eChapters

Pathology of nutritional deficiency diseases are described in chapter etiology of this book. However, specific deficiency of nutrition that leads to development of clinical signs and lesions in poultry are summarized as under (Fig.2.1 & Fig.2.2):

Vitamin Deficiency

1. Hypovitaminosis A

• Vitamin A is considered infection resisting vitamin because it facilitates the proper development of bursa, immunity and epithelium on mucosal and skin surfaces.

• Deficiency of vitamin A leads to swollen glands in oesophagus i.e. nutritional roup.

• Avian Inflammation

Inflammation is a process which begins following a sublethal injury to tissue and ends with complete healing or death. It is characterized by five cardinal signs. Cardinal signs of inflammation are:

• Redness

• Heat

• Swelling

• Pain

• Loss of function

• Inflammation is beneficial in most of cases expect

• In prolonged or unending process

• In inflammation of immunological origin i.e. hypersensitivity and autoimmunity.

• It provides basic foundation of pathogenesis and pathology.

• It is now said that immunity is the resistance of body, while inflammation is the process by which the immune mechanism are implemented.

• The basis of inflammation remains same be it mammal or birds. For details, one can refer the chapter inflammation and heading in book “Illustrated Veterinary Pathology”. However, there are some differences in reaction in birds which are briefly listed below:

The global herbal industry faces significant challenges due to varying regulatory frameworks, quality control standards, and traditional practices. This talk aims to bridge the gap by promoting “Herbal Harmony”- a unified approach to standardizing herbal products worldwide. Experts from diverse f ields will converge to discuss: Harmonization of regulatory frameworks, standardization of quality control and assurance, validation of traditional knowledge, innovative technologies for herbal analysis and global market trends and opportunities by fostering collaboration and knowledge sharing, “Herbal Harmony” seeks to: enhance consumer safety and confidence, promote sustainable herbal trade practices, support evidence-based herbal medicine and to facilitate international collaboration and trade.

Spermatozoa, the male reproductive cells, play a crucial role in fertilization and subsequent embryonic development. However, toxic substances such as heavy metals(lead) can disrupt spermatozoa function through various mechanisms, including oxidative stress, DNA damage, and disruption of cellular homeostasis. The toxic effects can impair sperm motility, viability, and acrosomal integrity, ultimately leading to reduced fertility. Livestock are not immune to these toxic insults, which can compromise their reproductive efficiency and agricultural productivity. Lead (Pb) is a toxic pollutant and is extensively distributed in the environmental and biological systems. This topic envisages the detrimental effects of lead on spermatozoa functions, shedding light on the underlying mechanisms, signal transduction pathways, and sperm kinematic alterations.

Vultures are obligate and highly efficient scavengers. They are keystone species providing important ecosystem services, but their adaptations to save energy, gorge themselves up to one third their body weight at a time, survive easily without food for up to a fortnight, conserve energy by using soaring and gliding flight, are just some of the unique and important characteristics of these magnificent birds. A highly efficient digestive system helps in extracting nutrients from otherwise non-nutrient sources like hide, tendons, and even bones. Vultures have been instrumental in keeping India clean and safe from disease outbreaks. A bird which is unaffected by multiple disease-causing micro-organisms helps to rid the environment from disease pandemics and epidemics. However, since the mid 1990ss these robust birds with a life span of 40-60 years, have declined drastically, from tens of millions to a few thousand currently, a decline of around 99%. For the formerly most abundant of these vultures, the white-rumped vulture, declines already happened by 99.9% in just 15 years! These declines led to multiple problems including increases in feral dog populations, economic and social losses and most importantly, 5,00,000 human deathsin five years,as a direct cause of the decline of vultures. The main cause of the vulture declines has been scientifically proven to be due to the use of veterinary diclofenac in cattle, their major source offood. Although veterinary diclofenac was banned since 2006, the drug has remained in the cattle carcasses at lower levels and new vulture toxic drugs have been discovered.

Role of Leptin in Uterine Function

Leptin is a 16 kDa protein consisting of 167 amino acids, encoded by the LEP gene located on chromosome 7q31.3. Structurally, leptin comprises four anti parallel alpha helices (A, B, C, and D), two long loops (AB and CD), and a short loop (BC). It has three binding sites: site I is in the C-terminal region of helix D, site II spans the surface of helices A and C, and site III is located near the N-terminal region of helix D. Its structural similarity to proinflammatory cytokines such as interleukin-6 and granulocyte colony-stimulating factor suggests its potential immune-modulatory roles.

Leptin’s effects on uterine contractions have been studied at length. In human uterine smooth muscle, leptin inhibits both spontaneous and oxytocin-induced contractions. Moynihan et al. (2008) reported that leptin caused a 46% reduction in spontaneous and a 42% reduction in oxytocin-induced contractions. A lesser degree of relaxation (36%) was noted in a larger study involving non-laboring human uterine tissue, while rat uterine tissue exhibited a 24% relaxation (Mumtaz et al., 2015). The concentrations used in these studies ranged from 1 nM to 1 µM, which includes the physiological range in pregnant women with normal body mass index (BMI). Leptin levels rise with increasing BMI during pregnancy (Hendler et al., 2005).

Use of veterinary drugs in prevention, control and treatment is becoming inevitable with the intensification of livestock production system. Food animals given veterinary drugs contain residues of parent compounds and/ or their metabolites may remain in edible products for a period of time after treatment. In such scenario if withdrawal period of the drug is not observed, then there is every chance for that residue to become a part of the human diet. Subsequently, people consuming such veterinary drug residue-containing foods may suffer from different adverse health effects like increasing incidence of AMR, in addition to hypersensitivity and allergic reactions in some sensitive individuals. On the other hand, some veterinary drugs like nitrofurans and its metabolites (SEM, AHD, AOZ & AMOZ) represents major concern in food due to their carcinogenic nature and their use in food animals have been banned in most countries. Responsible and prudent use of veterinary drugs in food animals is must to promote animal health and to ensure food safety. On that front, veterinarians who is holding the prescription decision, indeed play a crucial role in the mission for attainment of judicious use of veterinary drugs in food producing animals and complying the regulatory requirement to produce safe animal sourced foods.

Introduction

Research in different fields of biological science requires test systems to observe the effects of chemicals or drugs. Testing new chemical entity (NCE) in drug discovery and development requires either in vitro or in vivo systems, including cell culture, tissue, organs and whole animal. Various advantages and disadvantages of each test system force scientists to find an alternative test system. The use of laboratory animals like rodents and non-rodents for evaluation of the effects of drugs or toxicity studies having ethical concerns. The cell-based and tissue-based test systems have various disadvantages including problem related prediction of the desirable and undesirable effects in animals. All such factors favor the use of laboratory animals like rats, mice, guinea pigs, rabbits, dogs, and primates in the pre-clinical phase of drug discovery. However, cost, manpower, and time-consuming efforts can be considered unfavorable for the use of such animals for testing every newly synthesized compound. Because of such difficulties in the field of new research with animal models, scientists made efforts to identify a newer animal model that can replace currently available animal species in research up to a certain extent. The animal model that is used in such drug discovery programs and toxicological testing must have homology to human beings or target species. The limitations or disadvantages of currently available animal models may be solved up to a certain level by using aquatic animal species like zebrafish.

Toxicological screening is essential for the development of new drugs (ND) and exploring the therapeutic potential of existing compounds.While animal testing is still regarded as the “gold standard” in traditional toxicity assessments, there is a growing need to transition towards alternative methods for drug safety testing. This shift is driven by the emergence of cutting-edge technologies and the adoption of the 3Rs principle (replace, reduce, refine) which emphasizes animal welfare.Routine in vitro safety screeningalong with GLP (Good Laboratory Practice) and non-GLP toxicity testing follow regulatory frameworks established by agencies such as the FDA (Food and Drug Administration), ICH (International Council for Harmonization)and EMA (European Medicines Agency) (Tang et al., 2023).In recent years, there has been a shift towards enhanced safety screening during the lead optimization stages of drug discovery. Regulatory toxicology testing plays a pivotal role in determining the potential risks associated with new drug compounds and ensuring their safety before they can proceed to human clinical trials and, ultimately, be marketed to the public.

Radiation combined injury (RCI) is complex condition that arises from simultaneous exposure to ionizing radiation and other types of physical trauma, such as blunt force injuries, thermal burns, or chemical exposure. This combination significantly complicates diagnosis and treatment, leading to increased morbidity and mortality. The past experiences of Hiroshima, Nagasaki, and Chernobyl have revealed that a large fraction of victims of such nuclear accidents or attacks suffer from combined radiation injuries. The possibility of a nuclear attack seems very far-fetched, but the destruction that would occur in such events will be massive, with a huge loss in terms of lives. Therefore, preparedness for the same should be done beforehand. Ionizing radiation damages cellular structures, primarily through direct ionization of DNA, leading to a range of acute and chronic health effects.

The severity of radiation damage is influenced by the dose, type of radiation, and duration of exposure. Simultaneously, traumatic injuries can result from various mechanisms such as combat, accidents, explosions that may involve blunt trauma, lacerations, or burns. These injuries can lead to significant blood loss, organ failure, and infections, which may be aggravated by the immune suppression caused by radiation exposure. The interaction between radiation effects and traumatic injuries can create a unique clinical challenge, as each type of injury can exacerbate the other’s impact on the body. The pathophysiology and prognosis of RCI are more intricate and challenging to manage compared to simple burns, wound or radiation injuries. Although RCI is uncommon, it poses significant risks during unfortunate events like nuclear or radiological terrorist attacks and nuclear accidents. Historical nuclear incidents have shown that 65-70% of victims experienced varying degrees of thermal burns and other traumatic injuries alongside radiation exposure. These victims often sustain damage to nearly every organ system, particularly the gastrointestinal, cardiovascular, neurological, and hematopoietic systems, all crucial for survival.

Introduction

Pulmonary vascular tone regulation involves the balance between vasoconstriction and vasodilation, primarily controlled by pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (Lyle et al., 2017). This regulation is influenced by various factors, including ion channels, which modulates the flow of ions like K+, Ca2+, Na+ and Cl- across cell membranes, affecting vascular contraction and relaxation. Diseases like pulmonary artery hypertension (PAH) are attributed to dysregulation of vascular tone, which is essential for preserving ideal blood flow and pressure in the lungs (Christou and Khalil, 2022). Excessive vasoconstriction and impaired vasodilation increase pulmonary arterial pressure. This heightened resistance strains the right ventricle, leading to heart failure over time. Dysregulated ion channel movement in PASMCs is often a key factor in the development and progression of the disease. Ion channel receptors are promising candidates for medical therapy for the amelioration of pulmonary vascular disorders. Agents that regulate the functioning of ion channels may be employed to treat aberrant pulmonary blood vessel tone (Jouen-Tachoire et al., 2021).

The art of Indian traditional knowledge regarding herbal medicine has a long history and can be considered as a potential source of new medicine. India has great potential in the market for herbal medicine, which is evident by the fact that medicinal plants required to prepare 50% of the drugs mentioned in the British Pharmacopoeia are reported to be present in the Western Himalayan region alone and India has approximately 8% of the world’s biodiversity, including plant genetic diversity with medicinal properties (Singh, 2006). Traditional medicine is widely used in rural areas, where 70% of the country’s population resides. Almost 75% of the medicinal plants grow naturally in different states of India. These plants are known to cure many ailments in animals.

Ethno Veterinary Practices

Ethno Veterinary Practices, also known as Traditional Veterinary Medicinal Practices are regarded as information gained over a period of time passed on from generation to generation. It is a community based functional knowledge system which has been developed, preserved and refined by generations of people through continuous interaction, observation and experimentation with their surrounding environment. Rural farmers mostly rely on ancestral ethno veterinary practices to deal with the diseases of their livestock and poultry. Veterinarians also show considerable interest in the medicinal plants, employed in traditional systems. This emerging trend in favour of herbal medicine is also due to the issues related to the antimicrobial drug resistance and drug residues in foods (milk/meat/eggs) of animal origin.

Introduction to AI in Toxicology

Toxicology is the scientific study of the adverse effects of chemical, physical, or biological agents on living organisms and the environment. It explores the mechanisms of toxicity, prevention, and mitigation, while applying this knowledge to safety evaluation and risk assessment of xenobiotics. It encompasses various sub-disciplines like chemical, organ-specific, genetic, environmental, and clinical toxicology, as well as toxicokinetic and regulatory risk assessment. Traditionally, toxicological assessments involve complex experimental models, including in vitro, in vivo, and clinical studies, which are time-consuming and resource-intensive. This is where AI steps in to revolutionize the field.

Artificial Intelligence is a branch of computer science focused on developing systems capable of performing tasks that typically require human intelligence, such as learning, reasoning, and decision-making. Its subdomains—such as machine learning (ML), deep learning (DL), and natural language processing (NLP). In toxicology, AI, especially machine learning (ML), is applied to predict and evaluate chemical toxicokinetic and toxicity. ML uses algorithms to train computational models for problem-solving, and is categorized into supervised, unsupervised, and reinforcement learning methods. These AI techniques are increasingly utilized in toxicology for analyzing complex data and enhancing safety predictions. They are increasingly being used in various areas of toxicology, such as neurotoxicity, cardiovascular toxicology, nanotoxicology, toxicokinetic, dermal toxicity, and carcinogenesis. These approaches provide enhanced predictive and analytical capabilities across these diverse toxicological fields.AI methods can enhance in silico toxicology by integrating various data sources, including chemical structures, biological information, and in vitro results. This improves predictions of human toxicity, reducing the need for experimental studies, especially in vivo animal testing.

Antibiotics serve as a backbone of modern clinical management but are currently facing serious threats from nosocomial and community emerging antimicrobial-resistance (AMR). The misuse and overuse of antibiotics and other antimicrobial agents in humans and animals have accelerated the development of resistant strains. Amongst the drug-resistant microbes, major threat is posed by the ESKAPEE group, an acronym for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., and Escherichia coli, comprising high to critical drug-resistant, World Health Organization Critical Priority I and II pathogens. The dry pipeline of effective and new antibiotics further exacerbates the situation with looming threat of heading to a ‘post-antibiotic era’. In such daring scenario of AMR, where AMR is expected to be the largest killer by 2050, it is imperative to understand the AMR development mechanism in bacteria as survival mechanism to find out way to mitigate AMR development and transfer.

Herbal medicines have become popular these days as complementary therapies for various disorders. These are available as single compounds, enriched extracts, or polyherbal preparations. The polyherbal formulations behave very differently as compared to the single compounds due to the interaction of different chemical constituents, present therein, with multiple receptors/targets in the biological system. The presence of the multiple chemical constituents is also likely to exhibit pharmacokinetic and metabolic interactions. Thus, it becomes difficult to monitor and predict the exact pharmacokinetic profile of all the chemical constituentspresent in a polyherbal formulation (He et al. 2011; Xie et al. 2012). As a result, pharmacokinetic studies of polyherbal formulations have been a long-standing hurdlein phytotherapy research. Conventional scientific approach for studying thepharmacological behaviour of a multicomponent therapy is to isolate the individualcompound and study the effect of these compounds on various targets and enzymes, independently. To rationalize the use of herbal medicines,a clear understanding of their pharmacokinetics and metabolism in the physiologicalsystem is required. A fundamental knowledge of pharmacokinetics of phytopharmaceuticals will be helpful inauthenticating their use.

Nitrovasodilators are pharmaceutically key signalling molecule in the cardiovascular, immune and central nervous systems, and crucial steps in the regulation of NO bioavailability in health and diseases. These agents are well characterized and responsible for vasodilation by donation of nitric oxide (NO), and are principally employed for the treatment and prevention of angina pectoris, several cardiac diseases and regulation of vascular homeostasis (Carlstrom et al., 2024). NO has also been implicated in the pathology of many inflammatory diseases, including arthritis, myocarditis, colitis, and nephritis and a large number of pathologic conditions such as amyotrophic lateral sclerosis, cancer, diabetes, and neurodegenerative diseases. Several alternative strategies to increase NO signalling in the cardiovascular system have recently emerged, with promising therapeutic potential (Lundberg eta al., 2015). Nitroglycerin is commonly used in the treatment of angina pectoris because of its ability to decrease myocardial oxygen consumption. The use of nitroglycerin in the treatment of angina pectoris began not long after its original synthesis in 1847. Since then, the discovery of nitric oxide as a biological effector and better understanding of its roles in vasodilation, cell permeability, platelet function, inflammation, and other vascular processes have advanced our knowledge of the hemodynamic (mostly mediated through vasodilation of capacitance and conductance arteries) and nonhemodynamic effects of organic nitrate therapy, via both nitric oxide–dependent and –independent mechanisms (Divakaran and Loscalzo, 2017). These encompasses the identification of new pathways for enhancing NO synthase activity; ways to amplify the nitrate–nitrite–NO pathway; novel classes of NO-donating drugs; drugs that limit NO metabolism through effects on reactive oxygen species (Lundberg et al., 2015; Roy et al., 2023). Apart from the organic nitrates, direct activators of soluble guanylate cyclase, L-arginine, phosphodiesterase inhibitors and some other drugs also play critical role in vasoprotection (Gewaltig and Kojda, 2002).

Dehydroepiandrosterone (DHEA) is known for many biological activities including potent cardioprotective properties. Meta analysis of human data strongly correlated diminished plasma level of DHEA with hypertension and age related anomalies and has been in clinical trial for efficacies against CVDs and hypertension. It was isolated for the first time in 1934 by Butenandt and Dannenbaum, later in 1944 extracted from human plasma (Oka et al., 2007). It is a 3β-hydroxysteroid, metabolized from pregnenolone, secreted from cells of zonareticulata of adrenal gland. Age-related decline in serum DHEA and DHEA-S(sulphate) is found to be associated with number of diseases including cardiovascular diseases, insulin resistance, cancer etc. (Arlt et al., 1999). Besides, DHEA dilates arteries, modulate hypoxia-induced vasoconstriction by activating potassium channels through soluble guanylatecyclase (sGC) activation, (Oka et al., 2007) and enhance endothelial function in particular via increasing nitric oxide synthesis (Haixian et al., 2019), induced relaxation in high K+ -induced contraction in thoracic aorta of rat embryo (Ochi et al., 2018). However, DHEA has never been explored as a vasorelaxant in mesenteric vascular bed, the major resistance bed of the circulatory system as well as its contribution in blockade of VDCC as possible mechanism for vasorelaxation. To date, the physiological role of DHEA in systemic vascular tissue as a vasorelaxant remains largely unknown and its potential use in the treatment of hypertension in human still remain inconclusive due to the increase in the risk of hormone driven cancer (Clark et al, 2018). Hence, we have chosen to explore the potential of DHEA as a vasorelaxant in conduit blood vessels like aorta and resistance blood vessels like mesenteric artery and elucidation of possible mechanism of vasorelaxation. Further, we also wanted to test the hypothesis whether in-vivo treatment of hypertensive rats with proven traditional medicine with known efficacy and acceptability could restore the level of DHEA in animal model of hypertension so as to have the beneficial effect of DHEA but without any adverse effect from external administration.

Food Animals are the main protein source for human nutrition in the world.Sub-therapeutic doses of antibiotics are commonly used in food animal production, through their addition in feed and wateras antibiotic growth promoters (AGPs). Animal production is considered one of the main sources of antimicrobial resistances (AMR), thus the research for alternative strategies to the use of antibiotics in animal diet is essential to f ight the emergence of AMR. Currently, AMR causes the death of 700,000 people per year and it is forecasted that this will increase exponentially to 10 million by 2050, becoming the main cause of death worldwide.The reduction of antimicrobial resistance is a major challenge for the scientific community. In a few decades, infections by resistant bacteria are forecasted to be the main cause of death in the world. The withdrawal of antibiotics as growth promoters and their preventive use in animal production is essential to avoid these resistances, but this may impair productivity and health due to the increase in gut inflammation. The best alternative to Antibiotic growth promoters (AGPs) is a general improvement of conditions for food animals. In order to start a reformation of the Food Animal Industry as a whole, it’s essential to research to find out effective, resistance rare, low toxic and affordable alternatives to antibiotic growth promoters. Culinary herbs derived bioactives may be the promising products to address this challenge because it is traditionally proven to restore the gastrointestinal health due to beneficial effects on microbiota composition, mucosal barrier integrity, and immune system to control inflammation.

Animal models in diabetes research are very common when most of the existing models are developed as a conventional model either for Type 1 or for T2D. But very often a conventional model of diabetes cannot demonstrate the specific pathogenesis of diabetes related complications. Therefore, the necessity of the individual and specific model for diabetic complications has been raised in the recent years to achieve the authentic outcomes of specific research aims. A number of animal models of diabetic neuropathy have been developed in last few decades approaching from diverse point of views. However, most of them did not receive much popularity because of their considerable number of limitations and disadvantages. In a comprehensive review, Harati [4] reported that the major handicap in studying diabetic neuropathies is the lack of a suitable animal model that addresses acute and chronic events leading to diabetic neuropathy. Hence, in this review, the pathogenesis, advantages, disadvantages, and limitations of several genetic and nongenetic animal models of diabetic neuropathy have been discussed to substantiate their efficacy for human study and in order to guide diabetes research groups to more accurately select the most appropriate models to address their specific research questions.

Antimicrobial drugs are important medicines which are continuously developed and evolveddue to the phenomenon of development of antimicrobial resistance to antimicrobial agents by microorganisms since the discovery of Penicillin by Sir Alexander Fleming in 1928-29. It has become essential for both pharmacologists and clinicians to optimize the certain principles of pharmacokinetic-pharmacodynamic aspects in both development of new antimicrobial drugs and in getting better therapeutic outcome in actual clinical situations in the field conditions to overcome the challenge thrown by microorganisms to the mankind.

Pharmacokinetics (PK) describes the relationship between the dose of any drug given and the resulting concentration in the body. It includes the physiological process of absorption, distribution, metabolism and elimination whereas Pharmacodynamics (PD) describes the interaction between the drug concentration and pharmacological/therapeutic effect in vivo. It is determined as a definite concentration of a drugand its ability to kill or inhibit the cultured pathogenic microorganismin vitro that is aptly described asminimum inhibitory concentration (MIC) in case of antimicrobial drugs.