Comprehensive mutational analysis of the checkpoint signaling function of Rpa1/Ssb1 in fission yeast.

Replication protein A (RPA) is a heterotrimeric complex and the major single-strand DNA (ssDNA) binding protein in eukaryotes. It plays important roles in DNA replication, repair, recombination, telomere maintenance, and checkpoint signaling. Because RPA is essential for cell survival, understanding its checkpoint signaling function in cells has been challenging. Several RPA mutants have been reported previously in fission yeast. None of them, however, has a defined checkpoint defect. A separation-of-function mutant of RPA, if identified, would provide significant insights into the checkpoint initiation mechanisms. We have explored this possibility and carried out an extensive genetic screen for Rpa1/Ssb1, the large subunit of RPA in fission yeast, looking for mutants with defects in checkpoint signaling. This screen has identified twenty-five primary mutants that are sensitive to genotoxins. Among these mutants, two have been confirmed partially defective in checkpoint signaling primarily at the replication fork, not the DNA damage site. The remaining mutants are likely defective in other functions such as DNA repair or telomere maintenance. Our screened mutants, therefore, provide a valuable tool for future dissection of the multiple functions of RPA in fission yeast.

Fruit Extract and Phenolic Compounds of Phyllanthus emblica Fruits as Bioactivity Enhancer of Chloramphenicol Against Bacterial Species.

Phyllanthus emblica L. (syn. Emblica officinalis) fruits have been traditionally exploited to enhance the immune system and provide protection against bacterial and fungal diseases. The present study aimed to evaluate the synergistic interactions between chloramphenicol and several phenolic compounds found in P. emblica fruits against bacterial strains. The combination of P. emblica fruit extracts and its phenolic compounds demonstrated synergistic antibacterial activity when used in conjunction with chloramphenicol against both Gram-positive and Gram-negative bacteria. The combination of MICGA with ½MICChl exhibited a significant increase in bioactivity, with a 333.33-fold enhancement against B. subtilis. Similarly, the combination of MICGA with 2MICChl displayed a bioactivity enhancement of 16.02 folds against S. aureus. The co-administration of ½MICQ and ½MICChl resulted in a significant 35.71-fold increase in bioactivity against P. aeruginosa. Similarly, the combination of MIC GA and ½MICChl exhibited a remarkable 166.66-fold enhancement in bioactivity against E. coli. The combinations of 2MICFPE and ½MICChloramphenicol, as well as ½MICGA and ½MICChl demonstrated the highest bioactivity enhancement of 17.85 folds for K. pneumoniae. This study claimed that the fruit extracts of P. emblica and its phenolic compounds could be utilized to augment the effectiveness of conventional antibiotics, which have acquired resistance to bacterial infections.

Multitarget Potential of Phytochemicals from Traditional Medicinal Tree, Terminalia arjuna (Roxb. ex DC.) Wight & Arnot as Potential Medicaments for Cardiovascular Disease: An In-Silico Approach.

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Terminalia arjuna (Roxb. ex DC.) Wight & Arnot of the Combretaceae family is one of the most frequently approved and utilized medicinal trees in the traditional medicinal system, which was used for the treatment of a variety of diseases, including cardiovascular disorders. The present study aims to identify phytochemicals from T. arjuna, that do not exhibit any toxicity and have significant cardioprotective activity using an in-silico technique. Four different cardiovascular proteins, namely human angiotensin receptor (PDB ID: 4YAY), P38 mitogen-activated protein kinase (MAPK, PDB ID: 4DLI), 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co A) reductase (PDB ID: 1HW9), and human C-reactive protein (PDB ID: 1B09), were used as target proteins to identify potential inhibitors using a virtual screening of the phytochemicals in T. arjuna revealed casuarinin as a potential inhibitor of all selected target proteins with strong binding energy. Furthermore, MD simulations for a 100 ns time scale also revealed that most of the key protein contacts of all target proteins were retained throughout the simulation trajectories. Binding free energy calculations using the MM-GBSA approach also support a strong inhibitory effect of casuarinin on target proteins. Casuarinin's effective binding to these proteins lays the groundwork for the development of broad-spectrum drugs as well as the understanding of the underlying mechanism against cardiovascular diseases through in vivo and clinical studies.

Phytochemical Analysis, In Vitro Biological Activities, and Computer-Aided Analysis of Potentilla nepalensis Hook Compounds as Potential Melanoma Inhibitors Based on Molecular Docking, MD Simulations, and ADMET.

Potentilla nepalensis Hook is a perennial Himalayan medicinal herb of the Rosaceae family. The present study aimed to evaluate biological activities such as the antioxidant, antibacterial, and anticancer activities of roots and shoots of P. nepalensis and its synergistic antibacterial activity with antibacterial drugs. Folin-Ciocalteau and aluminium chloride methods were used for the calculation of total phenolic (TPC) and flavonoid content (TFC). A DPPH radical scavenging assay and broth dilution method were used for the determination of the antioxidant and antibacterial activity of the root and shoot extracts of P. nepalensis. Cytotoxic activity was determined using a colorimetric MTT assay. Further, phytochemical characterization of the root and shoot extracts was performed using the Gas chromatography-mass spectrophotometry (GC-MS) method. The TPC and TFC were found to be higher in the methanolic root extract of P. nepalensis. The methanolic shoot extract of P. nepalensis showed good antioxidant activity, while then-hexane root extract of P. nepalensis showed strong cytotoxic activity against tested SK-MEL-28 cells. Subsequently, in silico molecular docking studies of the identified bioactive compounds predicted potential anticancer properties. This study can lead to the production of new herbal medicines for various diseases employing P. nepalensis, leading to the creation of new medications.

Comparative genome analysis of commensal segmented filamentous bacteria (SFB) from turkey and murine hosts reveals distinct metabolic features.

BACKGROUND: Segmented filamentous bacteria (SFB) are intestinal commensal microorganisms that have been demonstrated to induce the innate and adaptive immune responses in mouse and rat hosts. SFB are Gram-positive, spore-forming bacteria that fail to grow optimally under in vitro conditions due to unique metabolic requirements. Recently, SFB have been implicated in improved health and growth outcomes in commercial turkey flocks. To assess the nature and variations in SFB of turkeys and how they may differ from mammalian-associated SFB, the genome of turkey-associated SFB was compared with six representative genomes from murine hosts using an in silico approach. RESULTS: The SFB-turkey genome is 1.6 Mb with a G + C content of 26.14% and contains 1,604 coding sequences (CDS). Comparative genome analyses revealed that all the seven SFB strain possesses a common set of metabolic deficiencies and auxotrophies. Specifically, the inability of all the SFB strains to synthesize most of the amino acids, nucleotides and cofactors, emphasizing the importance of metabolite acquisition from the host intestinal environment. Among the seven SFB genomes, the SFB-turkey genome is the largest and contains the highest number of 1,604 predicted CDS. The SFB-turkey genome possesses cellular metabolism genes that are absent in the rodent SFB strains, including catabolic pathways for sucrose, stachyose, raffinose and other complex glycans. Other unique genes associated with SFB-turkey genome is loci for the biosynthesis of biotin, and degradation enzymes to recycle primary bile acids, both of which may play an important role to help turkey associated SFB survive and secure mutualism with its avian host. CONCLUSIONS: Comparative genomic analysis of seven SFB genomes revealed that each strain have a core set of metabolic capabilities and deficiencies that make these bacteria challenging to culture under ex vivo conditions. When compared to the murine-associated strains, turkey-associated SFB serves as a phylogenetic outgroup and a unique member among all the sequenced strains of SFB. This turkey-associated SFB strain is the first reported non-mammalian SFB genome, and highlights the impact of host specificity and the evolution of metabolic capabilities.

Synergistic potential of essential oils with antibiotics to combat fungal pathogens: Present status and future perspectives.

The steady rise in the emergence of antibiotic-resistant fungal pathogens has rendered most of the clinical antibiotics available in the market to be ineffective. Therefore, alternative strategies are required to tackle drug-resistant fungal infections. An effective solution is to combine the available antibiotics with adjuvants such as phytochemicals or essential oils to enhance the efficacy and activity of antibiotics. The present review aims to summarize the studies on synergistic combinations of essential oils and anti-fungal antibiotics. The current findings, methods used for measuring synergistic effects, possible mechanisms of synergism, and future perspectives for developing synergistic EO-antibiotic therapeutic formulations are discussed in this study. Several essential oils exhibit synergistic effect in combination with antibiotics against human fungal pathogens such as Candida albicans. The possible mechanisms of synergy exhibited by essential oil- antibiotic combinations in fungi include disruption of cell wall structure/ ergosterol biosynthesis pathway, enhanced transdermal penetration of antibiotics, alterations in membrane permeability, intracellular leakage of cellular contents, inhibition of germ tube formation or fungal biofilm formation, and competition for a primary target. Synergistic combination of essential oils and antibiotics can prove to be a valid and pragmatic alternative to develop drugs with increased drug-efficacy, and low toxicity.

Distinct Osmoadaptation Strategies in the Strict Halophilic and Halotolerant Bacteria Isolated from Lunsu Salt Water Body of North West Himalayas.

Two strict halophilic bacterial strains, Halobacillus trueperi SS1, and Halobacillus trueperi SS3, and three halotolerant bacterial strains, Shewanella algae SS2, Halomonas venusta SS5, and Marinomonas sp. SS8 of Lunsu salt water body, Himachal Pradesh, India, were selected to study the mechanism of salt tolerance and the role of osmolytes therein. A combination of flame photometry, chromatographic and colorimetric assays was used to study the mechanism of salt tolerance in the selected strict halophilic and halotolerant bacterial strains. The strict halophiles and, one of the halotolerants, Marinomonas sp. SS8 were found to utilize both "salt-in strategy" and "accumulation of compatible solutes strategy" for osmoregulation in hypersaline conditions. On the contrary, the remaining two halotolerants used "accumulation of compatible solutes strategy" under saline stress and not the "salt-in strategy". The present study suggests towards distinct mechanisms of salt tolerance in the two classes, wherein strict halophiles accumulate compatible solutes as well as adopt salt-in strategy, while the halotolerant bacteria accumulate a range of compatible solutes, except Marinomonas sp. SS8, which utilizes both the strategies to combat salt stress.

Synergistic antibacterial activity of Phyllanthus emblica fruits and its phytocompounds with ampicillin: a computational and experimental study.

Phyllanthus emblica L. (syn. Emblica officinalis), popularly known as amla, Indian gooseberry, or the King of Rasyana, is a member of Phyllanthaceae family and is traditionally used in Ayurveda as an immunity booster. The present study aimed to investigate the synergistic interaction of Phyllanthus emblica (FPE) fruits and its selected phytocompounds with ampicillin against selected bacteria. Further, an in silico technique was used to find if major phytocompounds of FPE could bind to proteins responsible for antibiotic resistance in bacterial pathogens and enhance the bioactivity of ampicillin. FPE and all the selected phytocompounds were found to have synergistic antibacterial activity with ampicillin against tested bacteria in different combinations. However, ellagic acid and quercetin interactions with ampicillin resulted in maximum bioactivity enhancement of 32-128 folds and 16-277 folds, respectively. In silico analysis revealed strong ellagic acid, quercetin, and rutin binding with penicillin-binding protein (PBP-) 3, further supported by MD simulations. Ellagic acid and quercetin also fulfill Lipinski's rule, showing similar toxicity characteristics to ampicillin. FPE showed synergistic interaction with ampicillin, possibly due to the presence of phytocompounds such as gallic acid, ellagic acid, quercetin, and rutin. Molecular docking and MD simulations showed the strong interaction of ellagic acid and quercetin with PBP-3 protein. Therefore, these compounds can be explored as potential non-toxic drug candidates to combat bacterial antimicrobial resistance.

A review of botany, traditional applications, phytochemistry, pharmacological applications, and toxicology of Rubus ellipticus Smith fruits.

Rubus ellipticus Smith. (Family Rosaceae), often known as the yellow Himalayan raspberry (Yellow Hissar), is one of the most widely used edible fruits in Indian folk medicinal systems. The current review aims to identify the gap between research and existing applications of this fruit to help scientists explore the current trends and opportunities for future development. Fruits of R. ellipticus are the source of several classes of compounds. Fruits of R. ellipticus are also rich in nutrients such as carbohydrates, vitamins, and minerals. It has been shown to have significant medical value in a variety of studies, including as an anti-diabetic, nephroprotective, anti-inflammatory, analgesic, antipyretic, antitumor, wound healing, antifertility, oviposition deterrent, antibacterial, and antioxidant. Fruits of R. ellipticus have been the subject of several in vitro and in vivo investigations, all of which have corroborated their wide range of biological activities and demonstrated their potential for the identification of new therapeutic candidates and the development of innovative herbal food supplements. Additional mechanism-based pharmacological evaluation and clinical research should provide an adequate scientific basis for the traditional usage of R. ellipticus fruits, which is currently not sufficiently supported by the available research on its active components and molecular mechanisms.

A comprehensive review on traditional applications, phytochemistry, pharmacology, and toxicology of Thymus serpyllum.

Thymus serpyllum L. from the Lamiaceae family is an underexplored perennial medicinal shrub with traditional usage in treating respiratory and gastrointestinal issues in the upper foothills of India. This review aims to provide a comprehensive assessment of current knowledge concerning the traditional uses, phytochemistry, and pharmacology of T. serpyllum. The primary objective is to collect updated information on this plant and encourage further in vivo and in vitro research to validate local claims. Notably, the essential oil derived from T. serpyllum has gained significant attention as a plant-derived product due to its diverse pharmacological properties, including antioxidative, antimicrobial, anti-inflammatory, and anticancer activities. Ethnomedicinal research revealed a vast scope of T. serpyllum in developing new drugs to address numerous health sector challenges. While T. serpyllum has been used widely, pharmacological studies are not enough. Most studies are either in vivo or in vitro. More studies are required to assess these medicinal claims through well-planned pharmacological experiments. This review will provide the groundwork for future research. While T. serpyllum has been put to considerable conventional use, pharmacological studies are insufficient; most studies are either in vivo or in vitro. More compound isolation, comprehensive pharmacological analysis, and exploration of food applications are vital areas to investigate.

Molecular insights into the interaction of eighteen different variants of SARS-CoV-2 spike proteins with sixteen therapeutically important phytocompounds: in silico approach.

SARS-CoV-2 has mutated many times among different populations. We analyzed wild-type spike protein and 18 different variants of SARS-CoV-2 spike protein known until the beginning of 2022 (alpha, beta, B.1.429, B.1.616, B.1.620, B.1.617.3, C.1.2, delta, epsilon, eta, gamma, iota, kappa, lambda, mu, omicron, theta, and zeta) for their interaction with 16 phytocompounds and remdesivir, resulting into 425 combinations. The largest number of mutations has been reported in the omicron followed by delta variant. However, the virulence of the delta variant has been reported higher as compared to omicron. Mutations at a few locations (D215G, K417N, E484K, N501Y, D614G, and P681H) were common in most of the variants. 3 D structures of all the 18 spike proteins were created using SWISS-MODEL to test the binding affinities with caffeine theophylline, emodin, vitexin, berberine, curcumin, piperine, quercetin, artemisinin, carvacrol, capsaicin, tetrahydrocannabinol, cannabidiol, α- pinene, ß- pinene and gingerol. Phytocompounds and mutant variants were prepared using AutoDock 4.2.6 software. Binding affinities of the selected phytocompounds with the different mutant spike proteins were achieved using AutoDock Vina. Out of all combinations investigated, the best binding affinities were observed with 3 variants of SAR-CoV-2 with 5 phytocompounds along with remdesivir. The range of best binding energies varied from -9.1 to -8.0 kcal/mol. Further, MD simulation was done for selected 9 phytocompound-spike mutant complexes for analyzing the stability of interactions for 100 ns. ADMET studies via ProTox-II and SwissADME displayed that phytocompounds are safe and less toxic in comparison to remdesivir.Communicated by Ramaswamy H. Sarma.

Comprehensive mutational analysis of the checkpoint signaling function of Rpa1/Ssb1 in fission yeast.

Replication protein A (RPA) is a heterotrimeric complex and the major single-strand DNA (ssDNA) binding protein in eukaryotes. It plays important roles in DNA replication, repair, recombination, telomere maintenance, and checkpoint signaling. Because RPA is essential for cell survival, understanding its checkpoint signaling function in cells has been challenging. Several RPA mutants have been reported previously in fission yeast. None of them, however, has a defined checkpoint defect. A separation-of-function mutant of RPA, if identified, would provide significant insights into the checkpoint initiation mechanisms. We have explored this possibility and carried out an extensive genetic screening for Rpa1/Ssb1, the large subunit of RPA in fission yeast, looking for mutants with defects in checkpoint signaling. This screen has identified twenty-five primary mutants that are sensitive to genotoxins. Among these mutants, two have been confirmed partially defective in checkpoint signaling primarily at the replication fork, not the DNA damage site. The remaining mutants are likely defective in other functions such as DNA repair or telomere maintenance. Our screened mutants, therefore, provide a valuable tool for future dissection of the multiple functions of RPA in fission yeast. AUTHOR SUMMARY: Originally discovered as a protein required for replication of simian virus SV40 DNA, replication protein A is now known to function in DNA replication, repair, recombination, telomere maintenance, and checkpoint signaling in all eukaryotes. The protein is a complex of three subunits and the two larger ones are essential for cell growth. This essential function however complicates the studies in living cells, and for this reason, its checkpoint function remains to be fully understood. We have carried out an genetic screening of the largest subunit of this protein in fission yeast, aiming to find a non-lethal mutant that lacks the checkpoint function. This extensive screen has uncovered two mutants with a partial defect in checkpoint signaling when DNA replication is arrested. Surprisingly, although the two mutants also have a defect in DNA repair, their checkpoint signaling remains largely functional in the presence of DNA damage. We have also uncovered twenty-three mutants with defects in DNA repair or telomere maintenance, but not checkpoint signaling. Therefore, the non-lethal mutants uncovered by this study provide a valuable tool for dissecting the multiple functions of this biologically important protein in fission yeast.

A comprehensive review on the phytochemistry, pharmacological properties, and in vitro propagation of an endemic medicinal orchid, Dactylorhiza hatagirea.

Dactylorhiza hatagirea (D. Don) Soo, also known as Himalayan Marsh Orchid or Salam Panja, belongs to the Orchidaceae family. It is found in sub-alpine to alpine regions at 2500-5000 m above sea level. The present review aims to provide a comprehensive overview of the botany, phytochemistry, medicinal uses, toxicity, and conservation status of D. hatagirea and to find the research gaps to promote progress in studies of this orchid. Secondary metabolites, including alkaloids, terpenoids, flavonoids, phenolics, and saponins, were reported from the aerial and underground parts of this medicinal orchid. Several phytocompounds, such as dactylorhins A, B, C, D, and E and dactylose A and B, were isolated from the dried roots of D. hatagirea. A wide range of in vitro and in vivo assays was used to assess the biological properties of D. hatagirea, such as antirheumatic, anti-inflammatory, antiviral, diuretic, neuroprotective, antioxidant, wound healing, hypoglycemic, antitumor, antimicrobial, antiviral, and anticancer activities. It was also reported to boost testosterone levels, improving sexual desire and arousal. Due to overexploitation and a restricted habitat range, this essential medicinal plant has reached the extinction stage; therefore, a conservation-friendly harvesting approach is needed for this medicinal herb. In vitro techniques such as micropropagation, synthetic seed generation, and hairy root technology can contribute to its conservation. This review provides comprehensive insights into the botanical features, traditional uses, phytochemicals, pharmacological importance, and toxicity evaluation of this medicinal orchid. This review also provides detailed information on the conservation status of D. hatagirea and strategies to overcome the exploitation of this orchid.

Therapeutic potential and industrial applications of Terminalia arjuna bark.

ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia arjuna (Roxb. ex DC.) Wight & Arnot (Combretaceae) is one of the most frequently used medicinal trees in Indian traditional medicinal systems. It is used for the treatment of a variety of diseases including cardiovascular disorders. AIM OF THE STUDY: The purpose of this review was to provide a comprehensive overview of the phytochemistry, medicinal uses, toxicity, and industrial applications of T. arjuna bark (BTA), as well as to identify gaps in research and applications of this important tree. It also aimed to analyze trends and future research paths to utilize the full potential of this tree. MATERIALS AND METHODS: Extensive bibliographic research on the T. arjuna tree was carried out using scientific research engines and databases such as Google Scholar, PubMed, and Web of Science, covering all relevant English-language articles. The database "World Flora Online (WFO)" (http://www.worldfloraonline.org) was used to confirm plant taxonomy. RESULTS: To date, BTA has been traditionally employed for several disorders such as snakebites, scorpion stings, gleets, earaches, dysentery, sexual disorders, and urinary tract infections along with the cardioprotective activity. About 38 phytocompounds were identified from BTA and were classified as triterpenoids, tannins, flavonoids, and glycosides. A wide range of in vitro and in vivo pharmacological effects of BTA were reported such as anti-cancer, antimicrobial, antiviral, anti-inflammatory, antioxidant, hepatoprotective, anti-allergic, anti-diabetic, and wound healing activities. The oral administration of BTA (500 mg/kg) per day did not result in any toxicity in humans. The in vivo acute and sub-acute toxicity analysis of the methanol extract of BTA and one of its major compounds, 7-methyl gallate, did not produce any adverse effects up to a dose of 1000 mg/kg. CONCLUSIONS: This comprehensive review highlights various aspects of traditional knowledge, phytochemicals, and pharmacological significance of BTA. The review covered safety information on employing BTA in pharmaceutical dosage forms. Despite its long history of medicinal benefit, more studies are needed to understand the molecular mechanisms, structure-activity relationship, and potential synergistic and antagonistic effects of its phytocompounds, drug administration, drug-drug interactions, and toxicological effects.

Bacterial diversity in 110 thermal hot springs of Indian Himalayan Region (IHR).

Thermal hot springs are present throughout the world and constitute a unique habitat for microbial diversity. The current investigation is conducted to study the bacterial diversity of thermophilic microorganisms in thermal hot springs of the Indian Himalayan Region (IHR). As of today, 110 geothermal hot springs have been explored for microbial diversity. In this study, we observed that the growth of thermophilic bacteria isolated from thermal hot springs of IHR ranges between 40 and 100 °C, and pH of 3.5-8 have been reported in the literature. The major bacterial species reported from the thermal hot springs of IHR are Bacillus spp., Geobacillus spp., Paenibacillus spp., Pseudomonas spp., Anoxybacillus, Paenibacillus, Brevibacillus, Aneurinibacillus, Thermus aquaticus, Aquimonas, Flavobacterium, etc. Furthermore, bacterial isolates from thermal hot springs of IHR have been reported to produce various enzymes and metabolites such as amylase, ß-galactosidase, cellulase, nitrate reductase, acetoin, caffeine degradation enzymes, lipase, urease, and laccase. Metagenomic study and the entire genomic shotgun project have established the impact of physicochemical parameters (temperature and pH) on developing the microbiome. We have discussed the discoveries of microbiological data on the hot springs of IHR until the end of year 2021. As a whole, the microbiome adapts themselves as successful inhabitants to extreme environmental conditions and also serves as a diverse resource for potential applications in health, food, and environment.

Role of medicinal plants from North Western Himalayas as an efflux pump inhibitor against MDR AcrAB-TolC Salmonella enterica serovar typhimurium: In vitro and In silico studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Zingiber officinale Roscoe has been utilized traditionally to cure various diseases like cold, cough, diarrhoea, nausea, asthma, vomiting, toothache, stomach upset, respiratory disorders, joint pain, and throat infection. It is also consumed as spices and ginger tea. AIM OF THE STUDY: The current study was aimed to identify the phytocompounds of traditional medicinal plants of North-Western Himalaya that could inhibit the AcrAB-TolC efflux pump activity of Salmonella typhimurium and become sensitive to antibiotic killing at reduced dosage. MATERIAL AND METHODS: Medicinal plant extracts were prepared using methanol, aqueous, and ethyl acetate and tested for efflux pump inhibitory activity of Salmonella typhimurium NKS70, NKS174, and NKS773 strains using Ethidium Bromide (EtBr)-agar cartwheel assay. Synergism was assessed by the agar well diffusion method and EPI activity by berberine uptake and EtBr efflux inhibition assays. Microdilution method and checkerboard assays were done to determine the minimum inhibitory concentration (MIC) and fractional inhibitory concentration index (FICI) respectively for a bioactive compound. To validate the phytocompound and efflux pump interaction, molecular docking with 6IE8 (RamA) and 6IE9 (RamR) targets was done using autoDock vina software. Toxicity prediction and drug-likeness were predicted by using ProTox-II and Molinspiration respectively. RESULTS: Methanolic and ethyl acetate extracts of P. integerrima, O. sanctum, C. asiatica, M. charantia, Z. officinale, and W. somnifera in combination with ciprofloxacin and tetracycline showed synergistic antimicrobial activity with GIIs of 0.61-1.32 and GIIs 0.56-1.35 respectively. Methanolic extract of Z. officinal enhanced the antimicrobial potency of berberine (2 to 4-folds) and increased the EtBr accumulation. Furthermore, bioassay-guided fractionation leads to the identification of lariciresinol in ethyl acetate fraction, which decreased the MIC by 2-to 4-folds. The ΣFIC values varied from 0.30 to 0.55 with tetracycline, that indicated synergistic/additive effects. Lariciresinol also showed a good binding affinity with 6IE8 (-7.4 kcal mol-1) and 6IE9 (-8.2 kcal mol-1), which is comparable to tetracycline and chenodeoxycholic acid. Lariciresinol followed Lipinski's rule of five. CONCLUSION: The data suggest that lariciresinol from Z. officinale could be a potential efflux pump inhibitor that could lead to effective killing of drug resistant Salmonella typhimurium at lower MIC. Molecular docking confirmed the antibacterial EPI mechanism of lariciresinol in Salmonella typhimurium and confirmed to be safe for future use.

In vitro and in silico analysis of Thymus serpyllum essential oil as bioactivity enhancer of antibacterial and antifungal agents.

Wild thyme (Thymus serpyllum L.) of family Laminaceae is an unexplored perennial medicinal shrub. Aerial part of this plant is traditionally used for the treatment of respiratory and gastrointestinal problems. The current study was designed to evaluate the GC-MS, antimicrobial and synergistic potential of T. serpyllum essential oil (TEO). Chemical characterization of TEO showed the presence of thymol (15.79%), Phenol, 2-(1,1-dimethylethyl) (11.55%), o-Cymene (10.96%) as major phytocompounds. Antimicrobial activity of TEO in terms zone of inhibition (ZOI) varied from 13.66 ± 0.58 mm to 33.66 ± 1.52 mm, while, thymol (10%, v/v) showed ZOI ranged from 15.5 ± 0.5 mm to 26.33 ± 2.08 mm against tested bacterial and fungal species. MIC of TEO was 0.039% to 0.078% against tested bacterial and fungal species, whereas, thymol showed 1.25% to 2.5% MIC against tested bacterial and fungal species. Different combinations of TEO (2MIC to ½MIC) and thymol (2MIC to ½MIC) with antibacterial and antifungal antibiotics (2MIC to ½MIC) were found to increase the efficacy of antibiotics by 4-130 folds against bacterial and fungal pathogens. Molecular docking showed the good binding of thymol with both bacterial and fungal targets. Whereas MD simulation showed the stability of thymol complexed with target proteins over 100 ns time scale. Thymol also fulfills the Lipinski rule and showed characteristics similar to that of drugs. Therefore, it can be concluded from the present study that TEO and its major phytocompound, thymol can act as a bioactivity enhancer of antibacterial and antifungal antibiotics and could be used as a potential candidate to fight against antimicrobial drug resistance.Communicated by Ramaswamy H. Sarma.

A Review of Medicinal Plants of the Himalayas with Anti-Proliferative Activity for the Treatment of Various Cancers.

Cancer is a serious and significantly progressive disease. Next to cardiovascular disease, cancer has become the most common cause of mortality in the entire world. Several factors, such as environmental factors, habitual activities, genetic factors, etc., are responsible for cancer. Many cancer patients seek alternative and/or complementary treatments because of the high death rate linked with cancer and the adverse side effects of chemotherapy and radiation therapy. Traditional medicine has a long history that begins with the hunt for botanicals to heal various diseases, including cancer. In the traditional medicinal system, several plants used to treat diseases have many bioactive compounds with curative capability, thereby also helping in disease prevention. Plants also significantly contributed to the modern pharmaceutical industry throughout the world. In the present review, we have listed 33 medicinal plants with active and significant anticancer activity, as well as their anticancer compounds. This article will provide a basic set of information for researchers interested in developing a safe and nontoxic active medicinal plant-based treatment for cancer. The research will give a scientific foundation for the traditional usage of these medicinal herbs to treat cancer.

Bio-Inspired Smart Nanoparticles in Enhanced Cancer Theranostics and Targeted Drug Delivery.

Globally, a significant portion of deaths are caused by cancer.Compared with traditional treatment, nanotechnology offers new therapeutic options for cancer due to its ability to selectively target and control drug release. Among the various routes of nanoparticle synthesis, plants have gained significant recognition. The tremendous potential of medicinal plants in anticancer treatments calls for a comprehensive review of existing studies on plant-based nanoparticles. The study examined various metallic nanoparticles obtained by green synthesis using medicinal plants. Plants contain biomolecules, secondary metabolites, and coenzymes that facilitate the reduction of metal ions into nanoparticles. These nanoparticles are believed to be potential antioxidants and cancer-fighting agents. This review aims at the futuristic intuitions of biosynthesis and applications of plant-based nanoparticles in cancer theranostics.

Molecular docking studies of phytocompounds of Rheum emodi Wall with proteins responsible for antibiotic resistance in bacterial and fungal pathogens: in silico approach to enhance the bio-availability of antibiotics.

Rheum emodi Wall. (Himalayan rhubarb) has many pharmacological activities such as antioxidant, antimicrobial, antiviral, anticancer and wound healing. The present study was aimed to understand if major phytocompounds of Rheum emodi could bind proteins responsible for antibiotic resistance in bacterial and fungal pathogens and enhance the potency of antibiotics. The major phytocompounds of R. emodi (emodin, rhein-13c6 and chrysophenol dimethy ether) were retrieved from the Pubchem and target proteins were retrieved from RCSB protein data bank. The docking study was performed by using AutoDock vina software and Molinspiration, swiss ADME servers were used for the determination of Lipinski rule of 5, drug-likeness prediction respectively, whereas, admetSAR and Protox-II tools were used for toxicity prediction. To study the docking accuracy of protein-ligand complexes, MD simulation for 100 ns was done by using Desmond program version 2.0 (Academic version). Among all the selected phytocompounds, emodin showed the best binding affinity against bacterial (Penicillin binding protein 3, 3VSL and fungal target (cytochrome P450 14 alpha-sterol demethylase 1EA1) with binding energy -8.2 and -8.0 Kcal mol-1 respectively. Similarly, rhein-13C6 showed the best binding affinity against fungal target (n-myristoyl transferase 1IYL) with binding energy -8.0 Kcal mol-1 which is higher than antibacterial and antifungal antibiotics. All the selected phytocompounds also fulfill Lipinski rule, non-carcinogenic and non-cytotoxic in nature. These compounds also showed high LD50 value showing non-toxicity of these phytocompounds. MD simulation studies of phytocompounds (emodin and rhein-13C6) define the stability of protein-ligand complexes with in 100 ns time scale.Communicated by Freddie R. Salsbury.