Synergistic action of organophosphates and COVID-19 on inflammation, oxidative stress, and renin-angiotensin system can amplify the risk of cardiovascular maladies.

Organophosphates (OPs) are ubiquitous environmental contaminants, widely used as pesticides in agricultural fields. In addition, they serve as flame-retardants, plasticizers, antifoaming or antiwear agents in lacquers, hydraulic fluids, and floor polishing agents. Therefore, world-wide and massive application of these compounds have increased the risk of unintentional exposure to non-targets including the human beings. OPs are neurotoxic agents as they inhibit the activity of acetylcholinesterase at synaptic cleft. Moreover, they can fuel cardiovascular issues in the form of myocardities, cardiac oedema, arrhythmia, systolic malfunction, infarction, and altered electrophysiology. Such pathological outcomes might increase the severity of cardiovascular diseases which are the leading cause of mortality in the developing world. Coronavirus disease-19 (COVID-19) is the ongoing global health emergency caused by SARS-CoV-2 infection. Similar to OPs, SARS-CoV-2 disrupts cytokine homeostasis, redox-balance, and angiotensin-II/AT1R axis to promote cardiovascular injuries. Therefore, during the current pandemic milieu, unintentional exposure to OPs through several environmental sources could escalate cardiac maladies in patients with COVID-19.

Mechanistic investigation of mixing and segregation of ordered mixtures: experiments and numerical simulations.

Pulmonary delivery of cohesive and micronized drugs through dry powder inhalers (DPIs) is traditionally achieved through the formation of ordered mixtures. In order to improve the mechanistic understanding of formation of ordered mixtures, the system consisting of micronized lactose (AZFL, representative of an active pharmaceutical ingredient) and a coarse particle carrier (LH100) is investigated as a function of different process and material variables in a high shear mixer (HSM) and in a low shear double cone (DCN) blender, using both experimental and numerical methods. Process insight is developed using a Discrete Element Method (DEM) based numerical model which could predict the formation of ordered mixtures in the two blenders and was verified against experimental determinations. Spatial and temporal evolution of granular flow are visualized and quantified in silico to reveal distinguishing features of both blenders to aid in rational selection of blenders and process parameters.

Monitoring the effects of a lepidopteran insecticide, Flubendiamide, on the biology of a non-target dipteran insect, Drosophila melanogaster.

Various organisms are adversely affected when subjected to chronic fluoride exposure. This highly electronegative ion present in several insecticide formulations is found to be lethal to target pests. In the present study, Drosophila melanogaster is treated with sub-lethal concentrations of a diamide insecticide formulation, Flubendiamide. Chronic exposure to the diamide (0.5-100 µg/mL) was found to be responsible for increase in fluoride ion concentration in larval as well as adult body fluid. Interestingly, 100 µg/mL Flubendiamide exposure resulted in 107 and 298% increase in fluoride ion concentration whereas only 23 and 52% of Flubendiamide concentration increase in larval and adult body fluid, respectively. Further, in this study, selected life cycle parameters like larval duration, pupal duration and emergence time showed minimal changes, whereas percentage of emergence and fecundity revealed significant treatment-associated variation. It can be noted that nearly 79% reduction in fecundity was observed with 100 µg/mL Flubendiamide exposure. The variations in these parameters indicate probable involvement of fluoride ion in detectable alterations in the biology of the non-target model insect, D. melanogaster. Furthermore, the outcomes of life cycle study suggest change in resource allocation pattern in the treated flies. The altered resource allocation might have been sufficient to resist changes in selective life cycle parameters, but it could not defend the changes in fecundity. The significant alterations indicate a definite trade-off pattern, where the treated individuals happen to compromise. Thus, survival is apparently taking an upper hand in comparison to reproductive ability in response to Flubendiamide exposure. Graphical abstract The figure demonstrates increase in Fluoride and Flubendiamide concentrations in Drosophila melanogaster after chronic sub-lethal exposure to Flubendiamide. Treatment-induced alterations in larval and pupal duration, reduction in fecundity and alteration in male-female ratio is also observed.

Understanding the cross-talk between mediators of infertility and COVID-19.

COVID-19 is the ongoing health emergency affecting individuals of all ages around the globe. Initially, the infection was reported to affect pulmonary structures. However, recent studies have delineated the impacts of COVID-19 on the reproductive system of both men and women. Hence, the present review aims to shed light on the distribution of SARS-CoV-2 entry factors in various reproductive organs. In addition, impacts of COVID-19 mediators like disrupted renin angiotensin system, oxidative stress, cytokine storm, fever, and the mental stress on reproductive physiology have also been discussed. For the present study, various keywords were used to search literature on PubMed, ScienceDirect, and Google Scholar databases. Articles were screened for relevancy and were studied in detail for qualitative synthesis of the review. Through our literature review, we found a multitude of effects of COVID-19 mediators on reproductive systems. Studies reported expression of receptors like ACE-2, TMPRSS2, and CD147 in the testes, epididymis, prostrate, seminal vesicles, and ovarian follicles. These proteins are known to serve as major SARS-CoV-2 entry factors. The expression of lysosomal cathepsins (CTSB/CTSL) and/ neuropilin-1 (NRP-1) are also evident in the testes, epididymis, seminal vesicles, fallopian tube, cervix, and endometrium. The binding of viral spike protein with ACE-2 was found to alter the renin-angiotensin cascade, which could invite additional infertility problems. Furthermore, COVID-19 mediated cytokine storm, oxidative stress, and elevated body temperature could be detrimental to gametogenesis, steroidogenesis, and reproductive cycles in patients. Finally, social isolation, confinement, and job insecurities have fueled mental stress and frustration that might promote glucocorticoid-mediated subnormal sperm quality in men and higher risk of miscarriage in women. Hence, the influence of COVID-19 on the alteration of reproductive health and fertility is quite apparent.

Immunotoxic role of organophosphates: An unseen risk escalating SARS-CoV-2 pathogenicity.

Consistent gathering of immunotoxic substances on earth is a serious global issue affecting people under pathogenic stress. Organophosphates are among such hazardous compounds that are ubiquitous in nature. They fuel oxidative stress to impair antiviral immune response in living entities. Aside, organophosphates promote cytokine burst and pyroptosis in broncho-alveolar chambers leading to severe respiratory ailments. At present, we witness COVID-19 outbreak caused by SARS-CoV-2. Infection triggers cytokine storm coupled with inflammatory manifestations and pulmonary disorders in patients. Since organophosphate-exposure promotes necroinflammation and respiratory troubles hence during current pandemic situation, additional exposure to such chemicals can exacerbate inflammatory outcome and pulmonary maladies in patients, or pre-exposure to organophosphates might turn-out to be a risk factor for compromised immunity. Fortunately, antioxidants alleviate organophosphate-induced immunosuppression and hence under co-exposure circumstances, dietary intake of antioxidants would be beneficial to boost immunity against SARS-CoV-2 infection.

In silico study reveals binding potential of rotenone at multiple sites of pulmonary surfactant proteins: A matter of concern.

Rotenone is a broad-spectrum pesticide employed in various agricultural practices all over the world. Human beings are exposed to this chemical through oral, nasal, and dermal routes. Inhalation of rotenone exposes bio-molecular components of lungs to this chemical. Biophysical activity of lungs is precisely regulated by pulmonary surfactant to facilitate gaseous exchange. Surfactant proteins (SPs) are the fundamental components of pulmonary surfactant. SPs like SP-A and SP-D have antimicrobial activities providing a crucial first line of defense against infections in lungs whereas SP-B and SP-C are mainly involved in respiratory cycle and reduction of surface tension at air-water interface. In this study, molecular docking analysis using AutoDock Vina has been conducted to investigate binding potential of rotenone with the four SPs. Results indicate that, rotenone can bind with carbohydrate recognition domain (CRD) of SP-A, N-, and C- terminal peptide of SP-B, SP-C, and CRD of SP-D at multiples sites via several interaction mediators such as H bonds, C-H bonds, alkyl bonds, pi-pi stacked, Van der Waals interaction, and other. Such interactions of rotenone with SPs can disrupt biophysical and anti-microbial functions of SPs in lungs that may invite respiratory ailments and pathogenic infections.

DEM modeling of high shear wet granulation of a simple system.

High shear wet granulation (HSWG) is one of the most poorly understood processes with known difficulties in optimization and scale up. The purpose of the current study is to develop a DEM model which can be applied under dynamic process conditions with high predictive capacity to improve process insight. The DEM model is used to predict agglomeration as a function of impeller speed and liquid addition rate in a high shear wet granulator. The DEM model tracks dynamic formation and breakage of liquid bridges between particles as liquid binder in the system is added, and corrects for the change in material properties as a function of the binder content.

Flubendiamide affects visual and locomotory activities of Drosophila melanogaster for three successive generations (P, F1 and F2).

Flubendiamide is widely used in agricultural fields to exterminate a broad spectrum of pests (lepidopteran insects) by disrupting their muscle function. The main objective of this study was to find the effects of flubendiamide on a non-target organism, Drosophila melanogaster (dipteran insect). In the present study, different sub-lethal concentrations of Flubendiamide caused a significant (P < 0.05) decrease in acetylcholinesterase activity and increase in cytochrome P450 activity in adult D. melanogaster. Phototaxis and climbing behaviours were found to significantly (P < 0.05) alter in exposed flies. The observed alteration in phototaxis and climbing behaviours were not restricted to P generation, but were found to be transmitted to subsequent generations (F1 and F2 generation) that had never been directly exposed to the test chemical during their life time. It is only their predecessors (P generation) who have been affronted with different concentrations of Flubendiamide. Humans and Drosophilids share almost 60% genomic similarity and 75% disease gene resemblance. Moreover, most of the circuits governing the behaviours studied involve the inhibition and excitation of neurotransmitters, which are conserved in humans and flies. Thus, the present findings suggest that chronic flubendiamide exposure might induce alteration in neurotransmission leading to discrepancy in the behavioural responses (vision and flight) in other beneficial insects and insect-dependent organisms.

Flubendiamide induces transgenerational compound eye alterations in Drosophila melanogaster.

Pesticides are one of the major sources of environmental toxicity and contamination. This study reports potential of lepidopteran insecticide formulation, named Flubendiamide, in altering compound eye architecture and bristle pattern orientation for four consecutive generations (P, F1, F2 and F3) in a non-target diptera, Drosophila melanogaster Meigen (Diptera: Drosophilidae). The concentrations of the insecticide formulation selected for treatment of Drosophila (50 and 100 µg/mL) were in accordance with practiced Indian field doses (50 µg/mL for rice and 100 µg/mL for cotton). This study showed trans-generational insecticide-induced changes in the morphology of the compound eyes of the non-target insect D. melanogaster.

On the role of forces governing particulate interactions in pharmaceutical systems: A review.

Process understanding for designing, optimizing and scaling of pharmaceutical unit operations is fundamentally important to address concerns of high risks, monumental costs, and productivity decline in the pharmaceutical industry. This is especially important in the rapidly changing landscape of the pharmaceutical industry. Pharmaceutical processes majorly deal with multiphase, multicomponent flows, basics of which are discussed in terms of fundamental contact and non-contact forces. Also, basics of multiphase flow regimes, powder flow, and pertinent process modeling techniques relevant to pharmaceutical unit operations are discussed. The most fundamental contact and non-contact forces are then reviewed in detail on their molecular or physical origin, factors which influence these forces, numerical formalisms and modeling strategies to simulate flows and processes of pharmaceutical interest.

Investigation of multiphase multicomponent aerosol flow dictating pMDI-spacer interactions.

The use of Pressurized metered dose inhalers (pMDIs) for the treatment of asthma and other chronic obstructive pulmonary diseases is frequently associated with breath-actuation synchronization problems and poor pulmonary delivery, particularly amongst the pediatric and geriatric population groups. Spacers, or Valved Holding Chambers (VHCs), are frequently used to address these problems. However, the performance of spacers with different pMDIs is also highly variable and needs to be investigated. The purpose of the current study is to develop a computational fluid dynamics (CFD) model which can characterize multiphase multicomponent aerosol flow issuing from a commercial suspension-based pMDI into a spacer. The CFD model was initially calibrated against published experimental measurements in order to appropriately model the spray characteristics. This model was subsequently used to examine several combinations of inhaler, spacer and USP Throat geometries under different discharge rates of coflow air. The CFD model predictions compared favorably with experimental measurements. In particular, the predictions show, in accordance with experimental determinations, a decrease of drug retained by the spacers with increasing coflow air. The recirculation observed near the obstructions in axial path of the spray within either spacer is considered to be central for increasing spray retention and drug deposition behavior. Fluid flow patterns within the spacers were correlated with drug deposition behavior through a dimensionless variable, the Recirculation index (RCI). Bigger particles were found to be selectively retained within the spacer.

Development of a Rational Design Space for Optimizing Mixing Conditions for Formation of Adhesive Mixtures for Dry-Powder Inhaler Formulations.

The purpose of the present study was to develop guidance toward rational choice of blenders and processing conditions to make robust and high performing adhesive mixtures for dry-powder inhalers and to develop quantitative experimental approaches for optimizing the process. Mixing behavior of carrier (LH100) and AstraZeneca fine lactose in high-shear and low-shear double cone blenders was systematically investigated. Process variables impacting the mixing performance were evaluated for both blenders. The performance of the blenders with respect to the mixing time, press-on forces, static charging, and abrasion of carrier fines was monitored, and for some of the parameters, distinct differences could be detected. A comparison table is presented, which can be used as a guidance to enable rational choice of blender and process parameters based on the user requirements. Segregation of adhesive mixtures during hopper discharge was also investigated.

Trans-generational transmission of altered phenotype resulting from flubendiamide-induced changes in apoptosis in larval imaginal discs of Drosophila melanogaster.

The eye and wing morphology of Drosophila melanogaster maintain unique, stable pattern of genesis from larval eye and wing imaginal discs. Increased apoptosis in cells of eye and wing discs was found to be associated with flubendiamide (fluoride containing insecticide) exposure (at the range 0.25-10µg/mL) in D. melanogaster larvae. The chemical fed larvae on attaining adulthood revealed alterations in morphology and symmetry of their compound eyes and wings through scanning electron microscopy. Nearly 40% and 30% of flies (P generation) demonstrated alterations in eyes and wings respectively. Transmission electron microscopic study (at the range 1-20µg/mL) also established variation in the rhabdomere and pigment cell orientation as well as in the shape of the ommatidium. Subsequent SEM study with F1 and F2 generation flies also revealed structural variation in eye and wing. Decrease in percentage of altered eye and wing phenotype was noted in subsequent generations (P> F1>F2). Thus, the diamide insecticide, flubendiamide, expected to be environmentally safe at sub-lethal concentrations was found to increase apoptosis in larvae and thereby cause morphological alteration in the adult D. melanogaster. This study further demonstrated trans-generational transmission of altered phenotype in three subsequent generations of a non-target insect model, D. melanogaster.

A combined experimental and numerical approach to explore tribocharging of pharmaceutical excipients in a hopper chute assembly.

Electrostatic charging via contact electrification or tribocharging refers to the process of charge transfer between two solid surfaces when they are brought into contact with each other and separated. Charging of continuous particulate flows on solid surfaces is poorly understood and has often been empirical. This study aims toward understanding the tribocharging of pharmaceutical excipients using a simplified geometry of unidirectional flow in a hopper-chute assembly. Assuming electron transfer to be the dominant mechanism of electrification, a triboelectric series was generated using work functions estimated from quantum chemical calculations. A 3D-DEM model has been developed employing charge transfer and electrostatic forces. Using numerical simulations, the charge accumulation for an assemblage of particles during flow was determined under different conditions. To theoretically analyze the process of charging, parametric studies affecting powder flow have been investigated. A higher specific charge was observed at larger friction coefficients and lower restitution coefficients. The results obtained from the simulation model reinforce the collisional nature of triboelectrification. The simulation results revealed similar trends to experimental observations. However, to enable a priori prediction the model needs to be tested for additional materials or extended to other process operations.