Investigation of anti-nociceptive, anti-inflammatory potential and ADMET studies of pure compounds isolated from Isodon rugosus Wall. ex Benth.

The strong ethnopharmacological utilization of Isodon rugosus Wall. Ex. Benth is evident in the treatment of several types of pain and inflammation, including toothache, earache, abdominal pain, gastric pain, and generalized body pain and inflammation. Based on this background, the antinociceptive effects of the crude extract, various fractions, and essential oil have been reported previously. In this research work, we isolate and characterize pure bioactive compounds from I. rugosus and evaluate possible mechanisms using various in vivo and in vitro models. The pure compounds were analyzed for analgesic and anti-inflammatory activities through various assays. The column chromatography of the chloroform fraction of I. rugosus led to the identification of two pure compounds, i.e., 1 and 2. Compound 1 demonstrated notable inhibition (62% writhing inhibition, 72.77% COX-2 inhibition, and 76.97% 5-LOX inhibition) and anti-inflammatory potential (>50% paw edema inhibition at various intervals). The possible mechanism involved in antinociception was considered primarily, a concept that has already been elucidated through the application of naloxone (an antagonist of opioid receptors). The involvement of adrenergic receptors was investigated using a hot plate model (an adrenergic receptor antagonist). The strong ethnomedicinal analgesic background of I. rugosus, supported by previous reports and current observations, leads to the conclusion that I. rugosus is a potential source of antinociceptive and anti-inflammatory bioactive compounds. It may be concluded from the results that the isolated analgesic compounds of I. rugosus may be a possible alternative remedy for pain and inflammation management with admirable efficacy and safety profiles.

Influence of Allee effect on the spatiotemporal behavior of a diffusive predator-prey model with Crowley-Martin type response function.

The present paper is dealt with a predator-prey model in which the growth of the prey population is influenced by the Allee effect while the predator species are contended with the prey population following the Crowley-Martin type response function. The proposed model is comprehensively analyzed in terms of stability and manifestation of bifurcation of the system. The system unveils the bi-stability together with the existence of a separatrix. In view of the eminence of spatial ecology, the dynamical complexity emanating from the induction of the Allee effect in prey species of a Crowley-Martin reaction-diffusion predator-prey model is also investigated profoundly. The results of numerical simulations reveal that the present system dynamics is motivated by both the Allee effect and diffusion-controlled pattern formation growth to hot spots, stripe-hot spot mixtures, stripes, labyrinthine, stripe-cold spot mixtures, and cold spots replication. The theoretical consequences of the spatiotemporal model under study are validated through numerical simulations.

Comparative in-vitro anti-inflammatory, anticholinesterase and antidiabetic evaluation: computational and kinetic assessment of succinimides cyano-acetate derivatives.

This research was planned to synthesize cyano-acetate derivatives of succinimide and evaluate its comparative biological efficacy as anti-inflammatory, anti-cholinesterase and anti-diabetic, which was further validated by molecular docking studies. The three cyano-acetate derivatives of succinimide including compound 23 Methyl 2-cyano-2-(2,5-dioxopyrrolidin-3-yl)acetate, compound 31 Methyl 2-cyano-2-(1-methyl-2,5-dioxopyrrolidin-3-yl)acetate and compound 44 Methyl 2-cyano-2-(1-ethyl-2,5-dioxopyrrolidin-3-yl) acetate were synthesized. The mentioned compounds were checked for in vitro anti-inflammatory, anti-cholinesterase and anti-diabetic (α-amylase inhibition) activity. To validate the in vitro results, computational studies were carried out using molecular operating environment to analyse the BE, i.e. binding energies of all synthesized compounds against the respective enzymes. The Compounds 23, 31, 44 exhibited anti-inflammatory via inhibiting COX-2 (IC50 value of 204.08, 68.60 and 50.93 µM, respectively), COX-1 (IC50 value of 287, 185, and 143 µM, respectively) and 5-LOX (IC50 value of 138, 50.76 and 20, 87 µM respectively). They exhibited choline-mimetic potential, such as compound 23, 31 and 44 inhibited AChE enzyme (IC50 value of 240, 174, and 134 µM, respectively) and BChE enzyme (IC50 value of 203, 134 and 97 µM, respectively). The Compounds 23, 31, 44 exhibited anti-diabetic effect via inhibiting α-amylase enzyme (IC50 values of 250, 106 and 60 µM, respectively). Molecular docking studies revealed that the synthesized compounds have good binding affinity in the binding pockets of AChE, BChE, COX-2, 5-LOX and α-amylase enzyme and showed high binding energies. The synthesized succinimide derivatives, i.e. compound 23, 31, 44 showed marked inhibitory activities against cyclooxygenase, lipoxygenase, α-amylase and cholinesterase enzymes. Among these three, compound 44 and 31 showed strong anti-inflammatory and anti-diabetic activity while they displayed moderate anti-cholinesterase activity supported by molecular docking results.Communicated by Ramaswamy H. Sarma.

Global analysis of a time fractional order spatio-temporal SIR model.

We deal in this paper with a diffusive SIR epidemic model described by reaction-diffusion equations involving a fractional derivative. The existence and uniqueness of the solution are shown, next to the boundedness of the solution. Further, it has been shown that the global behavior of the solution is governed by the value of [Formula: see text], which is known in epidemiology by the basic reproduction number. Indeed, using the Lyapunov direct method it has been proved that the disease will extinct for [Formula: see text] for any value of the diffusion constants. For [Formula: see text], the disease will persist and the unique positive equilibrium is globally stable. Some numerical illustrations have been used to confirm our theoretical results.

Synthesis, Antioxidant, and Antidiabetic Activities of Ketone Derivatives of Succinimide.

The prevalence of diabetes mellitus is persistently increasing globally creating a serious public health affliction. Diabetes mellitus is categorized into two major types designated as type I and Type II. Type I diabetes mellitus is characterized by complete lack of secretion of insulin, while Type II diabetes mellitus is the resistance of peripheral tissues to the action of insulin and inadequate compensatory secretion of insulin. Chronic hyperglycemia associated with diabetes causes failure of cardiovascular system, nervous system, kidneys, and eyes. At present, different types of drugs are used for the management of diabetes, but each of them is associated with more or less serious side effects. Therefore, we need to develop new therapeutic agents that have better efficacy and safety profile. In this study, three ketone derivatives of succinimides were synthesized based on Michael addition and characterized using NMR. All the synthesized compounds were checked for their in vitro α-amylase and α-glucosidase inhibitory activities. Further the synthesized compounds were also explored for their antioxidant activities, i.e, DPPH and ABTS assays. Based on the in vitro results, the synthesized compounds were further evaluated for in vivo antidiabetic activity. The synthesized compounds were (2-oxocyclohexyl)-1-phenylpyrrolidine-2,5-dione (BW1), benzyl-3-(2-oxocyclohexyl) pyrrolidine-2,5-dione (BW2), and (4-bromophenyl)-3-(2-oxocyclohexyl) pyrrolidine-2,5-dione (BW3). BW1 showed the highest inhibitory activity for DPPH causing 83.03 ± 0.48 at 500 µg/ml with IC50 value of 10.84 µg/ml and highest inhibitory activity for ABTS causing 78.35 ± 0.23 at 500 µg/ml with IC50 value of 9.40 µg/ml against ascorbic acid used as standard. BW1 also exhibited the highest activity against α-amylase and α-glucosidase inhibition causing 81.60 ± 0.00 at concentrations of 500 µg/ml with IC50 value of 13.90 µg/ml and 89.08 ± 1.04 at concentrations of 500 µg/ml with IC50 value of 10.49 µg/ml, respectively, against the standard drug acarbose.

A new study on two different vaccinated fractional-order COVID-19 models via numerical algorithms.

The main purpose of this paper is to provide new vaccinated models of COVID-19 in the sense of Caputo-Fabrizio and new generalized Caputo-type fractional derivatives. The formulation of the given models is presented including an exhaustive study of the model dynamics such as positivity, boundedness of the solutions and local stability analysis. Furthermore, the unique solution existence for the proposed fractional order models is discussed via fixed point theory. Numerical solutions are also derived by using two-steps Adams-Bashforth algorithm for Caputo-Fabrizio operator, and modified Predictor-Corrector method for generalised Caputo fractional derivative. Our analysis allow to show that the given fractional-order models exemplify the dynamics of COVID-19 much better than the classical ones. Also, the analysis on the convergence and stability for the proposed methods are performed. By this study, we see that how the vaccine availability plays an important role in the control of COVID-19 infection.

Global proprieties of a delayed epidemic model with partial susceptible protection.

In the case of an epidemic, the government (or population itself) can use protection for reducing the epidemic. This research investigates the global dynamics of a delayed epidemic model with partial susceptible protection. A threshold dynamics is obtained in terms of the basic reproduction number, where for R0<1 the infection will extinct from the population. But, for R0>1 it has been shown that the disease will persist, and the unique positive equilibrium is globally asymptotically stable. The principal purpose of this research is to determine a relation between the isolation rate and the basic reproduction number in such a way we can eliminate the infection from the population. Moreover, we will determine the minimal protection force to eliminate the infection for the population. A comparative analysis with the classical SIR model is provided. The results are supported by some numerical illustrations with their epidemiological relevance.

A vigorous study of fractional order COVID-19 model via ABC derivatives.

The newly arose irresistible sickness known as the Covid illness (COVID-19), is a highly infectious viral disease. This disease caused millions of tainted cases internationally and still represent a disturbing circumstance for the human lives. As of late, numerous mathematical compartmental models have been considered to even more likely comprehend the Covid illness. The greater part of these models depends on integer-order derivatives which cannot catch the fading memory and crossover behavior found in many biological phenomena. Along these lines, the Covid illness in this paper is studied by investigating the elements of COVID-19 contamination utilizing the non-integer Atangana-Baleanu-Caputo derivative. Using the fixed-point approach, the existence and uniqueness of the integral of the fractional model for COVID is further deliberated. Along with Ulam-Hyers stability analysis, for the given model, all basic properties are studied. Furthermore, numerical simulations are performed using Newton polynomial and Adams Bashforth approaches for determining the impact of parameters change on the dynamical behavior of the systems.

Analysis of a discrete mathematical COVID-19 model.

To describe the main propagation of the COVID-19 and has to find the control for the rapid spread of this viral disease in real life, in current manuscript a discrete form of the SEIR model is discussed. The main aim of this is to describe the viral disease in simplest way and the basic properties that are related with the nature of curves for susceptible and infected individuals are discussed here. The elementary numerical examples are given by using the real data of India and Algeria.

Dynamics of a stochastic COVID-19 epidemic model with jump-diffusion.

For a stochastic COVID-19 model with jump-diffusion, we prove the existence and uniqueness of the global positive solution. We also investigate some conditions for the extinction and persistence of the disease. We calculate the threshold of the stochastic epidemic system which determines the extinction or permanence of the disease at different intensities of the stochastic noises. This threshold is denoted by ξ which depends on white and jump noises. The effects of these noises on the dynamics of the model are studied. The numerical experiments show that the random perturbation introduced in the stochastic model suppresses disease outbreak as compared to its deterministic counterpart. In other words, the impact of the noises on the extinction and persistence is high. When the noise is large or small, our numerical findings show that COVID-19 vanishes from the population if ξ < 1 ; whereas the epidemic cannot go out of control if ξ > 1 . From this, we observe that white noise and jump noise have a significant effect on the spread of COVID-19 infection, i.e., we can conclude that the stochastic model is more realistic than the deterministic one. Finally, to illustrate this phenomenon, we put some numerical simulations.

Non-standard finite difference scheme and analysis of smoking model with reversion class.

Smokers are at more risk to COVID-19 as the entertainment of smoking because their fingers are in touch with lips regularly during smoking that increases the probability of transmission of virus from hand to mouth. On other hand the smokers may have lung disease (or reduced lung capacity) which would greatly increase risk of serious illness especially COVID-19. For this esteem, in this research work, we first formulate a mathematical model contains the reversion class. Then, using different techniques for finding the local and global stability of the presented model related to equilibrium points that are free smoking and positive smoking equilibrium points. As the model consisting on the nonlinear equations, so we use the non-standard finite difference (NSFD) scheme, ODE45 and RK4 methods to find the numerical results. Finally, we show the graphs numerically through MATLAB.

Crowding effects on the dynamics of COVID-19 mathematical model.

A disastrous coronavirus, which infects a normal person through droplets of infected person, has a route that is usually by mouth, eyes, nose or hands. These contact routes make it very dangerous as no one can get rid of it. The significant factor of increasing trend in COVID19 cases is the crowding factor, which we named "crowding effects". Modeling of this effect is highly necessary as it will help to predict the possible impact on the overall population. The nonlinear incidence rate is the best approach to modeling this effect. At the first step, the model is formulated by using a nonlinear incidence rate with inclusion of the crowding effect, then its positivity and proposed boundedness will be addressed leading to model dynamics using the reproductive number. Then to get the graphical results a nonstandard finite difference (NSFD) scheme and fourth order Runge-Kutta (RK4) method are applied.

Stochastic mathematical model for the spread and control of Corona virus.

This work is devoted to a stochastic model on the spread and control of corona virus (COVID-19), in which the total population of a corona infected area is divided into susceptible, infected, and recovered classes. In reality, the number of individuals who get disease, the number of deaths due to corona virus, and the number of recovered are stochastic, because nobody can tell the exact value of these numbers in the future. The models containing these terms must be stochastic. Such numbers are estimated and counted by a random process called a Poisson process (or birth process). We construct an SIR-type model in which the above numbers are stochastic and counted by a Poisson process. To understand the spread and control of corona virus in a better way, we first study the stability of the corresponding deterministic model, investigate the unique nonnegative strong solution and an inequality managing of which leads to control of the virus. After this, we pass to the stochastic model and show the existence of a unique strong solution. Next, we use the supermartingale approach to investigate a bound managing of which also leads to decrease of the number of infected individuals. Finally, we use the data of the COVOD-19 in USA to calculate the intensity of Poisson processes and verify our results.

Dynamics of COVID-19 mathematical model with stochastic perturbation.

Acknowledging many effects on humans, which are ignored in deterministic models for COVID-19, in this paper, we consider stochastic mathematical model for COVID-19. Firstly, the formulation of a stochastic susceptible-infected-recovered model is presented. Secondly, we devote with full strength our concentrated attention to sufficient conditions for extinction and persistence. Thirdly, we examine the threshold of the proposed stochastic COVID-19 model, when noise is small or large. Finally, we show the numerical simulations graphically using MATLAB.

Dynamics of a fractional order mathematical model for COVID-19 epidemic.

In this work, we formulate and analyze a new mathematical model for COVID-19 epidemic with isolated class in fractional order. This model is described by a system of fractional-order differential equations model and includes five classes, namely, S (susceptible class), E (exposed class), I (infected class), Q (isolated class), and R (recovered class). Dynamics and numerical approximations for the proposed fractional-order model are studied. Firstly, positivity and boundedness of the model are established. Secondly, the basic reproduction number of the model is calculated by using the next generation matrix approach. Then, asymptotic stability of the model is investigated. Lastly, we apply the adaptive predictor-corrector algorithm and fourth-order Runge-Kutta (RK4) method to simulate the proposed model. Consequently, a set of numerical simulations are performed to support the validity of the theoretical results. The numerical simulations indicate that there is a good agreement between theoretical results and numerical ones.

Mathematical Model for Coronavirus Disease 2019 (COVID-19) Containing Isolation Class.

The deadly coronavirus continues to spread across the globe, and mathematical models can be used to show suspected, recovered, and deceased coronavirus patients, as well as how many people have been tested. Researchers still do not know definitively whether surviving a COVID-19 infection means you gain long-lasting immunity and, if so, for how long? In order to understand, we think that this study may lead to better guessing the spread of this pandemic in future. We develop a mathematical model to present the dynamical behavior of COVID-19 infection by incorporating isolation class. First, the formulation of model is proposed; then, positivity of the model is discussed. The local stability and global stability of proposed model are presented, which depended on the basic reproductive. For the numerical solution of the proposed model, the nonstandard finite difference (NSFD) scheme and Runge-Kutta fourth order method are used. Finally, some graphical results are presented. Our findings show that human to human contact is the potential cause of outbreaks of COVID-19. Therefore, isolation of the infected human overall can reduce the risk of future COVID-19 spread.

Evaluation of crude saponins, methanolic extract and subsequent fractions from Isodon rugosus Wall. ex Benth: Potentials of anti-angiogenesis in egg and anti-tumorigenesis in potato.

Based on the ethnomedicinal use of Isodon rugosus the current study was designed to evaluate its crude saponins (Ir.Sp), and subsequent fractions for anti-angiogenic and anti-tumor potentials. Chorioallantoic membrane (CAM) assay was used in anti-angiogenic potentials with Dexamethasone as positive control. The antitumor activity was evaluated with potato disk method using Vincristine sulfate as positive control. Moreover, antibacterial activity was also conducted against A. tumefaciens. The highest anti-angiogenic effect was observed with Ir.Sp, i.e., 79.00±0.58% at concentration of 1000 µg/ml which drop drown to 48.67±1.20% at lowest tested concentration of 31.25 µg/ml with IC50 of 41 µg/ml. Similarly, in the anti-tumor activity the Ir. Chf revealed excellent inhibition of tumor with IC50 value of 60 µg/ml. All the samples (excluding Ir. Sp and Ir. Cr) were inactive against A. tumefaciens, which demonstrates that the samples which did not show any antibacterial activity are rich in certain bioactive principles which may be responsible for the anti-tumor and anti-angiogenic potentials. Our results conclude that the Ir.Sp, Ir.Chfmay be good targets for isolation of bioactive compounds responsible for the inhibition of excessive proliferation of cells and angiogenesis.

Chemical Characterization, Analgesic, Antioxidant, and Anticholinesterase Potentials of Essential Oils From Isodon rugosus Wall. ex. Benth.

Isodon rugosus Wall. ex. Benth is an important species and is used in folk medicine for different types of pains such as abdominal pain, earache, toothache, gastric, and generalized body pain. Recently, we also have reported the antinociceptive potential of chloroform fraction of I. rugosus. In this research, we have investigated the antinociceptive, antioxidant and anti-cholinesterase potentials of essential oils from I. rugosus (Ir.EO), and have determined a possible mechanism of anti-nociception. The Ir.EO was subjected to gas chromatography-mass spectroscopy analysis to find out its chemical constituents. The Ir.EO was assayed for analgesic potential following acetic acid induced writhing, formalin test and hot plate method in animal models. The antioxidant activity was conducted against DPPH and ABTS free radicals following spectroscopic analysis. The cholinesterase inhibitory assays were performed using Ellman's assay. The GC-MS analysis of Ir.EO revealed the identification of 141 compounds. Ir.EO demonstrated strong antinociceptive potential in all three in-vivo models. With the use of nalaxone, it was confirmed that the essential oil was acting on the central pathway of nociception. The Ir.EO also exhibited strong free radicals scavenging potential, exhibiting IC50 values of 338 and 118 µg/ml for DPPH and ABTS free radicals respectively. In AChE and BChE inhibitory assays, the observed IC50 values were 93.56 and 284.19 µg/ml respectively. The encouraging antinociceptive, antioxidant and anticholinesterase results revealed that Ir.EO is a rich source of bioactive compounds as obvious from the GC-MS results.

Demonstration of biological activities of extracts from Isodon rugosus Wall. Ex Benth: Separation and identification of bioactive phytoconstituents by GC-MS analysis in the ethyl acetate extract.

BACKGROUND: Since long, natural sources have been explored for possible managements of various diseases. In this context, the study is designed to evaluate Isodon rugosus Wall. ex Benth for biological potentials including antibacterial, anthelmintic, insecticidal, anti-termites and anti-Pharaoh activities followed by GC-MS analysis of active fraction to identify various bioactive compounds. METHODS: I. rugosus was investigated against eight bacterial strains using well diffusion method and microdilution method with ceftriaxone as positive control. Similarly, the insecticidal activity was carried out against Tribolium castaneum, Rhyzopertha dominica, Monomorium pharaonis and Heterotermis indicola following contact toxicity method. Likewise, anthelmintic activity was performed against Ascaridia galli and Pherethima posthuma using albendazole as positive control, in which the paralysis and death times of the worms were observed. The GC-MS analysis of the most active solvent fraction was performed for identifications of various bioactive compounds. RESULTS: Among the tested samples of I. rugosus, flavonoids and ethyl acetate fraction exhibited high antibacterial activities. The crude saponins showed highest anthelmintic activity against Pherethima posthuma and Ascaridia galli with death times of 27.67 and 29.22 min respectively at concentrations of 40 mg/ml. In insecticidal activity, chloroform fraction and saponins exhibited notable results against R. dominica (60 and 70%) and T. castaneum (70 and 76%) at concentration of 200 mg/ml. In anti-termite assay, all the plant samples showed overwhelming results, i.e. all the 25 termites were killed on the 3rd day. Similarly, in anti-Pharaoh activity, the chloroform, ethyl acetate and saponins fractions were most potent, each exhibiting LD50 of <0.1 mg/ml. In GC-MS analysis, total of 57 compounds were identified. Some of the bioactive compounds identified in GC-MS analysis are palmitic acid, hinokiol, α-amyrin, phytol, ethyl linolate, cyclohexanone, hinokione, methyl palmitate, ethyl palmitate and stigmasterol acetate. CONCLUSIONS: Based on our current results, it can be concluded that I. rugosus possess strong antibacterial, insecticidal and anthelmintic potentials having crude saponins and ethyl acetate as the most active fractions. The GC-MS analysis and biological assays reveal that ethyl acetate fraction is a suitable target for the isolation of diverse array of bioactive compounds.