A synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of chronic kidney disease and the fourth leading cause of end-stage kidney disease, accounting for over 50% of prevalent cases requiring renal replacement therapy. There is a pressing need for improved therapy for ADPKD. Recent insights into the pathophysiology of ADPKD revealed that cyst cells undergo metabolic changes that up-regulate aerobic glycolysis in lieu of mitochondrial respiration for energy production, a process that ostensibly fuels their increased proliferation. The present work leverages this metabolic disruption as a way to selectively target cyst cells for apoptosis. This small-molecule therapeutic strategy utilizes 11beta-dichloro, a repurposed DNA-damaging anti-tumor agent that induces apoptosis by exacerbating mitochondrial oxidative stress. Here, we demonstrate that 11beta-dichloro is effective in delaying cyst growth and its associated inflammatory and fibrotic events, thus preserving kidney function in perinatal and adult mouse models of ADPKD. In both models, the cyst cells with homozygous inactivation of Pkd1 show enhanced oxidative stress following treatment with 11beta-dichloro and undergo apoptosis. Co-administration of the antioxidant vitamin E negated the therapeutic benefit of 11beta-dichloro in vivo, supporting the conclusion that oxidative stress is a key component of the mechanism of action. As a preclinical development primer, we also synthesized and tested an 11beta-dichloro derivative that cannot directly alkylate DNA, while retaining pro-oxidant features. This derivative nonetheless maintains excellent anti-cystic properties in vivo and emerges as the lead candidate for development.

XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in Pkd1 and Pkd2. They encode the polytopic integral membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are expressed on primary cilia. Formation of kidney cysts in ADPKD starts when a somatic second hit mechanism inactivates the wild-type Pkd allele. Approximately one quarter of families with ADPDK due to Pkd1 have germline nonsynonymous amino acid substitution (missense) mutations. A subset of these mutations is hypomorphic, retaining some residual PC1 function. Previous studies have shown that the highly conserved Ire1 α -XBP1 pathway of the unfolded protein response can modulate levels of functional PC1 in the presence of mutations in genes required for post-translational maturation of integral membrane proteins. We examine how activity of the endoplasmic reticulum chaperone-inducing transcription factor XBP1 affects ADPKD in a murine model with missense Pkd1 . METHODS: We engineered a Pkd1 REJ domain missense murine model, Pkd1 R2216W , on the basis of the orthologous human hypomorphic allele Pkd1 R2220W , and examined the effects of transgenic activation of XBP1 on ADPKD progression. RESULTS: Expression of active XBP1 in cultured cells bearing PC1 R2216W mutations increased levels and ciliary trafficking of PC1 R2216W . Mice homozygous for Pkd1 R2216W or heterozygous for Pkd1 R2216Win trans with a conditional Pkd1 fl allele exhibit severe ADPKD following inactivation in neonates or adults. Transgenic expression of spliced XBP1 in tubule segments destined to form cysts reduced cell proliferation and improved Pkd progression, according to structural and functional parameters. CONCLUSIONS: Modulating ER chaperone function through XBP1 activity improved Pkd in a murine model of PC1, suggesting therapeutic targeting of hypomorphic mutations.

Impact of Calcium Influx on Endoplasmic Reticulum in Excitotoxic Neurons: Role of Chemical Chaperone 4-PBA.

Excessive activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propoinic acid (AMPA) receptors instigates excitotoxicity via enhanced calcium influx in the neurons thus inciting deleterious consequences. Additionally, Endoplasmic Reticulum (ER) is pivotal in maintaining the intracellular calcium balance. Considering this, studying the aftermath of enhanced calcium uptake by neurons and its effect on ER environment can assist in delineating the pathophysiological events incurred by excitotoxicty. The current study was premeditated to decipher the role of ER pertaining to calcium homeostasis in AMPA-induced excitotoxicity. The findings showed, increased intracellular calcium levels (measured by flowcytometry and spectroflourimeter using Fura 2AM) in AMPA excitotoxic animals (male Sprague dawely rats) (intra-hippocampal injection of 10 mM AMPA). Further, ER resident proteins like calnexin, PDI and ERp72 were found to be upregulated, which further modulated the functioning of ER membrane calcium channels viz. IP3R, RyR, and SERCA pump. Altered calcium homeostasis further led to ER stress and deranged the protein folding capacity of ER post AMPA toxicity, which was ascertained by unfolded protein response (UPR) pathway markers such as IRE1α, eIF2α, and ATF6α. Chemical chaperone, 4-phenybutric acid (4-PBA), ameliorated the protein folding capacity and subsequent UPR markers. In addition, modulation of calcium channels and calcium regulating machinery of ER post 4-PBA administration restored the calcium homeostasis. Therefore the study reinforces the significance of ER stress, a debilitating outcome of impaired calcium homeostasis, under AMPA-induced excitotoxicity. Also, employing chaperone-based therapeutic approach to curb ER stress can restore the calcium imbalance in the neuropathological diseases.

AMPA induced cognitive impairment in rats: Establishing the role of endoplasmic reticulum stress inhibitor, 4-PBA.

Glutamate excitotoxicity and endoplasmic reticulum (ER) recently have been found to be instrumental in the pathogenesis of various neurodegenerative diseases. However, the paucity of literature deciphering the inter-linkage among glutamate receptors, behavioral alterations, and ER demands thorough exploration. Reckoning the aforesaid concerns, a prospective study was outlined to delineate the influence of ER stress inhibition via 4-phenylbutyric acid (PBA) on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) excitotoxicity-induced behavioral aspects and possible ER stress-glutamate linkage. Male SD rats were randomly divided into four groups namely sham (surgical control+vehicle, group 1), AMPA-induced excitotoxic group 2 receive a single intra-hippocampal injection of 10 mM AMPA, group 3 received AMPA along with PBA (i.p, 100 mg/kg body weight) for 15 days, and group 4 received PBA alone. Behavioral analyses were performed prior to the sacrifice of animals and hippocampus was extracted thereafter for further analysis. AMPA-induced excitotoxicity exhibited significant impairment of locomotion as well as cognitive functions. The levels of neurotransmitters such as dopamine, homo vanillic acid (HVA), norepinephrine, and serotonin were reduced accompanied by reduced expression of GLUR1 and GLUR4 (glutamate receptor) as well as loss of neurons in different layers of hippocampus. ER stress markers were upregulated upon AMPA excitotoxicity. However, chemical chaperone PBA supplementation remarkably mitigated the behavioral alterations along with expression of glutamate and ER stress intermediates/markers in AMPA excitotoxic animals. Therefore, the present exploration convincingly emphasizes the significance of ER stress and its inhibition via PBA in combating cognitive impairment as well as improving locomotion in excitotoxic animals.

Effect of endoplasmic reticulum stress inhibition on hyperoxaluria-induced oxidative stress: influence on cellular ROS sources.

PURPOSE: Hyperoxaluria-induced calcium oxalate crystallisation is associated with the generation of reactive oxygen species (ROS) via mitochondria and NADPH oxidase. Endoplasmic reticulum (ER) has emerged as an organelle which could influence mitochondrial functioning and ROS generation. Plugging an upstream pathway of mitochondrial and NADPH oxidase-induced ROS generation may have better prophylaxis. Therefore, we propose to investigate the linkage of hyperoxaluria-induced ROS generation with ER stress by inhibiting the later with 4-Phenylbutyric acid (4-PBA). METHODS: Male wistar rats were divided into three groups: a normal control group, an ethylene glycol with ammonium chloride-induced hyperoxaluric group (EA) and a third group which has hyperoxaluric animals given 4-PBA at a dose of 300 mg/kg. After 9 days of treatment, animals were sacrificed and renal tissues were analysed for histopathological examination, ROS, mitochondrial dysfunction, ER stress markers, inflammatory markers and NADPH oxidase subunits expression. RESULTS: Hyperoxaluric rats exhibited a significant increase in the levels of ROS, subsequently up-regulated levels of ER stress markers, inflammatory indicators, NADPH oxidase subunits and compromised mitochondrial functioning. However, ER stress amelioration appreciably curtailed the alterations caused by hyperoxaluric abuse. CONCLUSIONS: Therefore, suggesting the major role of ER in hyperoxaluric manifestations thereby providing an opportunity to target ER stress for future therapeutic interventions.

Implication of hyperoxaluria on osteopontin and ER stress mediated apoptosis in renal tissue of rats.

Hyperoxaluria is a stress that leads to calcium oxalate crystal deposition which further causes inflammation and renal cell necroptosis. Many studies have linked osteopontin expression with apoptosis and inflammation but so far its association with apoptosis with regard to hyperoxaluria is undiscovered. Moreover, a recent report has suggested that osteopontin induces endoplasmic reticulum stress and subsequently apoptosis in myocytes. In this study, the impact of hyperoxaluria on the modulation of osteopontin expression and endoplasmic reticulum (ER) stress mediated apoptosis in rats is explored. Hyperoxaluria was induced in rats by three different doses viz. ethylene glycol alone, ethylene glycol and ammonium chloride together and third group were fed with hydroxyl-l-proline. After hyperoxaluria induction rats were sacrificed and renal tissue was analysed for crystal depositions, osteopontin expression, inflammation, ER stress and subsequent unfolded protein response intermediates (UPR). Altered histoarchitecture of renal tissue and elevated levels of reactive oxygen species (ROS) along with the presence of calcium oxalate crystals were observed in the hyperoxaluric groups. As expected, inflammation and apoptosis was significantly high in all hyperoxaluria groups. Osteopontin expression showed significant up-regulation following hyperoxaluria. Further, a similar trend between expression of osteopontin and elevated ER stress level was observed. Moreover, UPR intermediates expression was also concurrent with osteopontin levels. It is observed that the extent of calcium oxalate crystal deposition is directly associated with the expression of osteopontin, inflammation and ER stress. The results advocate possible association of osteopontin with ER stress, thus suggesting that the ER could be a new target for developing therapeutic regimes for kidney stones.

Detection of Adulterants and Contaminants in Liquid Foods-A Review.

Milk and fruit juices have paramount importance in human diet. Increasing demand of these liquid foods has made them vulnerable to economic adulteration during processing and in supply chain. Adulterants are difficult to detect by consumers and thus necessitating the requirement of rapid, accurate and sensitive detection. The potential adulterants in milk and fruit juices and their limits set by different regulatory bodies have been briefly described in this review. Potential advantages and limitations of various techniques such as physicochemical methods, chromatography, immunoassays, molecular, electrical, spectroscopy with chemometrics, electronic nose, and biosensors have been described. Spectroscopy in combination with chemometrics has shown potential for rapid, precise, and sensitive detection of potential adulterants in these liquid foods.

Prediction of textural attributes using color values of banana (Musa sapientum) during ripening.

Banana is an important sub-tropical fruit in international trade. It undergoes significant textural and color transformations during ripening process, which in turn influence the eating quality of the fruit. In present study, color ('L', 'a' and 'b' value) and textural attributes of bananas (peel, fruit and pulp firmness; pulp toughness; stickiness) were studied simultaneously using Hunter Color Lab and Texture Analyser, respectively, during ripening period of 10 days at ambient atmosphere. There was significant effect of ripening period on all the considered textural characteristics and color properties of bananas except color value 'b'. In general, textural descriptors (peel, fruit and pulp firmness; and pulp toughness) decreased during ripening except stickiness, while color values viz 'a' and 'b' increased with ripening barring 'L' value. Among various textural attributes, peel toughness and pulp firmness showed highest correlation (r) with 'a' value of banana peel. In order to predict textural properties using color values of banana, five types of equations (linear/polynomial/exponential/logarithmic/power) were fitted. Among them, polynomial equation was found to be the best fit (highest coefficient of determination, R(2)) for prediction of texture using color properties for bananas. The pulp firmness, peel toughness and pulp toughness showed R(2) above 0.84 with indicating its potentiality of the fitted equations for prediction of textural profile of bananas non-destructively using 'a' value.

Influence of prismatic effect due to decentration of optical center in ophthalmic lens.

Background and Aims: Induced prismatic effects due to poor fitting spectacle frames is a common problem, seen in most of the spectacle wearers and this improper fitting is often due to optical center demarcation on lenses and this error causes asthenopic symptoms and diplopia. However, these errors are most common in developing countries due to lack of awareness, hence a standardized regulation is required. The current study aimed to estimate the amount of prismatic effect that is induced due to the decentration of an optical center in ophthalmic lens. Methods: A quantitative cross-sectional study was conducted in single vision spectacle wearers (N = 120) with a mean age of 25 ± 5 years. The pupillometric evaluation was performed to mark the pupil center on the spectacle lens. A lensometry evaluation was done to mark the optic center of the spectacle lens. A comparison was made to note whether the optic center is aligned with pupillary center. Objective assessment was performed through Prentice's rule (P = cF) and subjective symptoms were assessed through a validated visual comfort questionnaire. Results: In this sample, around 57% of the individual with single vision glasses were not looking through the optic center and experiencing induced prismatic effect of -0.7 to 0.6 prism diopter, with mean decentration of 3.5 mm. Forty percent of the individuals with misaligned optic center showed asthenopic symptoms and visual discomfort. Conclusion: Optometrist should check quality of dispensing and visual performance before handing over the newly dispensed glasses to the patients.

Impact of color vision deficiency on the quality of life in a sample of Indian population: Application of the CVD-QoL tool.

Purpose: To investigate the quality of life (QoL) in a sample of color vision deficit (CVD) patients in India and how color vision deficiency affects them psychologically, economically, and in productivity related to their work and occupation. Methods: A descriptive and case-control study design using a questionnaire was conducted on N = 120 participants, of whom 60 were patients of CVD (52 male and eight female) who visited two eye facilities in Hyderabad between 2020 and 2021 and 60 were age-matched normal color vision participants who served as controls. We validated English-Telugu adapted version of CVD-QoL, developed by Barry et al. in 2017 (CB-QoL). The CVD-QoL consists of 27 Likert-scale items with factors (lifestyle, emotions, and work). Color vision was assessed using the Ishihara and Cambridge Mollen color vision tests. A six-point Likert scale was used, with lower scores indicating poor QoL (from 1 = severe issue to 6 = no problem). Results: The CVD-QoL questionnaire's reliability and internal consistency were measured, including Cronbach's α (α =0.70-0.90). There was no significance between the group in age (t = -1.2, P = 0.67) whereas the Ishihara colour vision test, scores showed a significant difference (t = 4.50, P < 0.001). The QoL scores showed a significant difference towards lifestyle, emotions and work (P = 0.001). The CVD group had a poorer QoL score than the normal color vision group odds ratio [OR] =0.31, 95% confidence interval [CI], (P = 0.002, CI = 0.14-0.65, Z = 3.0) . In this analysis, a low CI indicated that the OR was more precise. Conclusion: Color vision deficiency affects Indians' QoL, according to this study. The mean scores of lifestyle, emotions, and work were lower than the UK sample.Since CVD is underreported and possibly affects developing countries more, advocacy for a new health care plan on CVD is essential. Increasing public understanding and awareness could also help diagnosing the CVD population.

Compatible and incompatible representations in visual sensory storage.

Sensory storage shows a short-lived part-report advantage that survives an aftercoming visual noise pattern (Smithson & Mollon, 2006). We tested whether such an advantage survives different types of high-contrast mask. The target was a 3 × 4 array of digits. The mask could be (a) a noise pattern, (b) an array of eights, or (c) an array of random digits. In a preliminary experiment, target and mask were interleaved (at 140 Hz) and target contrast was varied to determine the level at which performance fell to chance. In the main experiment, target and mask were separated by an inter-stimulus-interval (ISI) of 100, 150, or 200 ms. An auditory part-report cue that was presented 240 ms after target offset supported a part-report advantage at all ISIs for noise masks, at ISIs greater than 100 ms for digit-8 masks, but not at any ISI for random-number masks. Increasing cue delay, in the range 240 to 730 ms, produced a decline in the advantages we measured. The differences in part-report superiority with different types of mask call for revision of the model of visual sensory storage as a single canvas on which successive items are superposed. When mask and target are sufficiently different, a representation of low-contrast target digits can be maintained independently of the representation of an aftercoming, high-contrast mask. However, when the same target is followed by a mask composed of high-contrast random digits, an independent representation of the target does not remain available for access.

Optical biosensors for food quality and safety assurance-a review.

Food quality and safety is a scientific discipline describing handling, preparation and storage of food in ways that prevent food borne illness. Food serves as a growth medium for microorganisms that can be pathogenic or cause food spoilage. Therefore, it is imperative to have stringent laws and standards for the preparation, packaging and transportation of food. The conventional methods for detection of food contamination based on culturing, colony counting, chromatography and immunoassay are tedious and time consuming while biosensors have overcome some of these disadvantages. There is growing interest in biosensors due to high specificity, convenience and quick response. Optical biosensors show greater potential for the detection of pathogens, pesticide and drug residues, hygiene monitoring, heavy metals and other toxic substances in the food to check whether it is safe for consumption or not. This review focuses on optical biosensors, the recent developments in the associated instrumentation with emphasis on fiber optic and surface plasmon resonance (SPR) based biosensors for detecting a range of analytes in food samples, the major advantages and challenges associated with optical biosensors. It also briefly covers the different methods employed for the immobilization of bio-molecules used in developing biosensors.

4-PBA rescues hyperoxaluria induced nephrolithiasis by modulating urinary glycoproteins: Cross talk between endoplasmic reticulum, calcium homeostasis and mitochondria.

AIM: Urinary glycoproteins such as Tamm Horsfall Protein (THP) and Osteopontin (OPN) are well established key regulators of renal stone formation. Additionally, recent revelations have highlighted the influence of Endoplasmic Reticulum (ER) and mitochondria of crucial importance in nephrolithiasis. However, till date conclusive approach highlighting the influence of ER stress on urinary glycoproteins and chaperone in nephrolithiasis remains elusive. Therefore, the present study was focussed on deciphering the possible effect of 4-PBA mitigating ER stress on urinary glycoproteins and calnexin (chaperone) with emphasis on interlinking calcium homeostasis in hyperoxaluric rats. MATERIAL AND METHODS: Post 9 days of treatment, animals were sacrificed, and renal tissues were investigated for urinary glycoproteins, calnexin, calcium homeostasis, ER environment, redox status, and mitochondrial linkage. KEY FINDINGS: 4-PBA appreciably reversed the altered levels of THP, OPN, and calnexin observed along with curtailing the disrupted calcium homeostasis when assessed for SERCA activity and intra-cellular calcium levels. Additionally, significant improvement in the perturbed ER environment as verified by escalated ER stress markers, disturbed protein folding-aggregation-degradation (congo red assay) pathway, and redox status was found post 4-PBA intervention. Interestingly, linkage of ER stress and mitochondria was established under hyperoxaluric conditions when assessed for protein levels of VDAC1 and GRP75. SIGNIFICANCE: 4-PBA treatment resulted in rectifying the repercussions of ER-mitochondrial caused distress when assessed for protein folding/aggregation/degradation events along with disturbed calcium homeostasis. The present study advocates the necessity to adopt a holistic vision towards hyperoxaluria with emphasis on glycoproteins and ER environment.

Color vision devices for color vision deficiency patients: A systematic review and meta-analysis.

Background and Aims: There is insufficient evidence to support that using electronic or optical color vision devices improve color perception with current advanced technology. The purpose of this study is to compare and analyze the different color vision devices available for patients with color vision deficiency (CVD) and evaluate whether these devices improved their color perception. Methods: This review included randomized, experimental, comparative studies, as well as narrative reviews, prototype and innovation studies, and translational studies, followed by case-control and clinical trials with nonsurgical interventions studies, that is, electronic color vision devices, optical devices, and contact lens-based studies, with standardized inclusion and exclusion criteria. Results: The primary outcome studied was the performance of color vision devices, both objective and subjective. Secondary outcomes included the ease of use and accessibility of color vision devices and technology. The grading of recommendation, assessment, development, and evaluation framework was used to develop a systematic approach for consideration and clinical practice recommendation for CVD devices for color-deficient populations. We incorporated meta-analysis reports from a total of n = 16 studies that met the criteria which consisted of case-control studies, prototype and innovation studies, comparative studies, pre- and post-clinical trial studies, case studies, and narrative reviews. Proportion and standard errors, as well as correlations, were calculated from the meta-analysis for various available color vision devices. Conclusion: This review concludes that commercially available color vision devices, such as EnChroma Glasses, Chromagen filters, and EnChroma Cx-14 do not provide clinically significant evidence that subjective color perception has improved. As a result, recommending these color vision devices to the CVD population may not prove high beneficial/be counterproductive. However, only a few color shades can be perceived differently. This systematic review and analysis will aid future research and development in color vision devices.

Measurement techniques and application of electrical properties for nondestructive quality evaluation of foods-a review.

Non-destructive systems are recent trends for quality evaluation of fruits and vegetables. Information on post-harvest variations in electrical properties is needed to develop new instruments for this purpose. Electrical properties are finding increasing application in agriculture and food processing industries. Knowledge of dielectric properties of foods as a function of moisture content and temperature is essential in the design and control of drying systems. As simple, rapid and non-destructive measuring techniques, dielectric spectroscopy provides information about the dielectric response of materials to electromagnetic field. Electrical properties of agricultural materials have been of interest for many years. The interest in dielectric properties of materials has historically been associated with the design of electrical equipment. This review paper covers theoretical aspects of different electrical properties, their measurement techniques, applications of dielectric properties in agriculture/food processing sector and potential applications of thermal imaging (TI) for quality and safety assessment in food processing. The values of dielectric properties of a number of products including food grains, fruits and vegetables, and meat and meat products are presented in table form. This comprehensive coverage will be useful for academic, scientific and industrial community in treating and applying the facts in developing/testing new processes and products based on electromagnetic energy application.

Can Breathing Exercise or Pranayama Affect the Intraocular Pressure in the Short-term?

PURPOSE: To demonstrate any transient short-term effect of a particular type of breathing exercise (alternate nostril breathing of Nadi Shuddhi type of pranayama exercise) on the intraocular pressure (IOP) in glaucomatous as well as healthy eyes. METHODS: A prospective, nonrandomized, observational, cross-sectional study was conducted in a tertiary eyecare hospital setup recruiting 3 groups of subjects-glaucoma group and a normal group that underwent the breathing exercise as well as a normal group that did not. IOP was recorded at baseline, then at 4 minutes after 10 cycles of the breathing exercise and also after 10 minutes of rest-corresponding to IOPb, IOPc, and IOPr of all the study groups. Only those subjects were recruited who were above 18 and under 80 years and were naive to breathing exercise. RESULTS: A total of 56 normal eyes (28 subjects, Normalb) and 33 glaucomatous eyes (19 subjects) were recruited for the breathing exercise and were compared with the IOP as obtained for 26 eyes of 26 subjects that did not undergo the breathing exercise (Normalnb). IOPb did not differ between both normal groups (13.7±1.4 mm Hg in Normalb vs. 13.9±1.6 mm Hg in Normalnb, P=0.183) but was significantly different between groups (16.7±3.1 mm Hg in the glaucoma group and 13.7±1.4 in Normalb, P<0.001 and Normalnb 13.9±1.6 mm Hg, P<0.001) but analysis of variance was not significant within groups comparing IOPb, IOPc, and IOPr of all the study groups. CONCLUSION: There is no short-term transient effect of alternate nostril breathing exercise on IOP; a longitudinal study is recommended.

Amelioration of hyperoxaluria-induced kidney dysfunction by chemical chaperone 4-phenylbutyric acid.

Hyperoxaluria is characterized by an increased excretion of urinary oxalate which is caused by inherited disorders or high oxalate intake leading to renal stone ailment. Until date, reactive oxygen species and inflammation has been convicted for the progression of kidney stones for which antioxidant therapy has been employed. However, recent studies have linked the association of endoplasmic reticulum stress and oxidative imbalance in the progression of renal diseases. Considering oxidative stress being at forefront in causing hyperoxaluric consequences, current study was designed to correlate the impact of hyperoxaluria and regulation of oxidative imbalance via inhibition of endoplasmic reticulum stress by 4-phenylbutyric acid (4-PBA). Male wistar rats were subdivided into three groups, i.e., normal control (C), hyperoxaluric rats given ethylene glycol (EG), and hyperoxaluric rats treated with 4-PBA (EG + PBA). After 28 days of treatment, assessment of antioxidant defence system, inflammation, ER stress, and subsequent unfolded protein response was studied in renal tissue. It was found that the hyperoxaluric insult led to a marked damage to the renal tissue resulting in compromised antioxidant levels, upregulation of ER stress markers along with a steep surge in the extent of inflammation. However, 4-PBA treatment significantly curtailed the deleterious effects of hyperoxaluria by lowering down the level of stress markers as well as normalizing the antioxidant defence enzymes. Therefore, chemical chaperones can be deemed as a new class of drugs for the treatment of hyperoxaluric induced renal damage.

Exploring the Effect of Endoplasmic Reticulum Stress Inhibition by 4-Phenylbutyric Acid on AMPA-Induced Hippocampal Excitotoxicity in Rat Brain.

Excessive stimulation of ionotropic glutamate receptor is associated with glutamate-mediated excitotoxicity, thereby causing oxidative imbalance and mitochondrial dysfunction, resulting in the excitotoxic death of neurons. Eminent role of endoplasmic reticulum under glutamate-induced excitotoxicity has been highlighted in numerous literatures which have been observed to trigger endoplasmic reticulum stress (ER stress) as well as regulating oxidative stress. However, combating ER stress in excitotoxic neurons can provide a novel approach to alleviate the mitochondrial dysfunctioning and ROS generation. Therefore, we propose to investigate the cross-communication of α-amino-3-hydroxy-5-methyl-4-isoxzole-propionate (AMPA) excitotoxicity-induced oxidative injury with ER stress by employing ER stress inhibitor-4-phenlybutyric acid (4-PBA). Male SD rats were divided into four groups viz sham group (group 1), AMPA (10 mM)-induced excitotoxic group (group 2), curative group of AMPA-induced excitotoxic animals given 4-PBA at a dose of 100 mg/kg body weight (group 3), and alone 4-PBA treatment group (100 mg/kg body weight) (group 4). Animals were sacrificed after 15 days of treatment, and hippocampi were analyzed for histopathological examination, ROS, inflammatory markers, mitochondrial dysfunction, and ER stress markers. AMPA-induced excitotoxicity exhibited a significant increase in the levels of ROS, upregulated ER stress markers, inflammation markers, and compromised mitochondrial functioning in the hippocampus. However, 4-PBA administration significantly curtailed the AMPA-induced excitotoxic insult. This study suggests that targeting ER stress with a chemical chaperone can provide a better therapeutic intervention for neurological disorders involving excitotoxicity, and thus, it opens a new avenue to screen chemical chaperones for the therapeutic modalities.

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.

Probing visual consciousness: rivalry between eyes and images.

During binocular rivalry, one stimulus is visible (dominant), while the other stimulus is invisible (suppressed); after a few seconds, perception reverses. To determine whether these alternations involve competition between the eyes or between the images, we measured suppression depth to monocular probes. We did so in conventional rival stimuli and in rival stimuli swapping between the eyes at 1.5 Hz (both sorts of rivalry were shown either with or without 18-Hz flicker). The conventional conditions cause rivalry that could involve either competition between the eyes or between the images or both. The eye-swapping conditions cause rivalry that could involve competition between the images. Probes were either a small spot or a contrast increment to one of the rival stimuli. Using both yes-no and forced-choice procedures, we found that conventional conditions yielded large suppression depth and that eye-swapping conditions yielded small suppression depth. Weak suppression during image rivalry is consistent with conventional rivalry's involving competition between eyes and between images and flicker-and-swap rivalry's involving little, if any competition between eyes and mainly competition between images.