Biotechnological approaches for the production of camptothecin.

Camptothecin (CPT), an indole alkaloid popular for its anticancer property, is considered the third most promising drug after taxol and famous alkaloids from Vinca for the treatment of cancer in humans. Camptothecin was first identified in Camptotheca acuminata followed by several other plant species and endophytic fungi. Increased harvesting driven by rising global demand is depleting the availability of elite plant genotypes, such as Camptotheca acuminata and Nothapodytes nimmoniana, crucial for producing alkaloids used in treating diseases like cancer. Conservation of these genotypes for the future is imperative. Therefore, research on different plant tissue culture techniques such as cell suspension culture, hairy roots, adventitious root culture, elicitation strategies, and endophytic fungi has been adopted for the production of CPT to meet the increasing demand without affecting the source plant's existence. Currently, another strategy to increase camptothecin yield by genetic manipulation is underway. The present review discusses the plants and endophytes that are employed for camptothecin production and throws light on the plant tissue culture techniques for the regeneration of plants, callus culture, and selection of cell lines for the highest camptothecin production. The review further explains the simple, accurate, and cost-effective extraction and quantification methods. There is enormous potential for the sustainable production of CPT which could be met by culturing of suitable endophytes or plant cell or organ culture in a bioreactor scale production. Also, different gene editing tools provide opportunities for engineering the biosynthetic pathway of CPT, and the overall CPT production can be improved . KEY POINTS: • Camptothecin is a naturally occurring alkaloid with potent anticancer properties, primarily known for its ability to inhibit DNA topoisomerase I. • Plants and endophytes offer a potential approach for camptothecin production. • Biotechnology approaches like plant tissue culture techniques enhanced camptothecin production.

Impact of Saussurea lappa against foodborne parasite Trichinella spiralis experimental infections induced variation in DNA damage, oxidative stress and PCNA expression in rat skeletal muscles.

Trichinellosis is a parasite zoonosis that is spread through ingesting raw or undercooked meat that contains the Trichinella spiralis (T. spiralis) infective larvae. It has three clinical phases: intestinal, migratory, and muscular. Kuth root, also known as Costus (Saussurea lappa) roots, is used in many traditional medical systems all over the world to treat a variety of illnesses, such as dyspepsia, diarrhoea, vomiting, and inflammation. Current study assessed the therapeutic Potential of costus roots extract (CRE) treatment on experimental trichinellosis induce changes in DNA damage, oxidative stress and Proliferating cell nuclear antigen (PCNA) expression in muscle fibers in male rats. A total of 60 male Sprague Dawley rats were divided into 6 groups (Gps) [Gp1, Negative control; Gp2, Costus (CRE); Gp3, Positive control or Infected rats with T. spiralis, Gp4; Pre-treated infection with CRE; Gp5 & Gp6, Post treated infection with CRE for one and two weeks respectively]. Current results revealed that; Trichinella spiralis experimentally infection induced significant elevation in tissue malondialdehyde (MDA), DNA damage, PCNA expression and significant depletion in tissue glutathione (GSH), superoxide dismutase (SOD) and catalase (Cat) activities. Pre or/and post CRE treated infected rats with T. spiralis (Gp4-Gp6) induced improvements and depletion in DNA damage, PCNA expression, MDA and elevation in GSH, SOD, catalase as compared to infected rats with T. spiralis (Gp3) with best results for the pretreatments (Gp4). Trichinella spiralis experimental infection induced DNA damage and oxidative stress in rat skeletal muscles and treatments with costus roots extract modulates these changes.

Effect of asiatic acid supplementation in tris-extender on post-thaw functional competence, antioxidant enzyme activity and in vivo fertility of bull sperm.

Reactive oxygen species at supra-physiological levels trigger oxidative stress during cryopreservation, which can be neutralised by incorporating suitable antioxidants into the semen extender medium. This study was intended to explore the effect of asiatic acid (AA) as an antioxidant in semen extender on frozen-thawed sperm quality and in vivo fertility of bull sperm. Semen was collected from Holstein Friesian bulls for 10 consecutive weeks (total ejaculates = 60). Semen was cryopreserved with a Tris citric acid egg yolk-based extender supplemented with 0 (control), 20, 40, 60, and 100 µM AA. The supplementation of the extender with 40 and 60 µM AA improved (p < 0.05) post-thaw motility kinematics, plasma membrane integrity, acrosome integrity, sperm viability, and DNA integrity of bull sperm. Mitochondrial membrane potential was high (p < 0.05) with 60 µM of AA concentration in extender media. The catalase activity in seminal plasma was maintained (p < 0.05) when semen was added with 20, 40, and 60 µM of AA. The in vivo fertility was found to be significantly high with the semen extended with 60 µM AA. Conclusively, this study showed that AA supplementation in semen extender significantly improved sperm motility kinematics and cell integrity, conserved antioxidant enzyme activity, and improved in vivo fertility.

Tepotinib and tivantinib as potential inhibitors for the serine/threonine kinase of the mpox virus: insights from structural bioinformatics analysis.

The serine/threonine kinase (STK) plays a central role as the primary kinase in poxviruses, directing phosphoryl transfer reactions. Such reactions are pivotal for the activation of certain proteins during viral replication, assembly, and maturation. Therefore, targeting this key protein is anticipated to impede virus replication. In this work, a structural bioinformatics approach was employed to evaluate the potential of drug-like kinase inhibitors in binding to the ATP-binding pocket on the STK of the Mpox virus. Virtual screening of known kinase inhibitors revealed that the top 10 inhibitors exhibited binding affinities ranging from -8.59 to -12.05 kcal/mol. The rescoring of compounds using the deep-learning default model in GNINA was performed to predict accurate binding poses. Subsequently, the top three inhibitors underwent unbiased molecular dynamics (MD) simulations for 100 ns. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis and Principal Component Analysis (PCA) suggested tepotinib as a competitive inhibitor for Mpox virus STK as evidenced by its binding free energy and the induction of similar conformational behavior of the enzyme. Nevertheless, it is sensible to experimentally test all top 10 compounds, as scoring functions and energy calculations may not consistently align with experimental findings. These insights are poised to provide an attempt to identify an effective inhibitor for the Mpox virus.Communicated by Ramaswamy H. Sarma.

Defying gravity: WEEP promotes negative gravitropism in peach trees by establishing asymmetric auxin gradients.

Trees with weeping shoot architectures are valued for their beauty and are a resource for understanding how plants regulate posture control. The peach (Prunus persica) weeping phenotype, which has elliptical downward arching branches, is caused by a homozygous mutation in the WEEP gene. Little is known about the function of WEEP despite its high conservation throughout Plantae. Here, we present the results of anatomical, biochemical, biomechanical, physiological, and molecular experiments that provide insight into WEEP function. Our data suggest that weeping peach trees do not have defects in branch structure. Rather, transcriptomes from the adaxial (upper) and abaxial (lower) sides of standard and weeping branch shoot tips revealed flipped expression patterns for genes associated with early auxin response, tissue patterning, cell elongation, and tension wood development. This suggests that WEEP promotes polar auxin transport toward the lower side during shoot gravitropic response, leading to cell elongation and tension wood development. In addition, weeping peach trees exhibited steeper root systems and faster lateral root gravitropic response. This suggests that WEEP moderates root gravitropism and is essential to establishing the set-point angle of lateral roots from the gravity vector. Additionally, size exclusion chromatography indicated that WEEP proteins self-oligomerize, like other proteins with sterile alpha motif domains. Collectively, our results from weeping peach provide insight into polar auxin transport mechanisms associated with gravitropism and lateral shoot and root orientation.

Animal Models of Human Disease.

The use of animal models of human disease is critical for furthering our understanding of disease mechanisms, for the discovery of novel targets for treatment, and for translational research. This Special Topic entitled "Animal Models of Human Disease" aimed to collect state-of-the-art primary research studies and review articles from international experts and leading groups using animal models to study human diseases. Submissions were welcomed on a wide range of animal models and pathologies, including infectious disease, acute injury, regeneration, cancer, autoimmunity, degenerative and chronic disease. Seven participating MDPI journals supported the Special Topic, namely: Biomedicines, Cells, Current Issues in Molecular Biology, Diagnostics, Genes, the International Journal of Molecular Sciences, and the International Journal of Translational Medicine. In total, 46 papers were published in this Special Topic, with 37 full length original research papers, 2 research communications and 7 reviews. These contributions cover a wide range of clinically relevant, translatable, and comparative animal models, as well as furthering understanding of fundamental sciences, covering topics on physiological processes, on degenerative, inflammatory, infectious, autoimmune, neurological, metabolic, heamatological, hormonal and mitochondrial disorders, developmental processes and diseases, cardiology, cancer, trauma, stress, and ageing.

Assessment of intra- and inter-genetic diversity in tetraploid and hexaploid wheat genotypes based on omega, gamma and alpha-gliadin profiles.

Durum and bread wheat are well adapted to the Mediterranean Basin. Twenty-three genotypes of each species were grown to evaluate the intra- and inter-genetic diversity based on omega (ω), gamma (γ) and alpha (α)-gliadin profiles. To achieve this purpose, the endosperm storage proteins (both gliadins and glutenins) were extracted from wheat grains and electrophoresed on sodium dodecyl sulfate (SDS)-polyacrylamide gels. The results of SDS-Polyacrylamide Gel Electrophoresis (SDS-PAGE) revealed nine polymorphic loci out of 16 loci with durum wheat genotypes and nine polymorphic loci out of 18 loci with bead wheat genotypes. The polymorphisms revealed by the SDS-PAGE were 56% and 50% in durum and bread wheat genotypes, respectively. Using the cluster analysis, the durum wheat genotypes were clustered into five groups, while the bread wheat genotypes were grouped into six clusters using un-weighed pair group mean analyses based on ω, γ, and α-gliadins profiles. The 46 durum and bread wheat genotypes were grouped into seven clusters based on the combined ω, γ, and α-gliadins profiles revealed by the SDS-PAGE. The in silico analysis determined the intra-genetic diversity between bread and durum wheat based on the sequences of ω, γ, and α-gliadins. The alignment of ω-gliadin revealed the highest polymorphism (52.1%) between bread and durum wheat, meanwhile, the alignment of γ and α-gliadins revealed very low polymorphism 6.6% and 15.4%, respectively. According to computational studies, all gliadins contain a lot of glutamine and proline residues. The analysis revealed that the bread wheat possessed ω and γ -gliadins with a lower content of proline and a higher content of glutamine than durum wheat. In contrast, durum wheat possessed α-gliadin with a lower content of proline and a higher content of glutamine than bread wheat. In conclusion, the SDS-PAGE, in silico and computational analyses are effective tools to determine the intra- and inter-genetic diversity in tetraploid and hexaploid wheat genotypes based on ω, γ, and α-gliadins profiles.

Serine/threonine kinase of Mpox virus: computational modeling and structural analysis.

Kinases catalyze phosphoryl transfer from a nucleoside triphosphate (usually ATP) to an amino acid on a protein for activation purposes. Although kinases are well-appreciated drug targets in different viruses and cancers, these enzymes in poxviruses received limited attention from the research community. In poxvirus, the production of infectious particles in the infected cells depends on a serine/threonine protein kinase (STK) that activates proteins implicated in the assembly of new virions. This work aimed to elucidate the structure and dynamics of the major kinase STK from Mpox virus (Orthopoxvirus). A state-of-the-art computational approach was employed to decipher the structure and dynamics of the STK using AlphaFold2 and molecular dynamics (MD) simulations. Although the predicted structure showed an atypical kinase, the overall structural fold is conserved. Binding free energy calculations via Molecular Mechanics/Generalized Born and Surface Area (MM/GBSA) determined the hotspot residues contributing to binding of ATP. The structural analysis in this work provides insights into the structure and behavior of STK in Mpox virus and possibly its closest members of Poxviridae. These findings also set the basis for setting up a thorough experimental investigation to understand the enzymatic mechanism, peptide substrate binding, and the development of small-molecule inhibitors against this kinase.Communicated by Ramaswamy H. Sarma.

Impact of Some Toxic Metals on Important ABC Transporters in Soybean (Glycine max L.).

In plants, ATP-binding cassette (ABC) transporters facilitate the movement of substrates across membranes using ATP for growth, development, and defense. Soils contaminated with toxic metals such as cadmium (Cd) and mercury (Hg) might adversely affect the metabolism of plants and humans. In this study, a phylogenetic relationship among soybeans' (Glycine max) ATP binding cassette (GmABCs) and other plant ABCs was analyzed using sequence information, gene structure, chromosomal distribution, and conserved motif-domain. The ontology of GmABCs indicated their active involvement in trans-membrane transport and ATPase activity. Thirty-day-old soybean plants were exposed to 100 µM CdCl2 and 100 µM HgCl2 for 10 days. Physiological and biochemical traits were altered under stress conditions. Compared to Control, GmABC transporter genes were differentially expressed in response to Cd and Hg. The qRT-PCR data showed upregulation of seven ABC transporter genes in response to Cd stress and three were downregulated. On the other hand, Hg stress upregulated four GmABC genes and downregulated six. It could be concluded that most of the ABCB and ABCG subfamily members were actively involved in heavy metal responses. Real-time expression studies suggest the function of specific ABC transporters in Cd and Hg stress response and are helpful in future research to develop stress-tolerant varieties of soybean.

How helpful were molecular dynamics simulations in shaping our understanding of SARS-CoV-2 spike protein dynamics?

The SARS-CoV-2 spike protein (S) represents an important viral component that is required for successful viral infection in humans owing to its essential role in recognition of and entry to host cells. The spike is also an appealing target for drug designers who develop vaccines and antivirals. This article is important as it summarizes how molecular simulations successfully shaped our understanding of spike conformational behavior and its role in viral infection. MD simulations found that the higher affinity of SARS-CoV-2-S to ACE2 is linked to its unique residues that add extra electrostatic and van der Waal interactions in comparison to the SARS-CoV S. This illustrates the spread potential of the pandemic SARS-CoV-2 relative to the epidemic SARS-CoV. Different mutations at the S-ACE2 interface, which is believed to increase the transmission of the new variants, affected the behavior and binding interactions in different simulations. The contributions of glycans to the opening of S were revealed via simulations. The immune evasion of S was linked to the spatial distribution of glycans. This help the virus to escape the immune system recognition. This article is important as it summarizes how molecular simulations successfully shaped our understanding of spike conformational behavior and its role in viral infection. This will pave the way to us preparing for the next pandemic as the computational tools are tailored to help fight new challenges.

Effect of the molar ratio of (Ni2+ and Fe3+) on the magnetic, optical and antibacterial properties of ternary metal oxide CdO-NiO-Fe2O3 nanocomposites.

In this work, the effect of the molar ratio of (Ni2+ and Fe3+) on the properties of CdO-NiO-Fe2O3 nanocomposites was investigated. The synthesis of CdO-NiO-Fe2O3 nanocomposites was carried out by self-combustion. XRD, UV-Vis, PL and VSM were used to describe the physical properties of the materials. The results showed significant progress in structural and optical properties supporting antibacterial activity. For all samples, the particle size decreased from 28.96 to 24.95 nm with increasing Ni2+ content and decreasing Fe3+ content, as shown by the XRD pattern, which also shows the crystal structure of cubic CdO, cubic NiO, and cubic γ-Fe2O3 spinel. The Ni2+ and Fe3+ contents in the CdO-NiO-Fe2O3 nanocomposites have also been shown to enhance the ferromagnetic properties. Due to the significant coupling between Fe2O3 and NiO, the coercivity Hc values of the samples increase from 66.4 to 266 Oe. The potential of the nanocomposites for antibacterial activity was investigated against Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, Escherichia coli, and Moraxella catarrhalis) bacteria. Comparison of P. aeruginosa with E. coli, S. aureus and M. catarrhalis showed that it has a stronger antibacterial activity with a ZOI of 25 mm.

Biotechnological approaches for the production of gymnemic acid from Gymnema sylvestre R. Br.

Diabetes is a chronic disease that affects several organs and can be treated using phytochemicals found in medicinal plants. Gymnema sylvestre (Asclepiadaceae) is one such medicinal plant rich in anti-diabetic properties. The plant is commonly known as madhunashini in Sanskrit because of its ability to cure diabetes (sugar). Gymnemic acid (GA) is a phytochemical (a triterpenoid saponin) responsible for the herb's main pharmacological activity. This secondary metabolite has a lot of potential as a phytochemical with pharmacological properties including nephroprotection, hypoglycemia, antioxidant, antimicrobial, and anti-inflammatory. Gymnema has acquired a lot of popularity in recent years due to its low side effects and high efficacy in healing diabetes, which has led to overexploitation by pharmaceutical enterprises for its biomass in the wild for the purification of gymnemic acid. Modern biotechnological techniques involving the establishment of cell and organ cultures from G. sylvestre will assist us in fulfilling the need for gymnemic acid production. The present review provides insights on the establishment of cell and organ cultures for the production of a potent antidiabetic molecule gymnemic acid. Further, the review also delves into the intricacies of the different strategies for improved production of gymnemic acid using various elicitors. There is huge potential for sustainable production of gymnemic acid which could be met by establishment of bioreactor scale production. Understanding and engineering the biosynthetic pathway could also lead to improved GA production. KEY POINTS: • Gymnemic acid is one of the potential anti-diabetic molecules from madhunashini • Cell and organ culture offers potential approach for gymnemic acid production • Elicitation strategies have improved the gymnemic acid production.

Entomopathogenic Fungi: An Eco-Friendly Synthesis of Sustainable Nanoparticles and Their Nanopesticide Properties.

The agricultural industry could undergo significant changes due to the revolutionary potential of nanotechnology. Nanotechnology has a broad range of possible applications and advantages, including insect pest management using treatments based on nanoparticle insecticides. Conventional techniques, such as integrated pest management, are inadequate, and using chemical pesticides has negative consequences. As a result, nanotechnology would provide ecologically beneficial and effective alternatives for insect pest control. Considering the remarkable traits they exhibit, silver nanoparticles (AgNPs) are recognized as potential prospects in agriculture. Due to their efficiency and great biocompatibility, the utilization of biologically synthesized nanosilver in insect pest control has significantly increased nowadays. Silver nanoparticles have been produced using a wide range of microbes and plants, which is considered an environmentally friendly method. However, among all, entomopathogenic fungi (EPF) have the most potential to be used in the biosynthesis of silver nanoparticles with a variety of properties. Therefore, in this review, different ways to get rid of agricultural pests have been discussed, with a focus on the importance and growing popularity of biosynthesized nanosilver, especially silver nanoparticles made from fungi that kill insects. Finally, the review highlights the need for further studies so that the efficiency of bio-nanosilver could be tested for field application and the exact mode of action of silver nanoparticles against pests can be elucidated, which will eventually be a boon to the agricultural industry for putting a check on pest populations.

Plant Secondary Metabolites: The Weapons for Biotic Stress Management.

The rise in global temperature also favors the multiplication of pests and pathogens, which calls into question global food security. Plants have developed special coping mechanisms since they are sessile and lack an immune system. These mechanisms use a variety of secondary metabolites as weapons to avoid obstacles, adapt to their changing environment, and survive in less-than-ideal circumstances. Plant secondary metabolites include phenolic compounds, alkaloids, glycosides, and terpenoids, which are stored in specialized structures such as latex, trichomes, resin ducts, etc. Secondary metabolites help the plants to be safe from biotic stressors, either by repelling them or attracting their enemies, or exerting toxic effects on them. Modern omics technologies enable the elucidation of the structural and functional properties of these metabolites along with their biosynthesis. A better understanding of the enzymatic regulations and molecular mechanisms aids in the exploitation of secondary metabolites in modern pest management approaches such as biopesticides and integrated pest management. The current review provides an overview of the major plant secondary metabolites that play significant roles in enhancing biotic stress tolerance. It examines their involvement in both indirect and direct defense mechanisms, as well as their storage within plant tissues. Additionally, this review explores the importance of metabolomics approaches in elucidating the significance of secondary metabolites in biotic stress tolerance. The application of metabolic engineering in breeding for biotic stress resistance is discussed, along with the exploitation of secondary metabolites for sustainable pest management.

Defying Gravity: WEEP promotes negative gravitropism in Prunus persica (peach) shoots and roots by establishing asymmetric auxin gradients.

Trees with weeping shoot architectures are valued for their beauty and serve as tremendous resources for understanding how plants regulate posture control. The Prunus persica (peach) weeping phenotype, which has elliptical downward arching branches, is caused by a homozygous mutation in the WEEP gene. Until now, little was known about the function of WEEP protein despite its high conservation throughout Plantae. Here, we present the results of anatomical, biochemical, biomechanical, physiological, and molecular experiments that provide insight into WEEP function. Our data suggest that weeping peach does not have defects in branch structure. Rather, transcriptomes from the adaxial (upper) and abaxial (lower) sides of standard and weeping branch shoot tips revealed flipped expression patterns for genes associated with early auxin response, tissue patterning, cell elongation, and tension wood development. This suggests that WEEP promotes polar auxin transport toward the lower side during shoot gravitropic response, leading to cell elongation and tension wood development. In addition, weeping peach trees exhibited steeper root systems and faster root gravitropic response, just as barley and wheat with mutations in their WEEP homolog EGT2. This suggests that the role of WEEP in regulating lateral organ angles and orientations during gravitropism may be conserved. Additionally, size-exclusion chromatography indicated that WEEP proteins self-oligomerize, like other SAM-domain proteins. This oligomerization may be required for WEEP to function in formation of protein complexes during auxin transport. Collectively, our results from weeping peach provide new insight into polar auxin transport mechanisms associated with gravitropism and lateral shoot and root orientation.

Stilbenes, a Versatile Class of Natural Metabolites for Inflammation-An Overview.

Stilbenes are polyphenolic allelochemicals synthesized by plants, especially grapes, peanuts, rhubarb, berries, etc., to defend themselves under stressful conditions. They are now exploited in medicine for their antioxidant, anti-proliferative and anti-inflammatory properties. Inflammation is the immune system's response to invading bacteria, toxic chemicals or even nutrient-deprived conditions. It is characterized by the release of cytokines which can wreak havoc on healthy tissues, worsening the disease condition. Stilbenes modulate NF-κB, MAPK and JAK/STAT pathways, and reduce the transcription of inflammatory factors which result in maintenance of homeostatic conditions. Resveratrol, the most studied stilbene, lowers the Michaelis constant of SIRT1, and occupies the substrate binding pocket. Gigantol interferes with the complement system. Besides these, oxyresveratrol, pterostilbene, polydatin, viniferins, etc., are front runners as drug candidates due to their diverse effects from different functional groups that affect bioavailability and molecular interactions. However, they each have different thresholds for toxicity to various cells of the human body, and thus a careful review of their properties must be conducted. In animal models of autoinflammatory diseases, the mode of application of stilbenes is important to their absorption and curative effects, as seen with topical and microemulsion gel methods. This review covers the diversity seen among stilbenes in the plant kingdom and their mechanism of action on the different inflammatory pathways. In detail, macrophages' contribution to inflamed conditions in the liver, the cardiac, connective and neural tissues, in the nephrons, intestine, lungs and in myriad other body cells is explored, along with detailed explanation on how stilbenes alleviate the symptoms specific to body site. A section on the bioavailability of stilbenes is included for understanding the limitations of the natural compounds as directly used drugs due to their rapid metabolism. Current delivery mechanisms include sulphonamides, or using specially designed synthetic drugs. It is hoped that further research may be fueled by this comprehensive work that makes a compelling argument for the exploitation of these compounds in medicine.

Exploration of natural compounds against the human mpox virus DNA-dependent RNA polymerase in silico.

BACKGROUND: Last year, the human monkeypox virus (hMPXV) emerged as an alarming threat to the community, with a detectable outbreak outside the African continent for the first time. According to The American Centers for Disease Control and Prevention (CDC), the virus is reported globally, with 86,746 confirmed cases (until April 08, 2023). DNA-dependent RNA polymerase (DdRp) is an essential protein for viral replication; hence it is a promising drug target for developing antiviral drugs against DNA viruses. Therefore, this study was conducted to search for natural compounds that could provide scaffolds for RNA polymerase inhibitors. METHODS: In this study, the DdRp structure of hMPXV was modeled and used to screen the natural compounds database (COCONUT). The virtual screening revealed 15 compounds able to tightly bind to the active site of the DdRp (binding energies less than -7.0 kcal/mol) compared to the physiological nucleotide, guanosine triphosphate (GTP). Molecular dynamics simulation was then performed on the top four hits and compared to GTP RESULTS: The results revealed the potential of four compounds (comp289, comp295, comp441, and comp449) in binding the hMPXV DdRp active site with a comparable binding affinity (-17.06 ± 2.96, -11.6 ± 5.34, -14.85 ± 2.66, and -10.79 ± 4.49 kcal/mol) with GTP (-21.03 ± 7.55 kcal/mol) CONCLUSION: These findings may also pave the way for developing new hMPXV inhibitors based on natural product scaffolds. These results need further experimental validation but promising as it was validated by unbiased all-atom MD simulations and binding free energy calculations.

Betaine and nano-emulsified vegetable oil supplementation for improving carcass and meat quality characteristics of broiler chickens under heat stress conditions.

Introduction: This research aimed to examine the effects of water-added betaine (BET) and/or nano-emulsified vegetable oil (MAGO) on carcass and meat quality characteristics of broilers raised under thermoneutral (TN) and heat stress (HS) conditions. Methods: On day 21, 640 birds (Ross 308) were randomly assigned to one of two thermal conditions (thermoneutral 22 ± 1°C and heat stress 32 ± 1°C) each containing four treatment groups: Control, BET, MAGO, and a mixture of both (BETMAGO) in a 2 × 4 factorial arrangement (eight groups). Each group has eight replicates, with ten birds each. The birds' carcass and meat quality characteristics were evaluated at 35 days. Results and discussion: The dressing percentage, breast, leg, wing, heart, initial pH, color change, cooking loss (CL), water-holding capacity (WHC), shear force (SF), and texture profile with exception of springiness significantly affected by the treatments. The results showed that HS had negative effects on carcass weight and relative weights of the breast, spleen, and heart. Moreover, HS increased dressing percentage, wing, initial pH, final core temperature, initial lightness, WHC, and hardness. Significant differences in interactions between treatments and temperature were observed in the spleen, WHC, and SF. Conclusion: Water supplemented with BET effectively improved carcass dressing percentage, breast weight, and meat quality in terms of water-holding capacity and tenderness under HS conditions. More studies on the use of BET and/or MAGO at different levels were recommended.

The discovery of novel antivirals for the treatment of mpox: is drug repurposing the answer?

INTRODUCTION: Drugs that have demonstrated good activity against any member of the Orthopoxvirus genus are good candidates for repurposing studies against the mpox virus (MPXV). The conserved biology of poxviruses has proven beneficial from a clinical virology perspective. Evolutionarily conserved proteins tend to function in a highly similar way. Indeed, the smallpox vaccine was found to be 85% effective in protecting humans from mpox virus infection. Similarly, tecovirimat, the drug of choice for smallpox infections, was recently repurposed as a treatment option for mpox cases in Europe. AREA COVERED: This review article focuses on drug repurposing strategies to combat the newly emerged MPXV outbreak. The viral and host cell protein targets are challenged with a bunch of drugs and drug-like molecules in silico, in vitro, and in vivo. Some drugs show promising results and can be repurposed to eradicate MPXV infection. The authors also highlight potential limitations and provide their expert perspectives. EXPERT OPINION: Overall, it is clear that we cannot solely rely on the conventional drug discovery pipeline to find new treatments, despite advances in computational and experimental advances in the last few decades. Drug repurposing has successfully identified good candidate drugs against MPXV as it is one of the Orthopoxvirus genus family. Tecovirimat, brincidofovir, and cidofovir have shown promising results in preventing virus propagation. Consequently, drug repurposing represents an important strategy for the fast identification of new therapeutic options.

Computational identification of drug-like marine natural products as potential RNA polymerase inhibitors against Nipah virus.

Nipah virus (NiV) has been an alarming threat to human populations in southern Asia for more than a decade. It is one of the most deadly viruses in the Mononegavirales order. Despite its high mortality rate and virulence, no chemotherapeutic agent or vaccine is publicly available. Hence, this work was conducted to computationally screen marine natural products database for drug-like potential inhibitors for the viral RNA-dependent RNA polymerase (RdRp). The structural model was subjected to molecular dynamics (MD) simulation to obtain the native ensemble of the protein. The CMNPDB dataset of marine natural products was filtered to retain only compounds following Lipinski's five rules. The molecules were energy minimized and docked into different conformers of the RdRp using AutoDock Vina. The best 35 molecules were rescored by GNINA, a deep learning-based docking software. The resulting nine compounds were evaluated for their pharmacokinetic profiles and medicinal chemistry properties. The best five compounds were subjected to MD simulation for 100 ns, followed by binding free energy estimation via Molecular Mechanics/ Generalized Born Surface Area (MM/GBSA) calculations. The results showed remarkable behavior of five hits as inferred by stable binding pose and orientation to block the exit channel of RNA synthesis products in the RdRp cavity. These hits are promising starting materials for in vitro validation and structural modifications to enhance the pharmacokinetic and medicinal chemistry properties for developing antiviral lead compounds.