, but it elevated the levels of hexokinase, SDH, and glycogen. Furthermore, Al treatment increased the protein expression of GSK3 and decreased the PP1 expression, which were found to be reversed upon Zn administration. Hence, Zn is effective in regulating theAl-induced alterations in carbohydrate metabolism.

Association of ß(2)-adrenergic receptor polymorphisms with asthma in a North Indian population.

BACKGROUND: ß(2)-Adrenergic receptor (ß(2)AR), a G-protein coupled receptor, is present on the bronchial smooth muscle cells and results in bronchodilation upon activation. The genetic factors determining ß(2)AR expression and function may not only alter the response of an individual to the therapy but also may serve as predictive markers for response to the agonists used in the therapy. The present study aimed at evaluating the role of ß(2)AR-16 and ß(2)AR-27 gene polymorphisms in asthma. METHODS: A case-control study was performed with a total of 824 adult subjects, including 410 asthmatics and 414 healthy controls from regions of North India. The ß(2)AR-16 and ß(2)AR-27 polymorphisms were genotyped by PCR-RFLP. RESULTS: Statistical analysis for the ß(2)AR-16 polymorphism revealed that the mutant Gly16 allele was significantly associated with asthma, with OR = 0.80, 95 % CI = 0.65-0.99, and P = 0.032. The Gly16/Gly16 mutant genotype also confers decreased risk toward asthma, with OR = 0.65, 95 % CI = 0.41-1.02, and P = 0.049. However, the ß(2)AR-27 polymorphism was not associated with asthma as it did not reach statistical significance, with OR = 0.86, 95 % CI = 0.69-1.07, and P = 0.163. CONCLUSION: The ß(2)AR-16 polymorphism confers a decreased risk toward asthma while the ß(2)AR-27 polymorphism is not associated with asthma in the studied North Indian population.

GSTT1 and GSTM1 gene polymorphisms as major risk factors for asthma in a North Indian population.

BACKGROUND: According to the National Family Health Survey, asthma is one of the leading diseases in India. In order to understand the complexity of asthma, the susceptibility genes need to be targeted for their association. Glutathione S-transferases play a major role in the detoxification of metabolites of oxidative stress resulting in inflammation and asthma. In the present study, the hypothesis that GSTT1 and GSTM1 gene polymorphisms are associated with asthma was examined. METHODS: This is the first study to investigate the role of GSTT1 and GSTM1 gene polymorphisms in asthma pathogenesis in a North Indian population. A total of 824 subjects were recruited, of which 410 were asthma patients, including 323 patients suffering from allergic rhinitis. The other 414 recruits were healthy controls from regions of North India. Multiplex PCR was used for genotyping the GSTT1 and GSTM1 gene polymorphisms. RESULTS: The GSTT1 null allele was more prevalent in asthma patients (40 %) than in the control subjects (13.3 %), which yielded a nearly fourfold risk towards asthma with odds ratio (OR) (95 % CI) = 4.35 (3.04-6.24), χ(2) = 75.34, and p = 0.000. The GSTM1 polymorphism also revealed a greater prevalence of the GSTM1 null allele in asthma patients (46.6 %) than in controls (39.4 %). Statistical analysis yielded a marginal risk toward asthma with OR (95 % CI) = 1.34 (1.01-1.79), χ(2) = 4.37, and p = 0.036. CONCLUSIONS: Polymorphisms as a result of deletions in the GSTT1 and GSTM1 genes confer an increased risk towards asthma thereby suggesting the protective role of these functional genes in the development of the disease.

Blood-brain barrier: emerging trends on transport models and new-age strategies for therapeutics intervention against neurological disorders.

The integrity of the blood-brain barrier (BBB) is essential for normal central nervous system (CNS) functioning. Considering the significance of BBB in maintaining homeostasis and the neural environment, we aim to provide an overview of significant aspects of BBB. Worldwide, the treatment of neurological diseases caused by BBB disruption has been a major challenge. BBB also restricts entry of neuro-therapeutic drugs and hinders treatment modalities. Hence, currently nanotechnology-based approaches are being explored on large scale as alternatives to conventional methodologies. It is necessary to investigate the in-depth characteristic features of BBB to facilitate the discovery of novel drugs that can successfully cross the barrier and target the disease effectively. It is imperative to discover novel strategies to treat life-threatening CNS diseases in humans. Therefore, insights regarding building blocks of BBB, activation of immune response on breach of this barrier, and various autoimmune neurological disorders caused due to BBB dysfunction are discussed. Further, special emphasis is given on delineating BBB disruption leading to CNS disorders. Moreover, various mechanisms of transport pathways across BBB, several novel strategies, and alternative routes by which drugs can be properly delivered into CNS are also discussed.

Design, characterization and structure-function analysis of novel antimicrobial peptides based on the N-terminal CATH-2 fragment.

The emergence of multidrug resistance coupled with shrinking antibiotic pipelines has increased the demand of antimicrobials with novel mechanisms of action. Therefore, researchers across the globe are striving to develop new antimicrobial substances to alleviate the pressure on conventional antibiotic therapies. Host-Defence Peptides (HDPs) and their derivatives are emerging as effective therapeutic agents against microbial resistance. In this study, five analogs (DP1-5) of the N-terminal (N-15) fragment of CATH-2 were designed based on the delicate balance between various physicochemical properties such as charge, aliphatic character, amphipathicity and hydrophobicity. By means of in-silico and in-vitro studies a novel peptide (DP1) with the sequence "RFGRFLRKILRFLKK" was found to be more effective and less toxic than the N-terminal CATH-2 peptide. Circular dichroism spectroscopy and differential scanning calorimetry were applied for structural insights. Antimicrobial, haemolytic, and cytotoxic activities were also assessed. The resulting peptide was characterized by low cytotoxicity, low haemolytic activity, and efficient anti-microbial activity. Structurally, it displayed strong helical properties irrespective of the solvent environment and was stable in membrane-mimicking environments. Taken together, the data suggests that DP1 can be explored as a promising therapeutic agent with possible clinical applications.

Cyclodextrin Derivative Enhances the Ophthalmic Delivery of Poorly Soluble Azithromycin.

Azithromycin (AZM), a macrolide antibiotic used for the treatment of chlamydial conjunctivitis, is less effective for the treatment of this disease due to its poor bioavailability (38%). Various alternatives have been developed for improving the physicochemical properties (i.e., solubility) of the AZM without much success. To overcome the problems associated with AZM, an inclusion complex employing a modified cyclodextrin, i.e., sulfobutylether-ß-cyclodextrin (SBE-ß-CD), was prepared and characterized by phase solubility studies and PXRD techniques. The results portrayed the formation of an inclusion complex of AZM with SBE-ß-CD in 1:2 molar stoichiometric ratios. This inclusion complex was later incorporated into a polymer matrix to prepare an in situ gel. Various combinations of Carbopol 934P and hydroxypropyl methylcellulose (HPMC K4M) polymers were used and evaluated by rheological and in vitro drug release studies. The optimized formulation (F4) containing Carbopol 934P (0.2% w/v) and HPMC K4M (0.2% w/v) was evaluated for clarity, pH, gelling capacity, drug content, rheological properties, in vitro drug release pattern, ocular irritation test, and antimicrobial efficacy. Finally, owing to the improved antimicrobial efficacy and increased residence time, the AZM:SBE-ß-CD in situ gel was found to be a promising formulation for the efficient treatment of bacterial ocular disease.