Desmodin and isopongachromene as potential inhibitors of cyclin-dependent kinase 5: phytoconstituents targeting anticancer and neurological therapy.

Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine-threonine protein kinase vital for neuronal cell cycle arrest and differentiation. It activates by binding with p35 and p39 and is important for the functioning of the nervous system. A growing body of evidence suggests that CDK5 contributes to the onset and progression of neurodegeneration and tumorigenesis and represents itself as a potential therapeutic target. Our research illustrates virtual screening of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) library to search for potential inhibitors of CDK5. Initially, the compounds from the parent library were filtered out via their physicochemical properties following the Lipinski rule of five. Then sequentially, molecular docking-based virtual screening, PAINS filter, ADMET, PASS analysis, and molecular dynamics (MD) simulation were done using various computational tools to rule out adversities that can cause hindrances in the identification of potential inhibitors of CDK5. Finally, two compounds were selected via the extensive screening showing significant binding with CDK5 ATP-binding pocket and ultimately were selected as potent ATP-competitive inhibitors of CDK5. Finally, we propose that the elucidated compounds Desmodin and Isopongachromene can be used further in the drug discovery process and act as therapeutics in the medical industry to treat certain complex diseases, including cancer and neurodegeneration.Communicated by Ramaswamy H. Sarma.

Biocidal action, characterization, and molecular docking of Mentha piperita (Lamiaceae) leaves extract against Culex quinquefasciatus (Diptera: Culicidae) larvae.

Mosquitoes are found in tropical and subtropical areas and are the carriers of a variety of diseases that are harmful to people's health. e.g., malaria, filariasis, chikungunya, dengue fever, etc. Although several insecticides are available, however, due to insect resistance and environmental hazards, more eco-friendly chemicals are needed for insect control. So, the current research was planned to explore the prospective of Mentha piperita to be used for the formulation of larvicides against mosquito Culex quinquefasciatus. The ethanolic and water extracts of M. piperita leaves were prepared using the soxhlet apparatus. The extracts were dried and subjected to prepare five concentrations multiple of 80 ppm. Each concentration was applied for its larvicidal efficacy setting an experiment (in triplicate) in plastic containers of 1000 ml with extracts, 30 larvae of all four instars separately, and fed with dog biscuits along with controls. Observations were taken after each 12 hrs. till 72 hrs. The antioxidant perspective of M. piperita was determined by DPPH radical scavenging, total antioxidant capacity, and ferric reducing power assays. Using brine shrimp lethality bioactivity, the cytotoxic study was perceived. Standard techniques were used to classify the M. piperita extract using preliminary qualitative and quantitative phytochemicals, UV-Vis spectroscopy, FT-IR, and GC-MS analysis. M. piperita ethanolic leaves extract after 24 hrs. of exposure in 400 ppm showed 93% (LC50 = 208.976 ppm) mortality in ethanolic extract and 80% (LC90 = 246.900 ppm) in the water extract. In treated larvae, biochemical examination revealed a substantial (P<0.05) decrease in proteins, carbohydrates, and fat contents. The ethanol extract of M. piperita was the most efficient, killing brine shrimp nauplii in 50% to 90% of cases. TAC (125.4 3.5gAAE/mg DW) and FRP (378.1 1.0gAAE/mg DW) were highest in the ethanolic extract of M. piperita. The presence of medicinally active components such as alkaloids, carbohydrates, flavonoids, and others in M. piperita leaves extract in ethanol was discovered. The UV-Vis spectrum showed two peaks at 209.509 and 282.814 nm with the absorption of 2.338 and 0.796 respectively. The FT-IR consequences exhibited the occurrence of alcohols, alkanes, aldehyde, aromatic rings, ether linkage, ester, and halo- compounds. The GC-MS analysis according to peak (%) area and retention time showed ten phytochemicals consisting of six major and four minor compounds. Among all the compounds, 1, 2-benzene dicarboxylic acid, and 3-ethyl-5, 5-dimethyl -6-phenyl bound well to the NS3 protease domain with PDB ID: 2FOM. Hence, for the prevention of health hazards and mosquito control, M. Piperita is a potential source of chemicals for insecticide formulation.

Consensus statement on measures to promote equitable authorship in the publication of research from international partnerships.

Despite the acknowledged injustice and widespread existence of parachute research studies conducted in low- or middle-income countries by researchers from institutions in high-income countries, there is currently no pragmatic guidance for how academic journals should evaluate manuscript submissions and challenge this practice. We assembled a multidisciplinary group of editors and researchers with expertise in international health research to develop this consensus statement. We reviewed relevant existing literature and held three workshops to present research data and holistically discuss the concept of equitable authorship and the role of academic journals in the context of international health research partnerships. We subsequently developed statements to guide prospective authors and journal editors as to how they should address this issue. We recommend that for manuscripts that report research conducted in low- or middle-income countries by collaborations including partners from one or more high-income countries, authors should submit accompanying structured reflexivity statements. We provide specific questions that these statements should address and suggest that journals should transparently publish reflexivity statements with accepted manuscripts. We also provide guidance to journal editors about how they should assess the structured statements when making decisions on whether to accept or reject submitted manuscripts. We urge journals across disciplines to adopt these recommendations to accelerate the changes needed to halt the practice of parachute research.

The effect of 805 nm near-infrared photobiomodulation on proliferation and differentiation of bone marrow stem cells in murine rats.

OBJECTIVE: To evaluate the effect of near infra-red gallium-aluminium-arsenide (GaAlAs) diode laser (805 nm) irradiation on proliferation and differentiation of rat femoral bone marrow-derived mesenchymal stem cells (BMSCs) cultured in osteogenic medium. MATERIALS AND METHODS: BMSCs were obtained from femurs of 60 Sprague Dawley rats (200 gm). The control group comprised isolated BMSCs supplemented with an osteogenic differentiation medium. On the other hand, in the experimental group, the BMSCs were irradiated with a near-infrared laser in addition to an osteogenic differentiation medium. The experimental group was irradiated with a soft tissue laser comprising of allium-aluminium-arsenic (Ga-Al-Ar) Diode at a near-infrared wavelength of 805 nm in continuous mode. The different output powers applied were 0.5 W, 1.0 W, 1.5 W and 2.0 W respectively. Various energy levels of 1, 4, 7 and 10 J were used for irradiation. Alkaline phosphatase (ALP) assay and Alizarin staining were performed to confirm osteogenic differentiation. Statistical analysis was done using a one-way ANOVA and a p-value of <0.05 was considered significant. RESULTS: According to our findings, 1.27 J/cm2 was the optimal energy density value that significantly increased the BMSC proliferation at the output of 1.5 W with the power density of 1.27 W/cm2. On 1.27 J/cm2, there was a significant difference compared to the control group on the first day, and the osteogenic differentiation increased significantly on the 4th day compared to the 1st day. CONCLUSIONS: According to our findings, 1.27 J/cm2 was the optimal energy density value that significantly increased the BMSC proliferation at the output of 1.5 W with the power density of 1.27 W/cm2.

Assessment of antibacterial activity of Syzygium aromaticum extracts, antibiotics and silver sulphadiazine ointment against pathogenic bacteria isolated from the burned and unburned skin

Aims@#Skin burns remain a noteworthy general medical issue throughout the world, as it boosts a condition of immuno-suppression. The present research aimed to evaluate the efficacy of Syzygium aromaticum extracts, silver sulphadiazine ointment, and different commercially available topical antibiotics against pathogenic bacteria, isolated from the skin of burn patients.@*Methodology and results@#A total of 124 clinical pus samples were collected from the skin of burn patients, admitted to two different tertiary care burn units at Peshawar, Pakistan. From these pus samples, 6 bacterial isolates from burned skin (Staphylococcus epidermidis, Streptococcus, Klebsiella, Enterobacter, Bacillus and Pseudomonas spp.) were isolated, while 4 different bacterial isolates (Staphylococcus epidermidis, Staphylococcus aureus, Bacillus and Streptococcus spp.) were isolated from unburned skin via conventional culturing techniques. Further, antibacterial assays were performed to compare the efficacy of S. aromaticum extracts (methanolic and aqueous extract), silver sulphadiazine ointment, and different commercially available antibiotics against tested bacteria. It was observed that both methanolic and aqueous extracts of S. aromaticum were effective at all concentrations against all the tested bacteria. In addition, all the tested antibiotics expressed substantial activity against most of the bacterial isolates. While silver sulphadiazine ointment was observed to be less potent against isolated bacteria as compared to S. aromaticum extracts. @*Conclusion, significance and impact of study@#It was concluded that both aqueous and methanolic extracts of S. aromaticum were effective antimicrobial agents and could be used as an alternative to control bacterial infections of burn patients. This study would help to distinguish the risk factors of bacterial pathogenicity in burn patients and would also provide a guideline to utilize medicinal plants and their extracts to minimize the chances of antibiotic resistance phenomenon in burn patients.

Evidence-based neurosurgery. Basic concepts for the appraisal and application of scientific information to patient care (Part II).

Medical evidence is obtainable from approaches, which might be descriptive, analytic and integrative and ranked into levels of evidence, graded according to quality and summarized into strengths of recommendation. Sources of evidence range from expert opinions through well-randomized control trials to meta-analyses. The conscientious, explicit, and judicious use of current best evidence in making decisions related to the care of individual patients defines the concept of evidence-based neurosurgery (EBN). We reviewed reference books of clinical epidemiology, evidence-based practice and other previously related articles addressing principles of evidence-based practice in neurosurgery. Based on existing theories and models and our cumulative years of experience and expertise conducting research and promoting EBN, we have synthesized and presented a holistic overview of the concept of EBN. We have also underscored the importance of clinical research and its relationship to EBN. Useful electronic resources are provided. The concept of critical appraisal is introduced.

Atosiban and nifedipine in the suppression of pre-term labour: a comparative study.

This is a retrospective study comparing the efficacy and safety of atosiban and nifedipine in the suppression of pre-term labour. A total of 75 patients were included in this study; 34 received atosiban and 41 received nifedipine. There were no statistically significant differences in the baseline characteristics for both groups. A total of 68.3% of women in the atosiban group remained undelivered at 7 days or more, compared with 64.7% in the nifedipine group, which was not statistically significant. Average birth weight, admission to the neonatal intensive care unit and mode of delivery were similar in both groups. However, the gestational age at delivery was significantly higher in the nifedipine group. We concluded that atosiban and nifedipine are effective in delaying delivery for 7 days or more in women presenting with pre-term labour. They have the same efficacy and associated minor side-effects. However, flushing, palpitation and hypotension were significantly higher in the nifedipine group.

Gastroprotective activity of Nigella sativa oil and its constituent, thymoquinone, against gastric mucosal injury induced by ischaemia/reperfusion in rats.

Ischaemia/reperfusion (I/R) induced gastric lesion, is known to be linked with free radical (FR) formation. Therefore, this model was used to assess the antioxidant effects of Nigella sativa oil (N.O) and thymoquinone (TQ) on gastric mucosal redox state and gastric lesions, 1 and 24 h after reperfusion. Male Wistar rats were subjected to I/R and were injected with either N.O (2.5 and 5 ml/kg, p.o) or TQ (5, 20, 50 and 100 mg/kg, p.o). The results showed that I/R elevated the levels of lipid peroxide (LPX) and lactate dehydrogenase (LDH), while decreased those of reduced glutathione (GSH) and superoxide dismutase (SOD). These biochemical changes were accompanied by an increase in the formation of gastric lesions, which was reduced by either treatment. N.O tended to normalize the level of LDH, GSH and SOD. However, its effect to restore LPX was only seen 24 h after reperfusion. Moreover, the aforementioned parameters were nearly reinstated by TQ. On the other hand, high doses of TQ (50 and 100 mg/kg) severely reduced the GSH content, 1 h after reperfusion. These results indicate that both N.O and TQ possess gastroprotective effect against gastric lesions which may be related to the conservation of the gastric mucosal redox state.

Cross-reactivities between date palm (Phoenix dactylifera L.) polypeptides and foods implicated in the oral allergy syndrome.

BACKGROUND: Date fruit and pollen antigens share a number of cross-reactive epitopes. Date pollen has been shown to cross-react with antigens from Artemisia, cultivated rye (Secale cereale), Timothy grass (Phleum pratense), Sydney golden wattle (Acacia longifolia) and Bermuda grass (Cynodon dactylon) pollen. The present study was carried out to examine any cross-reactivities between date palm polypeptides and antigens of some common foods and vegetables that have been implicated in the oral allergy syndrome (OAS). Because most of such cross-reactivities in other allergens are attributable to the presence of carbohydrate chains and profilin, their role was also investigated. METHODS: Fresh extracts of 20 common fruits and vegetables were prepared. Putative date profilins were isolated by affinity chromatography using a poly L-proline column. Date fruit extracts were digested by various endoglycosidases and the immunoglobulin (Ig)E binding of the postdigest products was assessed in immunoblots. Rabbit antisera to whole date fruit extracts, Timothy grass profilin and putative date profilins, as well as human sera from date sensitive individuals were used in immunoblotting, ELISA and in inhibition experiments. RESULTS: IgG, ELISA and immunoblot results with the different rabbit antisera and date-sensitive atopic sera showed several antigenic cross-reactivities and similar cross-reactivities were seen with birch, date and timothy grass profilins. IgE, ELISA and immunoblot experiments with pooled date sensitive human sera showed a range of cross-reactivities with some food extracts. A number of the IgE cross-reactivities could be inhibited after preabsorption of pooled sera with date extracts. Sixty-six percent of individual date hypersensitive human sera bound IgE in putative date fruit profilin and their pooled sera bound IgE in birch pollen profilin. IgE-binding of the endoglycosidase digested date fruit extracts to atopic serum pool was restricted to only a very low molecular weight band of 6.5-8 kDa. CONCLUSION: These results indicate that date palm polypeptides share cross-reactive IgG and IgE epitopes with a number of foods implicated in the oral allergy syndrome, bind to birch and Timothy grass profilins and bind IgE through glycosyl residues. The clinical relevance of these cross-reactivities needs to be further elucidated.

The effect of Nigella sativa oil against the liver damage induced by Schistosoma mansoni infection in mice.

It has been reported that Nigella sativa oil possesses anticestode and antinematode actions. Besides, it produced a hepatoprotective effect in some models of liver toxicity. Therefore, our aim in this work was to study the effect of the Nigella oil (N.O) on Schistosomiasis mansoni infected mice. The oil was given in two dose levels (2.5 and 5 ml/kg, orally for two weeks) either alone or in combination with praziquantel (PZQ), the drug of choice for the treatment of schistosomiasis. Three aspects of drug action were investigated, the effect on Schistosomiasis mansoni infection, the effect on liver functions, and on redox state. The parasitological investigation included worm distribution, oogram pattern and ova count. Furthermore, liver granuloma diameters were measured. The biochemical parameters were the serum level of L-alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (AP), albumin (Alb) and total protein. Moreover, to assess the antioxidant capability of the Nigella oil, four parameters were studied, viz., liver lipid peroxide (LPD) and reduced glutathione (GSH) contents and the activity of the defence enzyme superoxide dismutase (SOD) and lactate dehydrogenase (LDH). When the oil was given alone, it reduced the number of S. mansoni worms in the liver and decreased the total number of ova deposited in both the liver and the intestine. Furthermore, it increased the number of dead ova in the intestinal wall and reduced the granuloma diameters markedly. When N.O was administered in combination with PZQ, the most prominent effect was a further lowering in the dead ova number over that produced by PZQ alone. Concerning the biochemical parameters, infection of mice with S. mansoni produced a pronounced elevation in the serum activity of ALT, GGT, with a slight increase in AP level. However, it tended to reduce serum albumin level. These changes were accompanied with an alteration in the liver contents of LPD and GSH along with a significant decline in the activity of the cytosolic SOD and LDH. Administration of Nigella sativa oil succeeded partially to correct the previous changes in ALT, GGT, AP activity, as well as the Alb content in serum. However, it failed in the liver to restore either LPD and GSH content or LDH and SOD activities to normal level. These results suggest that Nigella sativa oil may play a role against the alterations caused by S. mansoni infection, an effect which may be induced partly by improving the immunological host system and to some extent with its antioxidant effect.

Synthesis and evaluation of novel aldose reductase inhibitors: Effects on lens protein kinase Cgamma.

PURPOSE: To synthesize novel aldose reductase inhibitors (ARI) that will normalize losses in protein kinase Cgamma (PKCgamma) observed during diabetes and galactosemia. METHODS: ARI were synthesized as tricyclic pyrones 1-6 (HAR-1 through HAR-6) from 3-methyl-1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran and (5aS,7S)-7-isopropenyl-3-methyl-1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran and were tested by inhibition of aldose reductase enzyme activity in vitro and by inhibition of polyol formation in lens epithelial cells in culture. Identified compounds were further tested in galactosemic rat lens in vivo for (a) normalized PKCgamma levels by Western blot, (b) reduction of phosphorylation of the gap junction protein Cx46 by analyses of co-immunoprecipitated proteins, and (c) by normalization of gap junction activity as measured by dye transfer. RESULTS: HAR-1 (1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran-3-acetic acid) was identified as an ARI with IC50 for aldose reductase inhibition at 2 nM. Polyol accumulation in lens epithelial cells was reduced by 80% at 10 microM. Rats fed 40% galactose for 9 days had an 80% reduction in PKCgamma levels which were normalized by HAR-1 at 100 mg/kg/day, fed orally. Phosphorylation of Cx46 was increased by 50% and this was normalized in HAR-1 treated rats (6 day treatment). Gap junction activity of galactosemic rats was reduced by 55% and this was normalized by HAR-1 in six day-treated rats. CONCLUSIONS: HAR-1 is a novel ARI which normalized losses of PKCgamma, changes in Cx46 phosphorylation, and gap junction activity.

Ingenane diterpenes from Euphorbia petiolata.

From the whole plants of Euphorbia petiolata, four new ingenane-type diterpenoids, 3,20-O-diacetylingenol 5-O-(2' E,4' Z)-tetradecadienoate (1), 5,20-O-diacetylingenol 3- O-(2' E,4' Z)-tetradecadienoate (2), ingenol 3-O-(2' E,4' Z)-tetradecadienoate (3), and 5,20-O-isopropylidenylingenol 3-O-(2' E,4' Z)-tetradecadienoate (4) were isolated. Their structures were elucidated by spectroscopic methods and chemical transformations.

Maternal mortality in Giza, Egypt: magnitude, causes, and prevention.

This article presents results from a population-based study of the magnitude and causes of maternal mortality in the Giza governorate of Egypt in 1985-86. Deaths to women in the reproductive ages were identified through the death registration system. Family members of the deceased were interviewed using the "verbal autopsy" approach. Immediate and underlying causes of death were then assessed by a medical panel. This methodology allows for the classification of multiple causes of death and is appropriate when registration of adult deaths is nearly complete, but reporting on cause of death on death certificates is poor. Of all reproductive-age deaths, 19 percent were maternal deaths. The maternal mortality ratio for Giza is estimated to be, at minimum, 126 maternal deaths per 100,000 live births. The maternal mortality rate is estimated to be, at minimum, 22 maternal deaths per 100,000 women aged 15-49, over 100 times the rate in Sweden. An average of 2.3 causes per maternal death were reported; the most common causes were postpartum hemorrhage (31 percent of cases) and hypertensive diseases of pregnancy, such as toxemia and eclampsia (28 percent of cases). Women experiencing hemorrhage, hypertensive diseases of pregnancy, or other serious complications must have easy access to hospital and maternity centers equipped for handling these conditions. Since most deliveries occur at home, many with the help of traditional birth attendants, TBAs will need training in early diagnosis, treatment, and/or effective referral of problem pregnancies.

PIP: Researchers analyzed death records of 156 women who died from obstetric causes between August 1985-August 1986 collected from 5 health sectors in Giza, Egypt to examine incidence and causes of maternal deaths. Social workers interviewed family members about circumstances of the mother's pregnancy and death (verbal autopsy approach). The maternal mortality ratio stood at 126 deaths/100,000 live births and the rate stood at 22/100,000 15-49 year old women). The cumulative risk of maternal death was at least 1 in 155 women. 50% died at a maternity center or a hospital. Remaining deaths occurred at home, another person's home, en route to the hospital, or the traditional birth attendent's (TBA) home. 35-39 year old women had the highest maternal mortality rate (40.5) while 15-19 year old women had the lowest (6.6). 24% of maternal deaths occurred to women of at least parity 7. Even though family members and the medical panel concluded that medical complications (39.1% vs. 25%) such as heart failure and hemorrhage (19.2% vs. 30.7%) were the major causes of maternal mortality, the most frequently reported causes of death as determined by the medical panel were postpartum hemorrhage (31.4%), hypertensive disease of pregnancy (27.6%), and other maternal complications (25.6%) such as prolonged and obstructed labor. This discrepancy can be explained by the fact that 70% of the mothers died of multiple causes. The researchers emphasized the need to train TBAs to diagnose problem pregnancies and to treat or refer them to hospitals or maternity centers. Health professionals used the medical profiles produced for each deceased women to formulate prevention strategies for specific cause of death strategies. The leading policy implication of this study was that most of the maternal deaths could have been prevented.

Maternal mortality in Indonesia and Egypt.

Twenty-three percent of deaths to women of reproductive age (15-49 years) in Bali, Indonesia and Menoufia, Egypt were due to maternal causes. Among the younger women, the percentage was even higher. In both areas complications of pregnancy and childbirth were a leading cause of death (the first cause in Bali, the second in Menoufia). In both sites, postpartum hemorrhage was the most common cause of maternal death. Relative to the United States, the number of maternal deaths per 100,000 live births was 20 times higher in Menoufia and 78 times higher in Bali. Families of women of reproductive age who died were interviewed about the conditions leading to death and other characteristics of the deceased. Completed histories were reviewed by a Medical Panel who were able to assign a cause of death in more than 90% of cases. Two-thirds of the maternal deaths occurred to women who were over 30 and/or who had 3 children--the usual targets of family planning programs. Other possible intervention strategies include antenatal outreach programs, training of traditional birth attendants, and better hospital management of obstetric emergencies.

Effect of exposure to radiation on the inflammatory process and its influence by diclofenac.

The effect of radiation exposure on the inflammatory process was studied in rats using the carrageenan-induced paw oedema and adjuvant-induced arthritis tests. Irradiation (0.5,1 and 2 Grays) resulted in a significant augmentation of the tissue response to carrageenan and the early phase of adjuvant-induced arthritis, but suppressed the late phase. Diclofenac (1-5 mg kg-1) effectively reduced the exaggerated inflammatory response in irradiated animals in both the carrageenan paw oedema and adjuvant-induced arthritis tests. The drug also had a prophylactic value in guarding against the induction of radiation damage. The inflammatory responses produced by irradiation and the benefits obtained by drug treatment may be related to changes in tissue prostaglandin levels and/or changes in the immune system.

Penicillamine as an adjuvant to antimonial therapy of schistosomiasis: effect on liver function tests in rabbits and on antischistosomal activity.

Earlier work has shown that penicillamine reduces the acute toxicity of antimonyl potassium tartrate (APT) as well as the abnormal ECG changes it induces. In the present study, the possible protective effect of penicillamine on the hepatic toxicity of APT was investigated. Tests of liver function showed changes in the level of serum aspartate and alanine aminotransferase and of alkaline phosphatase, and in the beta-/alpha-lipoprotein ratio, in response to antimony treatment. The changes were significantly reduced by penicillamine, though the effect depended on the dose. Penicillamine was found to give the best overall protection without affecting the antischistosomal efficacy of the antimonial when a 1:2 APT/penicillamine ratio was used. The findings provide further evidence of the potential usefulness of penicillamine in the antimonial treatment of schistosomiasis.