Subjective biosafety assessment of bisdemethoxycurcumin from the rhizomes of Curcuma longa.

Introduction/Background: Curcuma longa, a plant native to the Indian subcontinent has a variety of biological activities. Curcumin is the most abundant and biologically active compound with many therapeutic properties. Demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) - the two other bioactive components present in Curcuma longa, besides curcumin, are collectively termed curcuminoids. Apart from the well-known curcumin, BDMC also has been reported to possess promising biological and pharmacological effects, but very little scientific evidence on its safety assessment has been published.Objective: The present study was undertaken to determine the safety of pure BDMC from Curcuma longa extract in rodents which comprises of general toxicity (both four weeks and three months duration), reproductive/developmental toxicity and genotoxicity studies.Methods: The Good Laboratory Practice studies were carried out in accordance with the test guidelines established by the Organization for Economic Cooperation and Development.Results: No treatment-related adverse findings were seen in general toxicity testing and a no observed adverse effect level (NOAEL) of 1000 mg/kg/day was established after four weeks (sub-acute) and three-months (sub-chronic) dosing. Evaluation of fertility, embryo-fetal, and post-natal reproductive and developmental parameters also showed no adverse findings with a NOAEL of 1000 mg/kg/day established. The results of genotoxicity as evaluated by in vitro reverse mutation assay, and in vivo micronucleus test in mice indicate that BDMC did not induce any genotoxic effects.Conclusion: Oral administration of BDMC is safe in rodents and non-mutagenic, with no adverse effects under experimental conditions.

Nanocosmetics and Skin Health: A Comprehensive Review of Nanomaterials in Cosmetic Formulations.

The development of nanocosmetics nanotechnology has ushered in a new age in cosmetic research, completely changing the skincare scene. This abstract investigates the relationship between skincare and nanotechnology, particularly emphasizing the effects of nanocosmetics on skin health. Cosmetics, known as "nanocosmetics," use materials at the nanoscale, typically between 1 and 100 nanometers, to improve the effectiveness and delivery of active chemicals. Nanotechnology in cosmetics allows for the development of sophisticated delivery methods that provide enhanced stability and tailored distribution, including nanoemulsions and nanocapsules. This breakthrough overcomes the constraints of conventional formulations by enabling the entry of active ingredients into the skin's deeper layers. Studies investigating nanocosmetics and skin health were included. This encompassed in vitro studies, animal models, and clinical studies of various designs. Exclusion criteria included studies focusing solely on nanotechnology unrelated to skin health or nanocosmetics and review articles editorials, commentaries, and conference abstracts. Nanocosmetics is a groundbreaking development in skincare that provides creative answers to a range of skin issues. As the area develops, realizing the full potential of nanotechnology in fostering ideal skin health will need sustained research and adherence to safety regulations.

Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans.

G protein-coupled receptors (GPCRs) mediate responses to various extracellular and intracellular cues. However, the large number of GPCR genes and their substantial functional redundancy make it challenging to systematically dissect GPCR functions in vivo. Here, we employ a CRISPR/Cas9-based approach, disrupting 1654 GPCR-encoding genes in 284 strains and mutating 152 neuropeptide-encoding genes in 38 strains in C. elegans. These two mutant libraries enable effective deorphanization of chemoreceptors, and characterization of receptors for neuropeptides in various cellular processes. Mutating a set of closely related GPCRs in a single strain permits the assignment of functions to GPCRs with functional redundancy. Our analyses identify a neuropeptide that interacts with three receptors in hypoxia-evoked locomotory responses, unveil a collection of regulators in pathogen-induced immune responses, and define receptors for the volatile food-related odorants. These results establish our GPCR and neuropeptide mutant libraries as valuable resources for the C. elegans community to expedite studies of GPCR signaling in multiple contexts.

Assessment of Safety Profile of Activated Curcumin C3 Complex (AC3®), Enriched Extract of Bisdemethoxycurcumin from the Rhizomes of Curcuma longa.

The present work was carried out to investigate the toxic effects of Activated Curcumin C3 Complex (AC3®) through the methods of acute, subacute, subchronic, reproductive/developmental toxicity, and genotoxicity when administered orally in experimental rodents. The studies were carried out in line with OECD principles of good laboratory practice. A single-dose acute oral toxicity study was conducted on female Wistar rats that produced no toxic effects after 14 days (the observation period) of treatment. Subacute, subchronic, and reproductive/developmental studies were conducted in Wistar rats, divided equally into vehicle control, 125, 250, and 500 mg/kg dose groups along with recovery groups for vehicle control and high dose. In all the studies, there were no abnormal clinical signs/behavioral changes, reproductive and developmental parameters, or gross and histopathological changes. Likewise, no alteration was found in the body weight, hematology, and other biochemical parameters. Also, it did not show mutagenicity in the in vitro AMES test or clastogenicity and aneugenicity in the in vivo micronucleus test, indicating that AC3® did not induce any genotoxic effects. This revealed that oral administration of AC3® is safe in rodents, nonmutagenic, and had no observed adverse effects under experimental conditions.

Histo-pathological patterns in hysterectomy specimens at a tertiary care centre in India.

It is of interest to document histo-pathological patterns in hysterectomy specimens at tertiary care centre in India. This study included 442 cases. In this study, leiomyoma (9.17 %) was the most common preoperatively clinical diagnosis made in hysterectomy specimen. In this study, uterine fibroid showed a 90.47% correlation between pre-operative and histological findings. There was a 50 % correlation noted between adenomyosis and endocervical polyp.

Let me give you something to think about: Does needing to remember something new make it easier to forget something old?

In an item-method directed forgetting task, memory instructions presumably operate by promoting further rehearsal of to-be-remembered (TBR) items and limiting encoding of to-be-forgotten (TBF) items. We asked whether diverting attentional resources away from TBF items and towards a new item that needed to be committed to memory would improve forgetting. To this end, study words in our experiments were presented singly followed by a remember instruction (single-TBR), by a forget instruction (single-TBF), or else were replaced by a new word to be remembered (replace-TBR) in place of the original study word which could be forgotten (replace-TBF). A typical directed forgetting effect was observed across single and replace trials. However, there was no compelling evidence that forgetting was better for replace-TBF compared to single-TBF words, suggesting that, by itself, the explicit redirection of attentional and other processing resources away from forget items may not be sufficient to improve item-method directed forgetting.

Association of air pollution and coronavirus disease 2019 (COVID-19) in India.

The COVID-19 pandemic has affected the world, leading to significant morbidity and mortality. Various meteorological parameters are considered essential for the viability and transmission of the virus. Multiple reports from various parts of the world suggest a correlation between the disease spread and air pollution severity. This study was carried out to identify the relationship between meteorological parameters, air pollution, and COVID-19 in New Delhi, one of the worst-affected states in India. We studied air pollution and meteorological parameters in New Delhi, India. We obtained data about COVID-19 occurrence, meteorological parameters, and air pollution indicators from various sources from Apr 1, 2020, till Nov 12, 2020. We performed correlational analysis and employed autoregressive distributed lag models (ARDLM) for identifying the relationship between COVID-19 cases with air pollution and meteorological parameters. We found a significant impact of PM 2.5, PM 10, and meteorological parameters on COVID-19. There was a significant positive correlation between daily COVID-19 cases and COVID-19-related deaths with PM2.5 and PM10 levels. Increasing temperature and windspeed were associated with a reduction in the number of cases while increasing humidity was associated with increased cases. This study demonstrated a significant association of PM2.5 and PM10 with daily COVID-19 cases and COVID-19-related mortality. This knowledge will likely help us prepare well for the future and implement air pollution control measures for other airborne disease epidemics.

Evaluation of clinical efficacy and laboratory indicators of non-cultured epidermal cell suspension and hair follicle cell suspension in surgical management of stable vitiligo: A randomized comparative trial.

BACKGROUND: Non-cultured epidermal cell suspension (ECS) and hair follicle cell suspension (HFCS) are well-established methods of surgical treatment of stable vitiligo. AIMS: The aim of the present study was to compare the laboratory indicators and clinical efficacy of ECS and HFCS in the treatment of stable vitiligo. METHODS: This was a single centre, open-labeled randomized trial. Vitiligo patches from 74 patients were randomized to receive either ECS or HFCS. Both cell suspensions were analyzed for total cell count, cell viability and melanocyte count. Percentage re-pigmentation was assessed at regular intervals for 36 weeks. RESULTS: The percentage re-pigmentation with ECS was significantly higher than HFCS at week 4 (p = .01) and week 16 (p = .03) however, no difference was observed at weeks 24 (p = .38) and 36 (p = .05). Forty-seven patients completed the study follow-up duration and excellent re-pigmentation (>90%) was achieved in 61.7% and 53.2% and complete re-pigmentation (100%) was observed in 6.4% and 12.8% of participants using ECS and HFCS, respectively. Significantly higher cell yield (p < .01) and percentage of HMB45+ melanocytes (p = .01) were obtained using ECS. No difference was noted in the percentage of viable cells or S100 + melanocytes. CONCLUSION: The median cell yield was eight times higher in ECS than in HFCS with a significantly higher percentage of HMB45+ melanocytes in the former group. The median percentage of re-pigmentation in both groups was 90% at the end of 36 weeks. ECS provides faster re-pigmentation; however, both ECS and HFCS have comparable safety and efficacy over a longer duration of follow-up.

Context-dependent reversal of odorant preference is driven by inversion of the response in a single sensory neuron type.

The valence and salience of individual odorants are modulated by an animal's innate preferences, learned associations, and internal state, as well as by the context of odorant presentation. The mechanisms underlying context-dependent flexibility in odor valence are not fully understood. Here, we show that the behavioral response of Caenorhabditis elegans to bacterially produced medium-chain alcohols switches from attraction to avoidance when presented in the background of a subset of additional attractive chemicals. This context-dependent reversal of odorant preference is driven by cell-autonomous inversion of the response to these alcohols in the single AWC olfactory neuron pair. We find that while medium-chain alcohols inhibit the AWC olfactory neurons to drive attraction, these alcohols instead activate AWC to promote avoidance when presented in the background of a second AWC-sensed odorant. We show that these opposing responses are driven via engagement of distinct odorant-directed signal transduction pathways within AWC. Our results indicate that context-dependent recruitment of alternative intracellular signaling pathways within a single sensory neuron type conveys opposite hedonic valences, thereby providing a robust mechanism for odorant encoding and discrimination at the periphery.

A persistent behavioral state enables sustained predation of humans by mosquitoes.

Predatory animals pursue prey in a noisy sensory landscape, deciding when to continue or abandon their chase. The mosquito Aedes aegypti is a micropredator that first detects humans at a distance through sensory cues such as carbon dioxide. As a mosquito nears its target, it senses more proximal cues such as body heat that guide it to a meal of blood. How long the search for blood continues after initial detection of a human is not known. Here, we show that a 5 s optogenetic pulse of fictive carbon dioxide induced a persistent behavioral state in female mosquitoes that lasted for more than 10 min. This state is highly specific to females searching for a blood meal and was not induced in recently blood-fed females or in males, who do not feed on blood. In males that lack the gene fruitless, which controls persistent social behaviors in other insects, fictive carbon dioxide induced a long-lasting behavior response resembling the predatory state of females. Finally, we show that the persistent state triggered by detection of fictive carbon dioxide enabled females to engorge on a blood meal mimic offered up to 14 min after the initial 5 s stimulus. Our results demonstrate that a persistent internal state allows female mosquitoes to integrate multiple human sensory cues over long timescales, an ability that is key to their success as an apex micropredator of humans.

The Anti-Obesity Potential of Cyperus rotundus Extract Containing Piceatannol, Scirpusin A and Scirpusin B from Rhizomes: Preclinical and Clinical Evaluations.

PURPOSE: Obesity is a complex medical problem that increases the risk of other diseases like diabetes, cardiovascular diseases, and fatty liver disease. The present study evaluated the efficacy and safety of Cyperus rotundus rhizome extract (CRE), standardized to contain Piceatannol, Scirpusin A, and Scirpusin B (5% total Stilbenoids) in overweight individuals. The mechanism of activity was evaluated in a diet-induced mice model of obesity and adipocytes in vitro. MATERIALS AND METHODS: The efficacy, safety, and tolerability of CRE were evaluated in 30 obese individuals with a BMI of 30 to 40 kg/m2 for 90 days in a randomized, double-blind, parallel-group, placebo-controlled study. In vitro studies were carried out in differentiated 3T3 L1 adipocytes, and the therapeutic efficacy was evaluated in high-fat diet-induced obese mice. RESULTS: The pilot clinical study showed a reduction in body weight with a significant decrease in waist circumference and BMI. The serum lipid profile showed a significant improvement in CRE-treated individuals. The extract was well tolerated, and no adverse effects were reported at the end of the study. CRE showed a dose-dependent adipogenesis reduction in vitro with an IC50 value of 9.39 µg/mL, while oral administration of CRE reduced weight gain in diet-induced obese mice. The efficacy in mice was associated with reduced levels of leptin, corticosteroids, and serum lipid levels, with no adverse effects. CONCLUSION: CRE has anti-adipogenic properties, is safe for human consumption, and effectively manages weight and hypercholesterolemia in overweight individuals.

Experiments in modeling recent Indian fertility pattern.

Modelling is a well-established concept for understanding the typical shape and pattern of age-specific fertility. The distribution of India's age-specific fertility rate (ASFR) is unimodal and positively skewed and is distinct from the ASFR of the developed countries. The existing models (P-K model, Gompertz model, Skew-normal model and G-P model considered here) that were developed, based on the experiences of the developed countries, failed to fit the single-year age-specific fertility pattern for India as a whole and for the six selected states. Our study has proposed four flexible models, to capture the diverse age pattern of fertility, observed in the Indian states. The proposed models were compared in three ways; among themselves, with the original models and with the popular Hadwiger model. The parameters of these proposed models were estimated through the Non-Linear Least Squares Method. To find the model with best fit, we used the corrected version of Akaike's Information Criterion (AICc). Optimization of the four original models was successfully done. When the model was fitted to the empirical data of the 4th round of the National Family Health Survey conducted in 2015-2016, the results of this study showed that all the four proposed models outperform their corresponding original models and the Hadwiger model. When comparison among the proposed models was done, the Modified Gompertz Model provided the best fit for India, Uttar Pradesh and Gujarat. Whereas, the Modified P-K model gave the best fit for West Bengal, Tripura and Karnataka. The Modified G-P model is the most suitable model for Punjab. Although our proposed models illustrated the fitting of ASFR for India as a whole and the selected six states only, it provides an important tool for the policymakers and the government authorities to project fertility rates and to understand the fertility transitions in India and various other states.

The levels and trends of contraceptive use before first birth in India (2015-16): a cross-sectional analysis.

BACKGROUND: Indian women are more prone to first birth at a relatively younger age after marriage. Also, we do not have sufficient literature available that focuses on contraceptive use before first birth. The analysis of the present study was done using data from the fourth round of National Family Health Survey (2015-16), India. The objectives of the present study were to measure the levels and trends of contraceptive use before first birth among Indian ever married women, aged 15-34 years. METHODS: The study includes 279,896 ever married women aged 15-34 years at the time of the NFHS-4 survey. To identify the socio-demographic determinants governing the pioneering study behavior, multivariable techniques have been used in the analysis. The statistical significance of the relationship between socio-demographic factors and contraceptive use prior to first birth was tested using a chi-squared test for association. Hosmer Lemeshow statistics and Nagelkerke R square have been used to check how well the logistic regression model fits the data. Map of India showing different zonal classification is made using the ArcGIS software version 10.3. RESULT: The trends of contraceptive usage show a decline in use before first birth and the various socio-demographic factors affecting the use of contraceptive before first birth are religion, caste, education, wealth index, media exposure, age at marriage and the zonal classifications. CONCLUSION: The noticeable result in this study is the comparative decline in contraceptive use by women in India before first birth in NFHS-4 with respect to previous NFHS done in India. The likelihood of using contraception before first birth is significantly affected by factors like place of residence, religion, caste, current age of women, age at marriage, education level of women, wealth index, media exposure and zonal classification.

Subchronic and Reproductive/Developmental Toxicity Studies of Tetrahydrocurcumin in Rats.

Tetrahydrocurcumin (THC) is a major metabolite of curcumin, which is obtained from Curcuma longa. THC has various benefits and overcomes the bioavailability issue of curcumin. To establish it as a pharmacologically active molecule, its safety profile has to be determined. Thus, the present study aimed to determine the preclinical safety profile of THC in a 90-day subchronic and reproductive/developmental toxicity study in Wistar rats. THC at oral doses of 100, 200, and 400 mg/kg was administered daily for 90 days. Rats in the recovery group were kept for 14 days after treatment termination. The animals were observed for treatment-related morbidity, mortality, and changes in clinical signs, clinical pathology, and histopathology. In the reproductive/developmental toxicity study, THC at 100, 200, and 400 mg/kg was administered orally to rats and the reproductive/developmental parameters in adult male and female rats and pups were observed. THC at up to 400 mg/kg/day of did not have any significant effect on all parameters in male and female rats in both toxicity studies. Thus, 400 mg/kg/day can be considered as the no-observed-adverse-effect-level of THC in rats.

Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies.

PURPOSE: Preclinical studies suggest SYK and JAK contribute to tumor-intrinsic and microenvironment-derived survival signals. The pharmacodynamics of cerdulatinib, a dual SYK/JAK inhibitor, and associations with tumor response were investigated. PATIENTS AND METHODS: In a phase I dose-escalation study in adults with relapsed/refractory B-cell malignancies, cerdulatinib was administered orally to sequential dose-escalation cohorts using once-daily or twice-daily schedules. The study enrolled 8 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 13 with follicular lymphoma, 16 with diffuse large B-cell lymphoma (DLBCL), and 6 with mantle cell lymphoma. Correlation of tumor response with pharmacodynamic markers was determined in patients with meaningful clinical responses. RESULTS: Following cerdulatinib administration, complete SYK and JAK pathway inhibition was achieved in whole blood of patients at tolerated exposures. Target inhibition correlated with serum cerdulatinib concentration, and IC50 values against B-cell antigen receptor (BCR), IL2, IL4, and IL6 signaling pathways were 0.27 to 1.11 µmol/L, depending on the phosphorylation event. Significant correlations were observed between SYK and JAK pathway inhibition and tumor response. Serum inflammation markers were reduced by cerdulatinib, and several significantly correlated with tumor response. Diminished expression of CD69 and CD86 (B-cell activation markers), CD5 (negative regulator of BCR signaling), and enhanced expression of CXCR4 were observed in 2 patients with CLL, consistent with BCR and IL4 suppression and loss of proliferative capacity. CONCLUSIONS: Cerdulatinib potently and selectively inhibited SYK/JAK signaling at tolerated exposures in patients with relapsed/refractory B-cell malignancies. The extent of target inhibition in whole-blood assays and suppression of inflammation correlated with tumor response. (ClinicalTrials.gov ID:NCT01994382).

Comparison of reversal activity and mechanism of action of UHRA, andexanet, and PER977 on heparin and oral FXa inhibitors.

Anticoagulants such as unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and direct oral anticoagulants (DOACs) targeting thrombin (IIa) or factor Xa (FXa) are widely used in prevention and treatment of thromboembolic disorders. However, anticoagulant-associated bleeding is a concern that demands monitoring and neutralization. Protamine, the UFH antidote, has limitations, while there is no antidote available for certain direct FXa inhibitors. Improved antidotes in development include UHRA (Universal Heparin Reversal Agent) for all heparin anticoagulants; andexanet alfa (andexanet), a recombinant antidote for both direct FXa inhibitors and LMWHs; and ciraparantag (PER977), a small-molecule antidote for UFH, LMWHs, and certain DOACs. The binding affinities of these antidotes for their presumed anticoagulant targets have not been compared. Here, isothermal titration calorimetry (ITC) was used to determine the affinity of each antidote for its putative targets. Clotting and chromogenic FXa assays were used to characterize neutralization activity, and electron microscopy was used to visualize the effect of each antidote on clot morphology in the absence or presence of anticoagulant. ITC confirmed binding of UHRA to all heparins, and binding of andexanet to edoxaban and rivaroxaban, and to the antithrombin-enoxaparin complex. PER977 was found to bind heparins weakly, but not the direct FXa inhibitors studied. For UHRA and andexanet, an affinity at or below the micromolar level was found to correlate with neutralization activity, while no reversal activity was observed for the PER977/anticoagulant systems. Standard metrics of clot structure were found to correlate weakly with PER977's activity. This is the first study comparing 3 antidotes in development, with each exerting activity through a distinct mechanism.

Safety profile of 40% Garcinol from Garcinia indica in experimental rodents.

The present study was taken up to evaluate the single dose acute toxicity, 28 days and 90 days repeated dose toxicity and reproductive/developmental toxicity of standardized 40% Garcinol in experimental rodents. The studies were conducted in compliance with OECD principles of good laboratory practice, guidelines for testing of chemicals no.420, 407, 408 and 421 respectively. Single dose acute oral toxicity was conducted on female Wistar rats as sighting study step-I (300 mg/kg) & sighting study step-II (2000 mg/kg) and main study (2000 mg/kg). Sub-acute, sub-chronic and reproductive/developmental studies were conducted in Wistar rats divided equally in vehicle control, 20, 50 and 100 mg/kg dose group along with recovery groups for vehicle control and high dose. Reproductive/developmental study was carried out for minimum of 28 days and in females during pregnancy and 4 days post partum. There were no abnormal clinical signs/behavioural changes, reproductive and developmental parameters, gross and histopathological changes as well as no alteration in the body weight, body temperature, haematology and other biochemical parameters in all the four studies. 40% Garcinol has a low toxicity profile in rodents and had no observed effects under experimental conditions used.

Multifunctional neuroprotective effect of Withanone, a compound from Withania somnifera roots in alleviating cognitive dysfunction.

Alzheimer's disease (AD) is a chronic disorder that slowly worsens and impairs the person's memory, learning, reasoning, judgment, communication and familiar tasks with loss of orientation. AD is characterized clinically by cognitive deficit and pathologically by the deposition of ß amyloid plaques, neurofibrillary tangles, associated with degeneration of the cholinergic forebrain. Withanone (WS-2), a compound isolated from root extract of Withania somnifera at doses administered orally/day to wistar rats for duration of 21 days showed significant improvement in the cognitive skill by inhibiting amyloid ß-42 and attenuated the elevated levels of pro-inflammatory cytokines like TNF alpha, IL-1 beta, IL-6, MCP-1, Nitric oxide, lipid peroxidation and both ß- and γ- secretase enzymatic activity. Administration of WS-2 also significantly reversed the decline in acetyl choline and Glutathione (GSH) activity. None of the treatments that are available today alter the underlying causes of this terminal disease. Few preliminary clinical treatments have demonstrated that some plant medicines do ameliorate and improve memory and learning in patients with mild-to-moderate AD. WS-2 showed promise in AD treatment because of cognitive benefits and more importantly, mechanisms of action with respect to the fundamental pathophysiology of the disease, not limited to the inhibition of AChE, but also include the modification of Aß processing, protection against oxidative stress and anti-inflammatory effects.