Using past performance to improve future clinical outcomes in pressure ulcer prevention.

OBJECTIVE: Episodes of inpatient care-related pressure ulcers (PU) lead to deleterious effects on patient quality of life, and additional costs associated with wound dressings, staff visits and hospitalisation. Accurate prediction of future incidence may be helpful in defining strategies for benchmarking and resource management. Observations of category 2 or above PUs during episodes of care at an NHS Foundation Trust were recorded monthly from 2010 to 2020. Trust-specific interventions designed to reduce PU incidence, such as procurement of specialised staff and equipment, were also recorded. This study aimed to investigate the historical pattern of PU incidence in the Trust to assess intervention effectiveness in reducing PU incidence, and to use historical data to derive estimates of future incidence. METHOD: Time-series analysis was conducted on monthly PU incidence data to quantify underlying trends, seasonality and effect of interventions, and to derive a suitable model to predict future incidence levels. RESULTS: Mean monthly PU incidence gradually reduced from 20.3 during 2012 to 5.08 during 2019; with a negative linear trend in the presence of concurrent seasonal effects. There was limited evidence that implementation of specific interventions was associated with raised rates of reduction; however, incidence reductions during intervention periods continued from lower baselines. Best estimate predictions revealed that incidence is likely to stay at current levels or below for the foreseeable future. CONCLUSION: Past data can be used to model future episodes of inpatient care PU occurrence. Interventions may be effective in reducing PU incidence rates.

Effect of transforming growth factor-ß3 on mono and multilayer chondrocytes.

Articular cartilage is an avascular and flexible connective tissue found in joints. It produces a cushioning effect at the joints and provides low friction to protect the ends of the bones from wear and tear/damage. It has poor repair capacity and any injury can result pain and loss of mobility. Transforming growth factor-beta (TGF-ß), a cytokine superfamily, regulates cell function, including differentiation and proliferation. Although the function of the TGF-ßs in various cell types has been investigated, their function in cartilage repair is as yet not fully understood. The effect of TGF-ß3 in biological regulation of primary chondrocyte was investigated in this work. TGF-ß3 provided fibroblastic morphology to chondrocytes and therefore overall reduction in cell proliferation was observed. The length of the cells supplemented with TGF-ß3 were larger than the cells without TGF-ß3 treatment. This was caused by the fibroblast like cells (dedifferentiated chondrocytes) which occupied larger areas compared to cells without TGF-ß3 addition. The healing process of the model wound closure assay of chondrocyte multilayer was slowed down by TGF-ß3, and this cytokine negatively affected the strength of chondrocyte adhesion to the cell culture surface.

Trends in prescription and cost of Sativex, a cannabinoid-based medicine, in treating patients with multiple sclerosis in England.

Aim: Cannabis-based medication has recently been made available in the NHS for reducing pain and spasticity in patients with multiple sclerosis (MS). The currently available preparation of Sativex (nabiximols) contains a combination of botanical cannabis extracts with cannabidiol (CBD) and tetrahydrocannabinol (THC) with almost equal amounts in addition to minor cannabinoids and terpenoids and is delivered via an oro-mucosal spray. The present study aims to examine the use and trends in prescribing cannabinoid-based Sativex to control pain in patients diagnosed with MS. Methods: Primary care prescribing data for cannabinoid-based Sativex (2013-2022) from the Prescription Cost Analysis were extracted and analysed. Linear regression analyses were performed to examine prescription trends and prescription costs (average change per year). Results: There was a general increasing trend in the number of prescriptions each year, from 4.42 items dispensed per 100,000 people in 2013 to 5.15 in 2022. Overall, prescription items for cannabinoid-based Sativex increased by 0.34% per year (95% CI:-3.98, 4.67, p = 0.860) on average between 2013 and 2022. On average, a 2.43% (95% CI: -5.78, 0.92, p = 0.133) increase per year was observed for the costs of cannabinoid-based Sativex from 2013 to 2022. Conclusion: The results suggested that cannabinoid-based Sativex should be considered an option due to its effectiveness, acceptable tolerance, and safety profile in the prescribing of Sativex.

Could cannabinoids provide a new hope for ovarian cancer patients?

It is known that gynecological cancers remain a worldwide problem and as shown by the statistics, there is a need for new gynecological cancer treatments. Cannabinoids, the pharmacologically active compounds of the Cannabis sativa plant, have been used for many centuries by individuals as a symptomatic treatment to alleviate pain, nausea, vomiting, and to help stimulate appetite. Research has revealed that cannabinoids also exert anti-cancer activity such as anti-proliferative and pro-apoptotic effects through a variety of mechanisms. There is significant value in the development of these compounds as anti-cancer therapies in clinical practice as they do not produce the typical toxic side effects that exist with conventional therapies and recent clinical trials have shown their great tolerability by patients at high doses. Cannabinoids can induce psychoactive effects that could limit their progression. Therefore, non-psychoactive cannabinoids are attracting pharmacological interest due to their inability to produce psychological effects. Recent studies have focussed on non-psychoactive cannabinoids in ovarian cancer and have revealed promising pre-clinical results that indicate that these compounds may have potential benefits in the treatment of these cancers. However, there are still unanswered questions and research gaps that need to be addressed. This review summarizes the current understanding of this topic and identifies the current gaps in knowledge that provide a useful direction for future work.

The impact of COVID-19 on electronic repeat dispensing (eRD) in general practice.

BACKGROUND: Electronic repeat dispensing (eRD) has been part of the community pharmacy contact since 2005 and a requirement in the General Medical Services contract since 2019. NHS England highlights benefits of eRD as increased efficiency in general practice of 2.7 million hours annually if 80% of all repeat prescriptions are issued as eRD. Despite clear benefits to patients, community pharmacies and general practices, the uptake of eRD remains low and variable across general practices in West Yorkshire, UK. OBJECTIVES: To investigate the impact of COVID-19 on eRD in general practice and understand the key enablers to its uptake. METHODS: A 19-item questionnaire was developed and piloted during cognitive interviews. A cross-sectional survey was conducted via emails to general practices in West Yorkshire, UK, between July 2020 and November 2020. RESULTS: Sixty-seven complete responses were received (23 pharmacists, 21 practice managers, 11 general practitioners, seven pharmacy technicians, four advanced practitioners, one prescription clerk). 59% of respondents were aware of eRD uptake in their surgery (mean value 4.56% ± 0.229%). Higher uptake of eRD was demonstrated where the general practice integrated eRD into routine workflows during the repeat prescription reauthorisation process (P < 0.001) and where an eRD service lead is nominated (P = 0.04). CONCLUSION: Utilising eRD in the respective practices should be considered due to potential efficiency gains and the increase in average eRD utilisation observed in the study participating general practices was from 7.2% average uptake in March 2020 to 10.4% November 2020, as the response to COVID-19. The stated benefits of eRD by NHS England of 2.7 million hours per annum predates the roll out of electronic transmission of prescriptions suggesting further research is needed to quantify the efficiency gains in present NHS general practice environments.

Investigation of the cytotoxicity induced by cannabinoids on human ovarian carcinoma cells.

Cannabinoids have been shown to induce anti-tumor activity in a variety of carcinoma cells such as breast, prostate, and brain. The aim of the present study is to investigate the anti-tumor activity of cannabinoids, CBD (cannbidiol), and CBG (cannabigerol) in ovarian carcinoma cells sensitive and resistant to chemotherapeutic drugs. Sensitive A2780 cells and resistant A2780/CP70 carcinoma cells and non-carcinoma cells were exposed to varying concentrations of CBD, CBG, carboplatin or CB1 and CB2 receptor antagonists, AM251 and AM630, respectively, alone or in combination, at different exposure times and cytotoxicity was measured by MTT assay. The mechanism of action of CBD and CB in inducing cytotoxicity was investigated involving a variety of apoptotic and cell cycle assays. Treatment with CBD and CBG selectively, dose and time dependently reduced cell viability and induced apoptosis. The effect of CBD was stronger than CBG in all cell lines tested. Both CBD and CBG induced stronger cytotoxicity than afforded by carboplatin in resistant cells. The cytotoxicity induced by CBD was not CB1 or CB2 receptor dependent in both carcinoma cells, however, CBG-induced cytotoxicity may involve CB1 receptor activity in cisplatin-resistant carcinoma cells. A synergistic effect was observed when cannabinoids at sublethal doses were combined with carboplatin in both carcinoma cells. The apoptotic event may involve loss of mitochondrial membrane potential, Annexin V, caspase 3/7, ROS activities, and cell cycle arrest. Further studies are required to investigate whether these results are translatable in the clinic. Combination therapies with conventional cancer treatments using cannabinoids are suggested.

Potential approaches using teneligliptin for the treatment of type 2 diabetes mellitus: current status and future prospects.

INTRODUCTION: Based on pharmacological properties and results from clinical studies, teneligliptin has a great potential to be used as an alternate-day therapy and also the daily dose can be reduced to 10 mg. Clinical data also suggest its excellent efficacy and safety among older subjects. AREAS COVERED: We have reviewed and discussed potential approaches using teneligliptin for the treatment of type 2 diabetes mellitus (T2DM) including alternate-day therapy and reduction of dose from 20 mg to 10 mg per day. We have also discussed the potential of teneligliptin to address the needs of older patients with T2DM. EXPERT OPINION: It is an excellent option for use in older patients as studies in the geriatric population have shown encouraging results. Teneligliptin has a desirable pharmacokinetic profile that makes it a potential drug for use on an alternate-day basis. Teneligliptin has shown anti-diabetic efficacy even at a dose of 10 mg. These approaches may improve treatment satisfaction and patient compliance and can lower the cost; however, it is crucial to identify the subset of T2DM patients who can obtain maximum benefits. To verify these effects, large clinical investigations need to be planned and robust clinical evidence should be generated.

COVID-19 and diabetes in 2020: a systematic review.

Attempts were made to review the literature on diabetic patients who experience complications when they contract COVID-19, and to determine whether ethnicity and other risk factors play an important role in the development of symptoms and their severity, as well as responding to medications. A literature search was performed using five keywords, namely COVID-19, diabetes, ethnicity, medications, and risk factors between January 2019 and December 2020 using electronic databases such as PubMed, Science Direct, Google Scholar, Springer Link, and Scopus. Forty studies were included. The review indicated that diabetes was a significant risk factor for poorer outcomes and increased mortality associated with COVID-19. There were several risk factors for diabetic patients that increased their likelihood of poorer outcomes associated with COVID-19. These included black and Asian ethnicity, male sex with high BMI. In conclusion, patients with diabetes of black or Asian origin with high BMI, male sex, and older age had an increased risk of poorer outcomes associated with COVID-19. This highlights the importance of considering the history of the patient in prioritising care and treatment.

Ovarian cancer and KiSS-1 gene expression: A consideration of the use of Kisspeptin plus Kisspeptin aptamers in diagnostics and therapy.

Gynaecological cancers continue to present a significant health burden upon the health of the global female population. This deficit is most prominent with ovarian cancer which possesses the lowest survival rate compared to all other cancers occurring within this anatomical region, with an annual UK-mortality of 7,300. The poor tolerability and selectively of the treatment options that are currently available is likely to have contributed to this high mortality rate thus, demonstrating the need for the development of enhanced therapeutic approaches. Aptamer technology would involve the engineering of specifically sequenced oligonucleotide chains, which bind to macromolecular targets with a high degree of affinity and selectively. Recent in-vitro studies conducted upon the clinical utility of this technique have supported its superiority in targeting individual therapeutic drug targets compared to various other targeting moieties currently within therapeutic use such as, monoclonal antibodies. For this reason, the employment of this technique is likely to be favourable in reducing the incidence of non-specific, chemotherapy-associated adverse effects. Kisspeptin is a naturally expressed polypeptide with an established role in the development of the reproductive system and other proposed roles in influencing the ability of ovarian cancer growths to exhibit the metastasis hallmark. This distinctive feature would indicate the potential for the manipulation of this pathway through the application of aptamer structures in developing a novel prophylactic strategy and improve the long-term outcome for ovarian cancer patients.

Investigation of the cytotoxicity induced by didocosahexaenoin, an omega 3 derivative, in human prostate carcinoma cell lines.

The aim of the present study was to investigate the cytotoxicity induced by an omega-3 derivative, didocosahexaenoin (Dido) on human prostate carcinoma cells and to compare the cytotoxicity to that of docosahexaenoic acid (DHA). Different carcinoma- and non-carcinoma cells were exposed to various concentrations of omega-3 compounds at varying exposure times and the cytotoxicity was measured by MTT assay. The mechanism of Dido-induced apoptosis was investigated in prostate carcinoma cells. Dido induced stronger cytotoxicity than DHA in human prostate carcinoma cells in a dose- and time-dependent manner. Dido was also more selective and potent in inducing cytotoxicity in prostate carcinoma cells than other carcinoma cell lines tested. Pre-treatment with Dido increased the level of reactive oxygen species (ROS) in prostate carcinoma cells. Pre-treatment with various antioxidants reduced the cytotoxicity induced by Dido. Pre-treatment with Dido ≥30 â€‹µM also induced apoptosis which was suggested to involve an externalisation of phosphatidyl serine, a significant increase in the mitochondrial membrane potential (p â€‹< â€‹0.01) and the level of activated caspase 3/7 (p â€‹< â€‹0.05) in prostate carcinoma cells. This study is the first to show that Dido induced cytotoxicity with high selectivity and higher potency than DHA in human prostate carcinoma cells. The mechanism of action is likely to involve an increase in the level of ROS, loss in the mitochondrial membrane potential as well as externalisation of phosphatidyl serine and increase in the caspase 3/7 activity. Dido may have potential to be used for the adjuvant therapy or combination therapy with conventional chemotherapeutic drugs.

Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein-Protein Interaction Inhibitors with an Alternative Binding Mode.

Inhibitors of Kelch-like ECH-associated protein 1 (Keap1) increase the activity of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) by stalling its ubiquitination and degradation. This enhances the expression of genes encoding proteins involved in drug detoxification, redox homeostasis, and mitochondrial function. Nrf2 activation offers a potential therapeutic approach for conditions including Alzheimer's and Parkinson's diseases, vascular inflammation, and chronic obstructive airway disease. Non-electrophilic Keap1-Nrf2 protein-protein interaction (PPI) inhibitors may have improved toxicity profiles and different pharmacological properties to cysteine-reactive electrophilic inhibitors. Here, we describe and characterize a series of phenyl bis-sulfonamide PPI inhibitors that bind to Keap1 at submicromolar concentrations. Structural studies reveal that the compounds bind to Keap1 in a distinct "peptidomimetic" conformation that resembles the Keap1-Nrf2 ETGE peptide complex. This is different to other small molecule Keap1-Nrf2 PPI inhibitors, including bicyclic aryl bis-sulfonamides, offering a starting point for new design approaches to Keap1 inhibitors.

Establishing and Evaluating a Study Questionnaire on Knowledge and Attitudes of Healthcare Professionals Towards Recreational and Medical Cannabis Across Europe.

BACKGROUND AND OBJECTIVE: The present survey was a preliminary to a European research project on the attitude and knowledge of healthcare professionals towards the use of medical cannabis. The objective was to evaluate the readability, understandability, and relevance of a first version of the study questionnaire before preparing the finalized questionnaire, which will be subsequently proposed to European healthcare professionals on a large scale. METHODS: A cross-sectional study was conducted between December 2019 and May 2020. We established an electronic evaluation questionnaire relating to the study questionnaire. This evaluation questionnaire was proposed to multidisciplinary experts from all over Europe. Feedback from the evaluation questionnaire was considered for improving and finalizing the study questionnaire. RESULTS: 66 evaluation questionnaires were collected from nine European countries (Cyprus, France, Germany, Italy, Lithuania, Portugal, Spain, Sweden, United Kingdom), which corresponded to a participation rate of 41.5%. Most participants were women (65.2%, n = 43). The mean age was 39.5 years ± 11.6. Each participant could specify several occupations. There were 25 pharmacologists, 24 physicians, ten pharmacists, four university teachers, three epidemiologists or public health experts, one nurse, one biotechnologist, one microbiologist, and one police researcher. Overall, 84.8% of participants were interested in the topic of the survey on the knowledge and attitudes of healthcare professionals towards recreational and medical cannabis across Europe. Participants were satisfied with all but six of the proposed questions. In addition, two additional questions were subject for comments despite a high level of satisfaction. Consequently, the concerned questions (n = 8) were modified. CONCLUSION: This evaluation survey was a necessary step to improve the quality of the future research project. The positive feedback encourages the authors to proceed with the project on a European scale, scheduled for 2021.

Frequency of beta S globin gene haplotypes among sickle cell patients in Nigeria.

OBJECTIVE: To determine the frequency of beta s globin gene haplotypes in Nigerian patients with sickle cell disease (SCD) and to measure their correlation with clinical and haematological characteristics. METHODS: This study enrolled patients with SCD and collected their peripheral blood for restriction fragment length polymorphism analysis in order to identify five polymorphic sites in the ß-globin gene cluster. RESULTS: A total of 245 homozygous SCD patients (490 alleles) were included in the study. Among the analysed alleles, 426 (86.9%) had the Benin (BEN) haplotype; 19 (3.9%) had the Senegal (SEN) haplotype; 31 (6.3%) had the Cameroon haplotype; five (1.0%) had the Bantu/Central African Republic haplotype; and nine 9 (1.8%) had atypical haplotypes. No significant association was observed between the haplotypes and haematological events, although patients with the BEN/SEN haplotype showed improved red blood cell counts, haemoglobin levels and red blood cell width index. No significant association was observed between the haplotypes and the three clinical manifestations, although patients with the BEN/SEN haplotype showed a four-fold lower frequency of painful episodes. CONCLUSION: These findings suggest that the SEN haplotype combined with the BEN haplotype might contribute toward a better haematological profile and milder clinical severity in SCD.

Fluoxetine selectively induces p53-independent apoptosis in human colorectal cancer cells.

Fluoxetine has been shown to induce anti-tumour activity. The aim of this study was to determine the effect of fluoxetine on HCT116+/+ and p53 gene-depleted HCT116-/- human colorectal cancer cells and the mechanisms, including potential p53-dependence, of its action. Fluoxetine-induced apoptosis was investigated by mitochondrial membrane potential assay, Annexin V assay, two-step cell cycle analysis using NC-3000™ system and pharmacological inhibition assays. Fluoxetine induced very selectively concentration-dependent apoptosis in human colorectal cancer cells by altering mitochondrial membrane potential and inducing translocation of phosphatidylserine to the outer membrane layer. Further evidence of the preponderance of apoptosis in fluoxetine-induced cell death is provided by the finding that the cell death was not blocked by inhibitors of parthanatos, a form of cell death that results from overactivation of the enzyme poly (ADP-ribose) polymerase (PARP) but is different from apoptosis. Data obtained indicate fluoxetine caused cell cycle event at Sub-G1 and G0/G1 phases in both cell lines. In terms of apoptosis, there is no significant difference between the responses of the two cell lines to fluoxetine. In conclusion, fluoxetine's cytotoxicity induces mainly apoptosis and causes DNA fragmentation in human colorectal cancer cells, which seemed to be independent of the p53 protein, as no significant difference in death profiles in response to fluoxetine treatment was observed in both the p53-intact and the p53-deleted cell lines. Fluoxetine, therefore, has potential for being repurposed as a drug for the treatment of colon cancer and thus deserves further investigations in this context.

Selective in vitro anti-cancer activity of non-alkylating minor groove binders.

Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating Strathclyde Minor Groove Binders (S-MGBs), including 14 novel compounds, for in vitro anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several S-MGBs with activities comparable to cis-platin and carboplatin, but with better in vitro selectivity indices, particularly S-MGB-4, S-MGB-74 and S-MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our S-MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, S-MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our S-MGBs are unlikely to act through an alkylating or DNA damage response mechanism.

Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells.

Ovarian cancer represents the seventh most commonly diagnosed cancer worldwide. Herein, we report on the development of a withaferin A (WA)-silyl ether library with 30 analogues reported for the first time. Cytotoxicity assays on human epithelial ovarian carcinoma cisplatin-sensitive and -resistant cell lines identified eight analogues displaying nanomolar potency (IC50 ranging from 1 to 32 nM), higher than that of the lead compound and reference drug. This cytotoxic potency is also coupled with a good selectivity index on a nontumoral cell line. Cell cycle analysis of two potent analogues revealed cell death by apoptosis without indication of cell cycle arrest in G0/G1 phase. The structure-activity relationship and in silico absorption, distribution, metabolism, and excretion studies demonstrated that the incorporation of silicon and a carbonyl group at C-4 in the WA framework enhances potency, selectivity, and drug likeness. These findings reveal analogues 22, 23, and 25 as potential candidates for clinical translation in patients with relapsed ovarian cancer.

Use of Central Nervous System (CNS) Medicines in Aged Care Homes: A Systematic Review and Meta-Analysis.

BACKGROUND: Both old age and institutionalization in aged care homes come with a significant risk of developing several long-term mental and neurological disorders, but there has been no definitive meta-analysis of data from studies to determine the pooled estimate of central nervous system (CNS) medicines use in aged care homes. We conducted this systematic review to summarize the use of CNS drugs among aged care homes residents. METHODS: MEDLINE, EMBASE, CINAHL, Scopus, and International Pharmaceutical Abstracts (IPA) databases were searched (between 1 January 2000 and 31 December 2018) to identify population-based studies that reported the use of CNS medicines in aged care homes. Pooled proportions (with 95% confidence interval), according to study location were calculated. RESULTS: A total of 89 studies reported the use of CNS medicines use in aged care. The pooled estimate of CNS drugs use varied according to country (from 20.3% in Ireland to 49.0% in Belgium) and region (from 31.7% in North America to 42.5% in Scandinavia). The overall pooled estimate of psychotropic medicines use was highest in Europe (72.2%, 95% CI, 67.1-77.1%) and lowest in ANZ region (56.9%, 95% CI, 52.2-61.4%). The pooled estimate of benzodiazepines use varied widely from 18.9% in North America to 44.8% in Europe. The pooled estimate of antidepressants use from 47 studies was 38.3% (95% CI 35.1% to 41.6%) with highest proportion in North America (44.9%, 95% CI, 35.3-54.5%). CONCLUSION: The overall use of CNS drugs varied among countries, with studies from Australia-New Zealand reported the lowest use of CNS drugs. The criteria for prescribing CNS drugs in clinical practice should be evidence-based. The criteria should be used not to prohibit the use of the listed medications but to support the clinical judgement as well as patient safety.

Further investigation of the effects of 5-hydroxytryptamine, 8-OH-DPAT and DOI to mediate contraction and relaxation responses in the intestine and emesis in Suncus murinus.

5-HT receptors are implicated in many gastrointestinal disorders. However, the precise role of 5-HT in mediating GI responses in Suncus murnius is still unclear. Therefore in this study, the effects of 5-HT and its agonists were investigated in Suncus. The involvement of 5-HT2C receptors in mediating emesis was also investigated. The ability of 5-HT and its agonists/antagonists at 5-HT1A and 5-HT2 to modify GI motility was investigated in vitro and in vivo. WAY100635 (a 5-HT1A antagonist) inhibited the contraction response to 5-HT in the proximal segments without affecting the maximum response; whilst enhancing the contraction to 5-HT (>30.0nM) in the distal intestine. The selective 5-HT2A and 5-HT2B receptor antagonists MDL-100907 and RS-127445 attenuated 5-HT-induced contractions (<10.0µM) in the distal segments. RS-127445 also attenuated 5-HT-induced contractions in the central segments. The selective 5-HT2C receptor antagonist SB-242084, attenuated the responses to 5-HT (> 3.0nM) in the proximal and central but not the distal regions. 8-OH-DPAT-induced relaxation was resistant to the antagonism by 5-HT1A/7 antagonists. DOI in the presence of 5-HT1A/2A/2B/2C antagonists induced greater contraction responses (>1.0µM) in most tissues, whilst RS-127445, or SB-242084, reduced the responses to DOI (< 1.0µM) in some tissues. SB-242084 also suppressed emesis-induced by motion and intragastric CuSO4. In conclusion, within different regions of intestine, 5-HT2 receptors are differently involved in contraction and emetic responses and that 8-OH-DPAT induces relaxation via non-5-HT1A/7 receptors. Suncus could provide a model to investigate these diverse actions of 5-HT.

Induction of HT-29 Colon Cancer Cells Apoptosis by Pyrogallol with Growth Inhibiting Efficacy Against Drug-Resistant Helicobacter pylori.

BACKGROUND: Colon cancer is the most aggressive form of cancers, that causes 0.5 million deaths per year around the globe. Targeting colon cancer by conventional therapeutic options elicits toxicity. Traditional medicines take a lead to alleviate the existing clinical challenges. OBJECTIVE: To investigate antibacterial activity against Helicobacter Pylori and in vitro anti-colon cancer activity by Acacia nilotica extract (ACE) and its active constituent pyrogallol. METHODS: Pyrogallol isolated from A. nilotica by column chromatography and HPLC and structure was elucidated by spectral analysis. Antibacterial activity was done by flow cytometry. Cytotoxicity was measured by MTT assay. Apoptotic morphology and nuclear fragmentation were assessed with AO/ethidium bromide and DAPI staining. DNA fragmentation was done by electrophoresis. Western blot used to analyze the molecular mechanism of apoptosis. Cell cycle arrest was determined using flow cytometry of propidium iodide stained cells. Cell migration was determined by wound healing assay. RESULTS: ACE (20 µg/ml) and pyrogallol (10 µg/ml) treatment reduced the survival of H.pylori at 61% and 62%, respectively. MTT results show that HT-29 cells are more sensitive to pyrogallol with an IC50 value of 35µg/ml compared to ACE. Pyrogallol treated HT-29 cells reached dead state i.e. late apoptotic state with severe nuclear fragmentation. Pyrogallol elicits dose dependent DNA fragmentation in HT-29 cells. Pyrogallol induced apoptosis by simultaneous down-regulation of Bcl-2 and up-regulation of BAX and cytochrome c. Pyrogallol arrested HT-29 cells in S and G2/M phase of cell cycle. Further pyrogallol exhibited marked antimetastatic potential by inhibiting the migration of HT-29 cells dose dependently. CONCLUSION: Both ACE and pyrogallol repressed the growth of H.pylori and as significant anti-colon cancer agent.

Role of Dietary Crocin in In Vivo Melanoma Tumor Remission

Background: Melanoma is a deadly form of malignancy. Early diagnosis might pave the way to cure but its aggressive nature leads to rapid dissemination and colonization of distant organs. Dietary herbs may play a significant role in prevention of cancer. In this study, we tested anti-tumor efficacy of the Crocus sativus derived active constituent crocin, it is well established to have anti-cancer properties in different cancer models by our group and other groups. Notably, crocin is reported to exert anti-proliferative effect on melanoma cells (B16F10) in vitro. However, roles of crocin on in vivo melanoma tumor remission have not yet been reported to our knowledge. Materials and Methods: Melanoma tumor model was established by transplanting B16F10 (5 X 105) cells into C57BL/6 mice, which were then observed for tumor development and once the tumor volume reached 6 mm, mice were divided into (Group I: tumor-bearing animals treated with normal saline and Group II: counterparts treated with crocin at 2 mg/kg body weight for 21 days). . Tumor remission and tumor growth related parameters such as tumor silent period (TSP), tumor volume doubling time (VDT), growth delay (GD), and mean survival time (MST) were determined. In addition, serum protein profiles were analyzed. Results: The 21 days crocin treatment significantly reduced the tumor burden in mice, extending the mean survival time significantly as compared to control. Crocin treatment also significantly increased the TGD and TSP and decreased VDT. Furthermore, while serum proteins such as albumin and globulin (alpha1, alpha2, beta, and gamma) were altered due to tumor burden, crocin treatment resulted in their levels near to normal at the end of the experimental period. Conclusion: Our study provided clear evidence that crocin may exhibit significant melanoma tumor remission properties by positively modulating tumor growth related parameters. In future, the molecular mechanisms of crocin action should be studied extensively in melanoma models before defining crocin-based melanoma drug formulations.