Modulating the antibacterial effect of the existing antibiotics along with repurposing drug metformin.

Owing to the extensive prevalence of resistant bacteria to numerous antibiotic classes, antimicrobial resistance (AMR) poses a well-known hazard to world health. As an alternate approach in the field of antimicrobial drug discovery, repurposing the available medications which are also called antibiotic resistance breakers has been pursued for the treatment of infections with antimicrobial resistance pathogens. In this study, we used Haloperidol, Metformin and Hydroxychloroquine as repurposing drugs in in vitro (Antibacterial Antibiotic Sensitivity Test and Minimum Inhibitory Concentration-MIC) and in vivo (Shigellosis in Swiss albino mice) tests in combination with traditional antibiotics (Oxytetracycline, Erythromycin, Doxycycline, Gentamicin, Ampicillin, Chloramphenicol, and Penicillin) against a group of AMR resistance bacteria (Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Shigella boydii). After observing the results of the conducted in vitro experiments we studied the effects of the above non antibiotic drugs in combination with the said antibiotics. As an repurposing adjuvant antibiotic drug, Metformin exhibited noteworthy activity in almost all in vitro, in vivo and in silico tests (Zone of inhibition for 30 to 43 mm for E.coli in combination with Doxycycline; MIC value decreased 50 µM to 0.781 µM with Doxycycline on S. boydii).In rodents Doxycycline and Metformin showed prominent against Shigellosis in White blood cell count (6.47 ± 0.152 thousand/mm3) and Erythrocyte sedimentation rate (10.5 ± 1.73 mm/hr). Our findings indicated that Metformin and Doxycycline combination has a crucial impact on Shigellosis. The molecular docking study was performed targeting the Acriflavine resistance protein B (AcrB) (PDB ID: 4CDI) and MexA protein (PDB ID: 6IOK) protein with Metformin (met8) drug which showed the highest binding energy with - 6.4 kcal/mol and - 5.5 kcal/mol respectively. Further, molecular dynamics simulation revealed that the docked complexes were relatively stable during the 100 ns simulation period. This study suggest Metformin and other experimented drugs can be used as adjuvants boost up antibiosis but further study is needed to find out the safety and efficacy of this non-antibiotic drug as potent antibiotic adjuvant.

Iron-Catalyzed Transfer Hydrogenation of Allylic Alcohols with Isopropanol.

Herein, we report an iron-catalyzed transfer hydrogenation of allylic alcohols. The operationally simple protocol employs a well-defined bench stable (cyclopentadienone)iron(0) carbonyl complex as a precatalyst in combination with K2CO3 (4 mol %) and isopropanol as the hydrogen donor. A diverse range of allylic alcohols undergo transfer hydrogenation to form the corresponding alcohols in good yields (33 examples, ≤83% isolated yield). The scope and limitations of the method have been investigated, and experiments that shed light on the reaction mechanism have been conducted.

Quantitative Evaluation of EEG-Biomarkers for Prediction of Sleep Stages.

Electroencephalography (EEG) is immediate and sensitive to neurological changes resulting from sleep stages and is considered a computing tool for understanding the association between neurological outcomes and sleep stages. EEG is expected to be an efficient approach for sleep stage prediction outside a highly equipped clinical setting compared with multimodal physiological signal-based polysomnography. This study aims to quantify the neurological EEG-biomarkers and predict five-class sleep stages using sleep EEG data. We investigated the three-channel EEG sleep recordings of 154 individuals (mean age of 53.8 ± 15.4 years) from the Haaglanden Medisch Centrum (HMC, The Hague, The Netherlands) open-access public dataset of PhysioNet. The power of fast-wave alpha, beta, and gamma rhythms decreases; and the power of slow-wave delta and theta oscillations gradually increases as sleep becomes deeper. Delta wave power ratios (DAR, DTR, and DTABR) may be considered biomarkers for their characteristics of attenuation in NREM sleep and subsequent increase in REM sleep. The overall accuracy of the C5.0, Neural Network, and CHAID machine-learning models are 91%, 89%, and 84%, respectively, for multi-class classification of the sleep stages. The EEG-based sleep stage prediction approach is expected to be utilized in a wearable sleep monitoring system.

Convergence between global BCG vaccination and COVID-19 pandemic.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has kept the whole world in tenterhooks due to its severe life-threatening infectious disease, COVID-19. The virus is distinct from its cousins, SARS-CoV and MERS-CoV in terms of severity of the infection. The obligated killing properties of the SARS-CoV-2 virus is mediated by its unique structure. Efforts for developing vaccines for COVID-19 are ongoing, but it is unlikely to be available in the immediate future. Due to the absence of precise treatment, the investigators are discovering other effective, protective, and healing choices. However, the lower than a predictable number of SARS-CoV-2 cases in countries with fragile health systems is mystifying. Recently, there has been a buzz about the protective effect of Bacille Calmette-Guérin (BCG) vaccine in COVID-19 through long-term boosting of trained immunity. Based on epidemiological correlations, we link up that BCG vaccination adopted by different countries might influence the SARS-CoV-2 transmission patterns and/or COVID-19 associated mortality through the vaccine's capacity to confer heterologous protection. A number of clinical studies are underway to investigate this possibility but even if they prove effective-many questions will remain. Moreover, responsible stewardship of the BCG vaccine in the context of the COVID-19 epidemic is directly needed.

Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer.

Macro-autophagy (autophagy) is a highly conserved eukaryotic intracellular process of self-digestion caused by lysosomes on demand, which is upregulated as a survival strategy upon exposure to various stressors, such as metabolic insults, cytotoxic drugs, and alcohol abuse. Paradoxically, autophagy dysfunction also contributes to cancer and aging. It is well known that regulating autophagy by targeting specific regulatory molecules in its machinery can modulate multiple disease processes. Therefore, autophagy represents a significant pharmacological target for drug development and therapeutic interventions in various diseases, including cancers. According to the framework of autophagy, the suppression or induction of autophagy can exert therapeutic properties through the promotion of cell death or cell survival, which are the two main events targeted by cancer therapies. Remarkably, natural products have attracted attention in the anticancer drug discovery field, because they are biologically friendly and have potential therapeutic effects. In this review, we summarize the up-to-date knowledge regarding natural products that can modulate autophagy in various cancers. These findings will provide a new position to exploit more natural compounds as potential novel anticancer drugs and will lead to a better understanding of molecular pathways by targeting the various autophagy stages of upcoming cancer therapeutics.

Co-targeting of lysosome and mitophagy in cancer stem cells with chloroquine analogues and antibiotics.

The catabolic autophagy eliminates cytoplasmic components and organelles via lysosomes. Non-selective bulk autophagy and selective autophagy (mitophagy) are linked in intracellular homeostasis both normal and cancer cells. Autophagy has complex and paradoxical dual role in cancers; it can play either tumour suppressor or tumour promoter depending on the tumour type, stage, microenvironment and genetic context. Cancer stem cells (CSCs) cause tumour recurrence and promote resistant to therapy for driving poor clinical consequences. Thus, new healing strategies are urgently needed to annihilate and eradicate CSCs. As chloroquine (CQ) analogues show positive clinical outcome in several clinical trials either standalone or combination with several chemotherapies. Moreover, CQ analogues are known to eliminate CSCs via altering DNA methylation. However, several obstacles such as higher concentrations and dose-dependent toxicity are noticeable in the treatment of cancers. As tumour cells predominantly rely on mitochondrial actions, mitochondrial targeting FDA-approved antibiotics are reported to effectively eradicate CSCs alone or combination with chemotherapy. However, antibiotics cause metabolic glycolytic shift in cancer cells for survival and repopulation. This review will provide a sketch of the inhibiting roles of current chloroquine analogues and antibiotic combination in CSC autophagy process and discuss the possibility that pre-clinical and clinical potential therapeutic strategy for anticancer therapy.

Flavonoids compounds from Tridax procumbens inhibit osteoclast differentiation by down-regulating c-Fos activation.

The total flavonoids from Tridax procumbens (TPFs) have been reported significantly to suppress on RANKL-induced osteoclast differentiation and bone resorption in mouse primary cultured osteoclasts. However, the effects of ethyl ether fraction of Tridax procumbens flavonoids (TPF) on osteoclastogenesis remain unknown. In this study, we investigated the effects of TPF on lipopolysaccharides (LPS)-induced osteoclast differentiation, actin ring formation, and explored its molecular mechanism in vitro. Matured osteoclast was counted as the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, and activity of osteoclast was assessed by performing the pit formation assays. Real-time polymerase chain reaction (RT-PCR) was performed for evaluation of the expression of osteoclast differentiation-related genes. TPF reduced the TRAP-positive multinucleated osteoclasts, inhibited TRAP and acid phosphatase (ACP) activities and decreased the expression of osteoclast differentiating genes, including cathepsin K, metalloproteinase-2 (MMP-2), MMP-9, MMP-13 and osteoclast-associated receptor (OSCAR). Furthermore, osteoclast-dependent actin rings formation and resorption pits were dramatically inhibited by the treatment with TPF. TPF markedly decreased the expression levels of transcription factors such as c-Fos, nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and activator protein-1 (AP-1). Taken together, our findings indicated that TPF suppressed both osteoclast differentiation and activities. Therefore, TPF might be a promising and emerging drug candidate for the treatment of bone diseases such as osteoporosis.

Potential of a fly gut microbiota incorporated gel-based larval diet for rearing Bactrocera dorsalis (Hendel).

BACKGROUND: The Oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae), is an important polyphagous pest of horticultural produce. The sterile insect technique (SIT) is a proven control method against many insect pests, including fruit flies, under area-wide pest management programs. High quality mass-rearing process and the cost-effective production of sterile target species are important for SIT. Irradiation is reported to cause severe damage to the symbiotic community structure in the mid gut of fruit fly species, impairing SIT success. However, studies have found that target-specific manipulation of insect gut bacteria can positively impact the overall fitness of SIT-specific insects. RESULTS: Twelve bacterial genera were isolated and identified from B. dorsalis eggs, third instars larval gut and adults gut. The bacterial genera were Acinetobacter, Alcaligenes, Citrobacter, Pseudomonas, Proteus, and Stenotrophomonas, belonging to the Enterobacteriaceae family. Larval diet enrichment with the selected bacterial isolate, Proteus sp. was found to improve adult emergence, percentage of male, and survival under stress. However, no significant changes were recorded in B. dorsalis egg hatching, pupal yield, pupal weight, duration of the larval stage, or flight ability. CONCLUSIONS: These findings support the hypothesis that gut bacterial isolates can be used in conjunction with SIT. The newly developed gel-based larval diet incorporated with Proteus sp. isolates can be used for large-scale mass rearing of B. dorsalis in the SIT program.

Tridax procumbens flavonoids: a prospective bioactive compound increased osteoblast differentiation and trabecular bone formation.

BACKGROUND: The Tridax procumbens extracts (TPE) are known for their ethno-medicinal properties to increase osteogenic functioning in mesenchymal stem cells. Recently, we found that the T. procumbens flavonoids (TPF) significantly suppressed the RANKL-induced osteoclasts differentiation and bone resorption. The TPF also promoted osteoblasts differentiation and bone formation demonstrated by increasing bone formation markers in cultured mouse primary osteoblasts. However, the effects of the TPF on in vivo bone formation remain unclear. In this study, we investigated the effects of the TPF on in vivo bone formation, injected the TPF (20 mg/kg) twice a day in the low calcium diet mice and killed them after 21 day. Radiographic and histomorphometric analyses were performed on the dissected bones to determine the anabolic effects of the TPF. RESULTS: Bone mineral density and bone mineral content of the TPF-treated mice were significantly increased compared to the control mice. Bone formation-related indices like osteoblast number, osteoblast surface, bone volume, mineralizing surface, mineral apposition rate and bone formation rate were significantly increased in the TPF-treated mice compared to the control mice. CONCLUSION: Our findings point towards the stimulation of bone formation by TPF, suggested that the TPF could be a potential natural anabolic agent to treat patients with bone loss-associated diseases such as osteoporosis.

Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases.

Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases.

Flavonoids isolated from Tridax procumbens (TPF) inhibit osteoclasts differentiation and bone resorption.

BACKGROUND: The Tridax procumbens flavonoids (TPF), are well known for their medicinal properties among local natives. The TPF are traditionally used for dropsy, anaemia, arthritis, gout, asthma, ulcer, piles, and urinary problems. It also used in treating gastric problems, body pain, and rheumatic pains of joints. The TPF have been reported to increase osteogenic functioning in mesenchymal stem cells. However, their effects on osteoclastogenesis remain unclear. The TPF isolated from T. procumbens and investigated the effects of the TPF inhibit on osteoclast differentiation and bone resorption activities using primary osteoclastic cells. Osteoclast formation was assessed by counting the number of tartrate resistant acid phosphatase (TRAP) positive multinucleated cells and by measuring both TRAP activities. RESULTS: The TPF significantly suppressed the RANKL-induced differentiation of osteoclasts and the formation of pits in primary osteoclastic cells. The TPF also decreased the expression of mRNAs related to osteoclast differentiation, including Trap, Cathepsin K, Mmp-9, and Mmp-13 in primary osteoclastic cells. The treatment of primary osteoclastic cells with the TPF decreased Cathepsin K, Mmp-9, and Mmp-13 proteins expression in primary osteoclastic cells. CONCLUSION: These results indicated that TPF inhibit osteoclastogenesis and pits formation activities. Our results suggest that the TPF could be a potential anti-bone resorptic agent to treat patients with bone loss-associated diseases such as osteoporosis.

Tridax procumbens flavonoids promote osteoblast differentiation and bone formation.

BACKGROUND: Tridax procumbens flavonoids (TPFs) are well known for their medicinal properties among local natives. Besides traditionally used for dropsy, anemia, arthritis, gout, asthma, ulcer, piles, and urinary problems, it is also used in treating gastric problems, body pain, and rheumatic pains of joints. TPFs have been reported to increase osteogenic functioning in mesenchymal stem cells. Our previous study showed that TPFs were significantly suppressed the RANKL-induced differentiation of osteoclasts and bone resorption. However, the effects of TPFs to promote osteoblasts differentiation and bone formation remain unclear. TPFs were isolated from Tridax procumbens and investigated for their effects on osteoblasts differentiation and bone formation by using primary mouse calvarial osteoblasts. RESULTS: TPFs promoted osteoblast differentiation in a dose-dependent manner demonstrated by up-regulation of alkaline phosphatase and osteocalcin. TPFs also upregulated osteoblast differentiation related genes, including osteocalcin, osterix, and Runx2 in primary osteoblasts. TPFs treated primary osteoblast cells showed significant upregulation of bone morphogenetic proteins (BMPs) including Bmp-2, Bmp-4, and Bmp-7. Addition of noggin, a BMP specific-antagonist, inhibited TPFs induced upregulation of the osteocalcin, osterix, and Runx2. CONCLUSION: Our findings point towards the induction of osteoblast differentiation by TPFs and suggested that TPFs could be a potential anabolic agent to treat patients with bone loss-associated diseases such as osteoporosis.

Pesticidal and pest repellency activities of rhizomes of Drynaria quercifolia (J. Smith) against Tribolium castaneum (Herbst).

BACKGROUND: Tribolium castaneum (Herbst) is a harmful pest of stored grain and flour-based products in tropical and subtropical region. In the present study, rhizome of Drynaria quercifolia (J. Smith) was evaluated for pesticidal and pest repellency activities against T. castaneum, using surface film method and filter paper disc method, respectively. In addition, activity of the isolated compound 3,4-dihydroxybenzoic acid was evaluated against the pest. RESULTS: Chloroform soluble fraction of ethanol extract of rhizome of D. quercifolia showed significant pesticidal activity at doses 0.88 to 1.77 mg/cm(2) and significant pest repellency activity at doses 0.94 to 0.23 mg/cm(2). No pesticidal and pest repellency activity was found for petroleum ether, ethyl acetate and methanol soluble fractions of ethanol extract as well as for 3,4-dihydroxybenzoic acid. CONCLUSION: Considering our findings it can be concluded that chloroform soluble fraction of rhizome of D. quercifolia is useful in controlling T. castaneum of stored grain and flour-based products.

Tuberculosis-diabetes comorbidities: Mechanistic insights for clinical considerations and treatment challenges.

Tuberculosis (TB) remains a leading cause of death among infectious diseases, particularly in poor countries. Viral infections, multidrug-resistant and ex-tensively drug-resistant TB strains, as well as the coexistence of chronic illnesses such as diabetes mellitus (DM) greatly aggravate TB morbidity and mortality. DM [particularly type 2 DM (T2DM)] and TB have converged making their control even more challenging. Two contemporary global epidemics, TB-DM behaves like a syndemic, a synergistic confluence of two highly prevalent diseases. T2DM is a risk factor for developing more severe forms of multi-drug resistant-TB and TB recurrence after preventive treatment. Since a bidirectional relationship exists between TB and DM, it is necessary to concurrently treat both, and promote recommendations for the joint management of both diseases. There are also some drug-drug interactions resulting in adverse treatment outcomes in TB-DM patients including treatment failure, and reinfection. In addition, autophagy may play a role in these comorbidities. Therefore, the TB-DM comorbidities present several health challenges, requiring a focus on multidisciplinary collaboration and integrated strategies, to effectively deal with this double burden. To effectively manage the comorbidity, further screening in affected countries, more suitable drugs, and better treatment strategies are required.

Mechanistic insights into fasting-induced autophagy in the aging heart.

Autophagy is a prosurvival mechanism for the clearance of accumulated abnormal proteins, damaged organelles, and excessive lipids within mammalian cells. A growing body of data indicates that autophagy is reduced in aging cells. This reduction leads to various diseases, such as myocardial hypertrophy, infarction, and atherosclerosis. Recent studies in animal models of an aging heart showed that fasting-induced autophagy improved cardiac function and longevity. This improvement is related to autophagic clearance of damaged cellular components via either bulk or selective autophagy (such as mitophagy). In this editorial, we summarize the mechanisms of autophagy in normal and aging hearts. In addition, the protective effect of fasting-induced autophagy in cardiac aging has been highlighted.

Evaluation of In Vitro Antimicrobial, Cytotoxic, Thrombolytic, and Antiarthritic Property of Different Parts of Bari Orchid.

Many different herbal extracts have historically been utilized to treat microbe-induced infections, injuries, cancer, thrombosis, and arthritis. The purpose of this study was to determine the antibacterial, cytotoxic, in vitro thrombolytic, and in vitro antiarthritic properties of ethanolic extracts of stem and seed of Bari orchid 1 (BO) plant. This orchid plant was developed by the Bangladesh Agriculture Research Institute (BARI) in Gazipur. Fourteen microbes were employed in the antimicrobial investigation, and samples of orchids were compared to ciprofloxacin as a reference. The BO/seed extract was found to possess more antibacterial activity. The lethality test of brine shrimps was used to assess the LC50 values. The BO/stem extract exhibited a higher cytotoxicity potential, in comparison to the BO/seed extract. Two concentrations (1000 and 100 ppm) and two incubation times (24 hours and 1.5 hours) were used to assess the thrombolytic activity of the extracts. Regarding the thrombolytic effect, the BO/stem extract has demonstrated greater promise. Furthermore, the herbal extract's antiarthritic activity was investigated at four different concentrations, and the results were evaluated in comparison with those of diclofenac sodium. When comparing BO/stem extract to other extracts, the greatest values for protein denaturation were obtained.

The impact of unconditional cash and food assistance on contraceptive expenditure of rural households in Coastal Bangladesh: Evidence from fuzzy RDD.

This study investigates the impact of unconditional cash and food (UCF) assistance on the monthly contraceptive expenditure of rural households in coastal Bangladesh using a fuzzy regression discontinuity design (RDD). Eligibility for UCF assistance was based on the running variable of land ownership in acres. We used eligibility as an instrumental variable to estimate the local average treatment effect of UCF assistance on contraceptive expenditures. The results show that UCF assistance results in increases in monthly contraceptive expenditures.