Evaluation of the immune responses in buffaloes vaccinated with a live-attenuated lumpy skin disease vaccine (Lumpi-ProVacInd).

Since 2019, Lumpy skin disease (LSD) has suddenly spread in many Asian countries, including India. LSD primarily occurs in cattle. However, recent LSD outbreaks in India have also revealed significant morbidity and production losses in buffaloes. This has raised concerns about the role of buffaloes in the epidemiology and transmission of LSD and necessitates the inclusion of buffaloes in the mass vaccination program for the prevention and control of the disease in the country. However, there is no significant data on the immune response in buffaloes following vaccination with the LSD vaccine. In this study, we evaluated antibody- and cell-mediated immune responses following vaccination with a newly developed live-attenuated LSD vaccine (Lumpi-ProVacInd). The detectable amount of anti-LSDV antibodies was observed at 1-2 months following vaccination, with a peak antibody titer at 3 months. Upon stimulation of the peripheral blood mononuclear cells (PBMCs) with the UV-inactivated LSDV antigen, there was a significant increase in CD8 + T cell counts in vaccinated animals as compared to the unvaccinated animals. Besides, vaccinated animals also showed a significant increase in IFN-γ levels upon antigenic stimulation of their PBMCs with LSDV antigen. In conclusion, the buffaloes also mount a potent antibody- and cell-mediated immune response following vaccination with Lumpi-ProVacInd.

Non-canonical NF-κB signaling limits the tolerogenic ß-catenin-Raldh2 axis in gut dendritic cells to exacerbate intestinal pathologies.

Dendritic cell (DC) dysfunction is known to exacerbate intestinal pathologies, but the mechanisms compromising DC-mediated immune regulation in this context remain unclear. Here, we show that intestinal dendritic cells from a mouse model of experimental colitis exhibit significant levels of noncanonical NF-κB signaling, which activates the RelB:p52 heterodimer. Genetic inactivation of this pathway in DCs alleviates intestinal pathologies in mice suffering from colitis. Deficiency of RelB:p52 diminishes transcription of Axin1, a critical component of the ß-catenin destruction complex, reinforcing ß-catenin-dependent expression of Raldh2, which imparts tolerogenic DC attributes by promoting retinoic acid synthesis. DC-specific impairment of noncanonical NF-κB signaling leads to increased colonic numbers of Tregs and IgA+ B cells, which promote luminal IgA production and foster eubiosis. Experimentally introduced ß-catenin haploinsufficiency in DCs with deficient noncanonical NF-κB signaling moderates Raldh2 activity, reinstating colitogenic sensitivity in mice. Finally, inflammatory bowel-disease patients also display a deleterious noncanonical NF-κB signaling signature in intestinal DCs. In sum, we establish how noncanonical NF-κB signaling in dendritic cells can subvert retinoic acid synthesis to fuel intestinal inflammation.

A safe, cost-effective, and high-throughput SARS-CoV-2 antigen capture ELISA suitable for large-scale screening in low-resource settings.

Diagnostics employing multiple modalities have been essential for controlling and managing COVID-19, caused by SARS-CoV-2. However, scaling up Reverse Transcription-Quantitative Polymerase Chain Reaction (RT-qPCR), the gold standard for SARS-CoV-2 detection, remains challenging in low and middle-income countries. Cost-effective and high-throughput alternatives like enzyme-linked immunosorbent assay (ELISA) could address this issue. We developed an in-house SARS-CoV-2 nucleocapsid capture ELISA, and validated on 271 nasopharyngeal swab samples from humans (n = 252), bovines (n = 10), and dogs (n = 9). This ELISA has a detection limit of 195 pg/100 µL of nucleocapsid protein and does not cross-react with related coronaviruses, ensuring high specificity to SARS-CoV-2. Diagnostic performance was evaluated using receiver operating characteristic curve analysis, showing a diagnostic sensitivity of 67.78 % and specificity of 100 %. Sensitivity improved to 74.32 % when excluding positive clinical samples with RT-qPCR Ct values > 25. Furthermore, inter-rater reliability analysis demonstrated substantial agreement (κ values = 0.73-0.80) with the VIRALDTECT II Multiplex RT-qPCR kit and perfect agreement with the CoVeasy™ COVID-19 rapid antigen self-test (κ values = 0.89-0.93). Our findings demonstrated that the in-house nucleocapsid capture ELISA is suitable for SARS-CoV-2 testing in humans and animals, meeting the necessary sensitivity and specificity thresholds for cost-effective, large-scale screening.

Optimizing forage harvest and the nutritive value of Italian ryegrass-based mixed forage cropping under northwestern Himalayan conditions.

The scarcity of high-quality forage has a significant influence on the productivity and profitability of livestock. Addressing this concern, an investigation was undertaken to assess the effects of distinct Italian ryegrass genotypes, namely, Punjab ryegrass-1, Kashmir collection, and Makhan grass, in conjunction with varying seeding ratios of Italian ryegrass to Egyptian clover. The seeding ratios considered were 100:0 (Italian ryegrass to Egyptian clover), 75:25, 50:50, and 25:75. All possible combinations of Italian ryegrass and Egyptian clover with seeding ratios were set up in a randomized complete block design and replicated thrice. Co-cultivating Italian ryegrass and Egyptian clover at a 75:25 seeding ratio yields the best yield benefit, as determined by the land equivalent ratio. It is noteworthy that in this configuration, real yield loss is higher for Egyptian clover and for Italian ryegrass when the seeding ratio is 25:75. The higher competitiveness of Italian ryegrass in comparison to Egyptian clover is highlighted by the competitive ratio. Notably, the nutritive parameter, crude protein yield, was significantly higher in the Makhan grass-based 50:50 and 75:25 seeding ratio. Results of the study ascertained the compatibility of grass-legume co-cultivation with significantly higher quantity and quality forage harvested under mixed cropping systems whereas Makhan grass as the superior and dominant genotype in comparison to Kashmir collection. The outcomes of this study revealed that the 100:0 seeding ratio, coupled with the Makhan grass genotype, exhibited superior performance in terms of cumulative forage harvest, dry matter accumulation, net returns, and benefit-cost ratio.

Annulative coupling of α-substituted acrylic acids and sulfoxonium ylides: easy access to bioactive γ-butyrolactones.

We present a straightforward, catalyst- and additive-free method for synthesizing keto γ-butyrolactones using readily available ß-keto sulfoxonium ylides and acrylic acids. This robust approach demonstrates exceptional compatibility with various functional groups on ß-keto sulfoxonium ylides and α-substituted acrylic acids, resulting in good to high yields of the anticipated products. Moreover, the practicality of this approach was validated through large-scale reactions and the successful conversion of some synthesized derivatives into bioactive natural products, including L-factor, muricatacin, and cytosporanone A.

Backstepping based intelligent control of tractor-trailer mobile manipulators with wheel slip consideration.

In this research, a new hybrid backstepping control strategy based on a neural network is proposed for tractor-trailer mobile manipulators in the presence of unknown wheel slippage and disturbances. To minimize the negative impacts of wheel slippage, the desired velocities of the tractor's wheels are computed with a proposed kinematic control model with an adaptive term. As the system's dynamical model contains unavoidable uncertainties, model-based backstepping control technique is unable to effectively manage these systems. Hence, the proposed controller blends a radial basis function neural network with the merits of a dynamical model-based backstepping approach. The neural networks are employed to approximate the non-linear unknown smooth function. To minimize the impact of external disturbances, and network reconstruction error an adaptive term is added to the control law. The Lyapunov theorem and Barbalat's lemma are employed to guarantee the stability of the control method. The tracking error is shown to be bounded and to rapidly converge to zero with the proposed method. To demonstrate the efficacy and validity of the control mechanism, comparison simulation results are presented.

Microplastics - A Growing Concern as Carcinogens in Cancer Etiology: Emphasis on Biochemical and Molecular Mechanisms.

In today's world, the widespread presence of microplastics is undeniable, with concentrations found in various environments, including up to 1000 particles per liter in seawater and up to 10 particles per cubic meter in the atmosphere. Originating from diverse sources, both intentional and unintentional, these minuscule fragments, measuring less than 5 mm, pose significant threats to environmental and human health. Recent research has uncovered a concerning link between microplastics and cancer, prompting urgent investigation. Studies demonstrate microplastics can infiltrate cells, disrupt biological processes, and potentially foster carcinogenic environments. From inducing DNA damage and oxidative stress to triggering inflammatory responses and dysregulating cellular pathways, microplastics exhibit a multifaceted capability in contributing to cancer development. Furthermore, microplastics act as carriers for a range of contaminants, compounding their impact on human health. Their accumulation within tissues and organs raises concerns for short and long-term health consequences, including chronic diseases, reproductive issues, and developmental abnormalities. This review explores the biochemical and molecular mechanisms underlying the interaction between microplastics and cellular systems, providing insights into routes of exposure and health effects, with a focus on lung, skin, and digestive system cancers. As we confront this pressing environmental and public health challenge, a deeper understanding of the microplastic-cancer relationship is crucial to safeguarding the well-being of present and future generations.

p38-MAPK is prerequisite for the synthesis of SARS-CoV-2 protein.

The inhibition of p38 mitogen-activated protein kinase (p38-MAPK) by small molecule chemical inhibitors was previously shown to impair severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, however, mechanisms underlying antiviral activity remains unexplored. In this study, reduced growth of SARS-CoV-2 in p38-α knockout Vero cells, together with enhanced viral yield in cells transfected with construct expressing p38α, suggested that p38-MAPK is essential for the propagation of SARS-CoV-2. The SARS-CoV-2 was also shown to induce phosphorylation (activation) of p38, at time when transcription/translational activities are considered to be at the peak levels. Further, we demonstrated that p38 supports viral RNA/protein synthesis without affecting viral attachment, entry, and budding in the target cells. In conclusion, we provide mechanistic insights on the regulation of SARS-CoV-2 replication by p38 MAPK.

Therapeutic potential of extracellular vesicles derived from human amniotic epithelial cells for perinatal cerebral and pulmonary injury.

Lung and brain injury that occurs during the perinatal period leads to lifelong disability and is often driven and/or exacerbated by inflammation. Human amniotic epithelial cells (hAEC), which demonstrate immunomodulatory, anti-fibrotic, and regenerative capabilities, are being explored as a therapeutic candidate for perinatal injury. However, limitations regarding scalable manufacturing, storage, transport, and dose-related toxicity have impeded clinical translation. Isolated therapeutic extracellular vesicles (EVs) from stem and stem-like cells are thought to be key paracrine mediators of therapeutic efficacy. The unique characteristics of EVs suggest that they potentially circumvent the limitations of traditional cell-based therapies. However, given the novelty of EVs as a therapeutic, recommendations around ideal methods of production, isolation, storage, and delivery have not yet been created by regulatory agencies. In this concise review, we discuss the pertinence and limitations of cell-based therapeutics in perinatal medicine. We also review the preclinical evidence supporting the use of therapeutic EVs for perinatal therapy. Further, we summarize the arising considerations regarding adequate cell source, biodistribution, isolation and storage methods, and regulatory roadblocks for the development of therapeutic EVs.

The Utilisation of Mushroom Leftovers, Oats, and Lactose-Free Milk Powder for the Development of Geriatric Formulation.

This study aims to focus on developing a food supplement for the geriatric population using disposal mushrooms, oats, and lactose-free milk powder. Lactose intolerance is most common in older adults, raising the demand for lactose-free foods. One of the major global challenges currently faced by humankind is food waste (FW). Most of the food that is produced for human consumption has not been utilized completely (1/3rd-1/2 unutilized), resulting in agricultural food waste. Mushrooms are highly valuable in terms of their nutritional value and medicinal properties; however, a significant percentage of mushroom leftovers are produced during mushroom production that do not meet retailers' standards (deformation of caps/stalks) and are left unattended. Oats are rich in dietary fibre beta-glucan (55% water soluble; 45% water insoluble). Lactose-free milk powder, oats, and dried mushroom leftover powder were blended in different ratios. It was observed that increasing the amount of mushroom leftover powder increases the protein content while diluting calories. The product with 15% mushroom powder and 30% oat powder showed the highest sensory scores and the lowest microbial count. The GCMS and FTIR analyses confirmed the presence of ergosterol and other functional groups. The results of the XRD analysis showed that the product with 15% mushroom powder and 30% oat powder had a less crystalline structure than the product with 5% mushroom powder and 40% oat powder and the product with 10% mushroom powder and 35% oat powder, resulting in more solubility. The ICP-OES analysis showed significant concentrations of calcium, potassium, magnesium, sodium, and zinc. The coliform count was nil for the products, and the bacterial count was below the limited range (3 × 102 cfu/g). The product with 15% mushroom powder and 30% oat powder showed the best results, so this developed product is recommended for older adults.

Evaluation of Immune Exhaustion and Co-Inhibitory Receptor Expression in Mycobacterium avium Subspecies paratuberculosis (MAP) Seropositive Diarrhoeic Bovines.

Mycobacterium avium subspecies paratuberculosis (MAP) infection leads to chronic, persistent granulomatous enteritis, causing prolonged diarrhoea and emaciation. The disease is managed using medications such as antibiotics, live vaccines, mycobacteriophage therapies and other treatments; however, a notable proportion of affected animals do not show improvement with this approach. We hypothesise that immunoinhibitory receptors TIM-3 (T cell immunoglobulin mucin protein-3) and PD-1 (Programmed death receptor 1) may be upregulated on Peripheral blood mononuclear cells (PBMCs) of MAP-seropositive bovines, potentially contributing to immune exhaustion. Samples (blood and faeces) were collected from 32 diarrhoeic bovines suspected of MAP infection; eight apparently healthy buffaloes from the dairy farm at Hisar, Haryana and from 14 cows (suffering from chronic diarrhoea, weakness and emaciation) housed in stray cattle shed. MAP infection was estimated using indigenous ELISA (i-ELISA), faecal IS900 PCR, culture and acid-fast staining. TIM-3 and PD-1 gene expression on PBMCs were determined using qRT-PCR. TIM3 expression was relatively higher (~400-fold, 330-fold, 112-fold, 65-fold and 16-fold) in 5 chronically diarrhoeic PBMCs samples (MAP-seropositive), and higher PD-1 expression (around ~7-fold, 1.75-fold, 2.5-fold, 7.6-fold) was recorded in 4 diarrhoeic MAP-seropositive animals, compared to apparently healthy and other MAP-seronegative diarrhoeic animals. High co-expression of TIM-3 and PD-1 levels was also recorded in chronically diarrhoeic, emaciated stray cattle. Understanding immune responses in field conditions might aid in the therapeutic management of paratuberculosis.

A review on the diversity of antimicrobial peptides and genome mining strategies for their prediction.

Antibiotic resistance has become one of the most serious threats to human health in recent years. In response to the increasing microbial resistance to the antibiotics currently available, it is imperative to develop new antibiotics or explore new approaches to combat antibiotic resistance. Antimicrobial peptides (AMPs) have shown considerable promise in this regard, as the microbes develop low or no resistance against them. The discovery and development of AMPs still confront numerous obstacles such as finding a target, developing assays, and identifying hits and leads, which are time-consuming processes, making it difficult to reach the market. However, with the advent of genome mining, new antibiotics could be discovered efficiently using tools such as BAGEL, antiSMASH, RODEO, etc., providing hope for better treatment of diseases in the future. Computational methods used in genome mining automatically detect and annotate biosynthetic gene clusters in genomic data, making it a useful tool in natural product discovery. This review aims to shed light on the history, diversity, and mechanisms of action of AMPs and the data on new AMPs identified by traditional as well as genome mining strategies. It further substantiates the various phases of clinical trials for some AMPs, as well as an overview of genome mining databases and tools built expressly for AMP discovery. In light of the recent advancements, it is evident that targeted genome mining stands as a beacon of hope, offering immense potential to expedite the discovery of novel antimicrobials.

Utility of Itraconazole in Combination with Liposomal Amphotericin B in Rhizopus oryzae Associated Mucormycosis-An Exploratory Study.

BACKGROUND: During the COVID-19 pandemic-associated mucor epidemic, acute antifungal drug shortage necessitated the exploration of other antifungals based on culture sensitivity. Itraconazole is a cheap, safe, and effective antifungal in sensitive cases. METHODOLOGY: We enrolled itraconazole-sensitive COVID-19-associated mucormycosis during the mucormycosis pandemic. After the intensive phase course of liposomal amphotericin B, Itraconazole was offered in susceptible cases during the maintenance phase along with standard of care. These patients were clinically and radiologically followed for 6 months. RESULTS: We enrolled 14 patients (Male: Female-11:3) of Rhino-orbito-cerebral mucormycosis (ROCM) which included 12 diabetics. All patients had facial swelling, orbital swelling, visual impairment, and headache. MRI showed involvement of bilateral sinus (10/14), orbital extension (13/14), cavernous sinus (5/14), cerebral part of the internal carotid artery (3/14), and brain infarcts (4/14). All 14 patients showed sensitivity to Itraconazole with 12 having minimum inhibitory concentration (MIC) ≤ 1 µg/ml and 2 having MIC ≤ 2 µg/ml. Follow-up at 6 months showed clinical improvement in the majority (11/14) and radiological improvement in six out of seven scanned patients. CONCLUSION: Our study shows the potential therapeutic role of oral Itraconazole in ROCM.

Methionine as a regulator of bone remodeling with fasting.

Caloric restriction improves metabolic health but is often complicated by bone loss. We studied bone parameters in humans during a 10-day fast and identified candidate metabolic regulators of bone turnover. Pro-collagen 1 intact N-terminal pro-peptide (P1NP), a bone formation marker, decreased within 3 days of fasting. Whereas dual-energy x-ray absorptiometry measures of bone mineral density were unchanged after 10 days of fasting, high-resolution peripheral quantitative CT demonstrated remodeling of bone microarchitecture. Pathway analysis of longitudinal metabolomics data identified one-carbon metabolism as fasting dependent. In cultured osteoblasts, we tested the functional significance of one-carbon metabolites modulated by fasting, finding that methionine - which surged after 3 days of fasting - affected markers of osteoblast cell state in a concentration-dependent manner, in some instances exhibiting a U-shaped response with both low and high concentrations driving putative antibone responses. Administration of methionine to mice for 5 days recapitulated some fasting effects on bone, including a reduction in serum P1NP. In conclusion, a 10-day fast in humans led to remodeling of bone microarchitecture, potentially mediated by a surge in circulating methionine. These data support an emerging model that points to a window of optimal methionine exposure for bone health.

Dietary intake and glutamine-serine metabolism control pathologic vascular stiffness.

Perivascular collagen deposition by activated fibroblasts promotes vascular stiffening and drives cardiovascular diseases such as pulmonary hypertension (PH). Whether and how vascular fibroblasts rewire their metabolism to sustain collagen biosynthesis remains unknown. Here, we found that inflammation, hypoxia, and mechanical stress converge on activating the transcriptional coactivators YAP and TAZ (WWTR1) in pulmonary arterial adventitial fibroblasts (PAAFs). Consequently, YAP and TAZ drive glutamine and serine catabolism to sustain proline and glycine anabolism and promote collagen biosynthesis. Pharmacologic or dietary intervention on proline and glycine anabolic demand decreases vascular stiffening and improves cardiovascular function in PH rodent models. By identifying the limiting metabolic pathways for vascular collagen biosynthesis, our findings provide guidance for incorporating metabolic and dietary interventions for treating cardiopulmonary vascular disease.

Alarming Incidence of Gastric Outlet Obstruction Related to NSAIDS and Synthetic Opioid in North West India.

BACKGROUND: In recent years, there has been an alarming increase in cases of gastric outlet obstruction (GOO) at our center due to drug abuse. So, we conducted this study to know the incidence of nonsteroidal anti-inflammatory drugs (NSAIDs) and synthetic opioid abuse in cases of GOO. METHODS: This was an observational study involving consecutive cases of GOO diagnosed from September 2017 to February 2019. A detailed history, including drug addiction history and clinical examination, was done. Investigations included routine biochemical and hematological tests, upper gastrointestinal endoscopy (UGIE), ultrasonography, rapid urease test (RUT), and histopathology of the diseased area. RESULTS: Among the 102 cases diagnosed with GOO, 62 (60.78%) cases had a history of drug addiction. The drug addiction history was as follows: NSAIDs and opioids in 56, opioids alone in four, and NSAIDs alone in two cases. The most common site of stricture was the second part of the duodenum. The features on histopathology were ulcerations of the mucosa infiltrated by eosinophils, plasma cells, and lymphocytes. CONCLUSION: There is an alarming increase in the incidence of GOO due to NSAIDs and opioid abuse at our center. Efforts should be made to control the indiscriminate use of these over-the-counter drugs to prevent dreaded complications.

In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model.

Alzheimer's disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer's disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid ß aggregation. Three potent compounds, i.e., VN-3, VN-14, and VN-19 were identified that displayed remarkable activities against different targets. These compounds displayed IC50 values of 80 nM, 2.52 µM, and 140 nM against the AChE enzyme, respectively, and IC50 values of 2.07 µM, 70 nM, and 450 nM against the MAO-B isoform, respectively. VN-3 displayed potent activity against self-induced Aß1-42 aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 µM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 µM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound VN-19 exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aß1-42 enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. VN-19 was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, VN-3, VN-14, and VN-19 were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.

Effect of naringin on sodium fluoride­induced neurobehavioral deficits in Wistar rats.

There is a lack of treatment for the detrimental effects of fluorosis. Sodium fluoride at a concentration of 10 ppm induces stress, depression and memory impairment in adult Wistar rats. Naringin, a flavanone glycoside isolated from citrus fruits such as lemons and oranges, possesses anti-inflammatory, antioxidant and neuroprotective properties; therefore, it was used for treatment of fluoride induced toxicity in the present study. Adult Wistar rats were divided into eight groups (n=8). The normal control (NOR) group was provided with normal tap water. The sodium fluoride (FLU)10 group received water containing 10 ppm sodium fluoride for 60 days. The treatment groups (FLU10NAR100 and FLU10NAR50) received drinking water with 10 ppm sodium fluoride ad libitum along with Naringin 100 and 50 mg/kg body weight (bw) per oral gavage, respectively. The NAR100 and NAR50 groups received Naringin 100 and 50 mg/kg bw. The PRONAR100 and PRONAR50 groups received Naringin 100 and 50 mg/kg bw for the first 15 days and then subsequently received FLU10 ppm for 60 days (total of 75 days). All animals were subjected to behavioural tests consisting of the open field test (OFT), forced swim test (FST) and novel object recognition test (NORT). After euthanasia, the hippocampus and prefrontal cortex were stained with Cresyl violet. To measure the oxidative stress caused by fluoride and its effect on antioxidant levels, estimation of reduced glutathione (GSH) by Ellman's method, lipid peroxidation (LPO) measured in terms of the MDA:thiobarbituric acid reaction and catalase was performed. To evaluate the effect of fluoride on activity of acetylcholine, estimation of acetylcholinesterase (AChE) by Ellman's method was performed. In NORT and FST, significant changes (P<0.05) were present in the FLU10NAR100 and FLU10NAR50 groups compared with the FLU10 group, showing recovery from memory deficit and depression. The OFT results were insignificant. The LPO was reduced in all the other groups except the FLU10 group, with statistically significant changes. Catalase activity was significantly lower in FLU10 as compared with the NAR100, NAR50, PRONAR100 and PRONAR50 groups. GSH and AChE activities did not show significant changes as compared with the FLU10 group. The CA3 and prefrontal cortex viable and degenerated neuron count in the FLU10 group were insignificant compared with all other groups, except for the NAR100 and NAR50 groups. Thus, Naringin can be a useful drug to avoid the neurological effects of fluoride.