Effect of Mirabegron in Men With Overactive Bladder and Erectile Dysfunction: A Prospective Observational Study.

BACKGROUND: As it has been observed that the erect penis has been the epitome of virility for the male community for decades, it became necessary to search for alternative treatments for the cause. So, the study was performed to evaluate the potential impact of mirabegron in men with mild to moderate erectile dysfunction (ED) and overactive bladder (OAB). METHODS: It was a prospective, observational study that was carried out at the Department of Urology at Rajendra Institute of Medical Sciences, Ranchi, for a duration of two years and included a total of two hundred fifty patients. The individuals included had a diagnosis of mild to moderate erectile dysfunction (ED) along with symptoms of OAB. The overactive bladder questionnaire (OAB-q) score and the International Index of Erectile Dysfunction-5 (IIEF-5) score were used, respectively, to measure the impact of mirabegron on ED and OAB. Then, the changes in ED and OAB were evaluated at two, four, eight, and 12 weeks. RESULTS: Among the total 250 patients recruited, around 32.5% of them had mild ED, 17.5% were diagnosed with mild to moderate ED, and 50% suffered from moderate ED. The IIEF-5 scores improved by four points or more in 86.25%, 91.25%, and 71.25% of patients after four, eight, and 12 weeks, respectively. OAB-q scores were likewise shown to decline in the fourth (13.1 ± 4.3) and eighth (12.8 ± 4.2) weeks when compared to the baseline (17.4 ± 5.5). Also, adverse events reported did not hamper the progress of the study. CONCLUSION: The study concluded that mirabegron has a beneficial impact on controlling OAB symptoms among men diagnosed with mild to moderate ED. The effects last for only eight weeks, and then they decline. Furthermore, mirabegron was well-tolerated among patients and had no safety concerns with its use.

Fisetin induces G2/M phase arrest and caspase-mediated cleavage of p21Cip1 and p27Kip1 leading to apoptosis and tumor growth inhibition in HNSCC.

The anticancer potential and associated mechanisms of flavonoid fisetin are yet to be fully investigated on human head and neck squamous cell carcinoma (HNSCC). In the present study, fisetin (25-75 µM for 24-48 h) dose-dependently inhibited growth and induced death in HNSCC Cal33 and UM-SCC-22B cells, without showing any death in normal cells. Fisetin (25-50 µM) induced G2/M phase arrest via decrease in Cdc25C, CDK1, cyclin B1 expression, and an increase in p53(S15). A concentration-dependent increase in fisetin-induced DNA damage and apoptosis in HNSCC cells was authenticated by comet assay, gamma-H2A.X(S139) phosphorylation, and marked cleavage of PARP protein. Interestingly, fisetin-induced cell death occurred independently of p53 and reactive oxygen species production. The activation of JNK and inhibition of PI3K/Akt, ERK1/2, EGFR, and STAT-3 signaling were identified. Further, fisetin-induced apoptosis was mediated, in part, via p21Cip1 and p27Kip1 cleavage by caspase, which was reversed by z-VAD-FMK, a pan-caspase inhibitor. Subsequently, fisetin was also found to induce autophagy; nevertheless, autophagy attenuation exaggerated apoptosis. Oral fisetin (50 mg/kg body weight) treatment to establish Cal33 xenograft in mice for 19 days showed 73% inhibition in tumor volume (p < 0.01) along with a decrease in Ki67-positive cells and an increase in cleaved caspase-3 level in tumors. Consistent with the effect of 50 µM fisetin in vitro, the protein levels of p21Cip1 and P27Kip1 were also decreased by fisetin in tumors. Together, these findings showed strong anticancer efficacy of fisetin against HNSCC with downregulation of EGFR-Akt/ERK1/2-STAT-3 pathway and activation of JNK/c-Jun, caspases and caspase-mediated cleavage of p21Cip1 and p27Kip1.

Silymarin prevents endothelial dysfunction by upregulating Erk-5 in oxidized LDL exposed endothelial cells.

Extracellular signal-regulated kinase (Erk)-5 is a key mediator of endothelial cell homeostasis, and its inhibition causes loss of critical endothelial markers leading to endothelial dysfunction (ED). Circulating oxidized low-density lipoprotein (oxLDL) has been identified as an underlying cause of ED and atherosclerosis in metabolic disorders. Silymarin (Sym), a flavonolignan, possesses various pharmacological activities however its preventive mechanism in ED warrants further investigation. Here, we have examined the effects of Sym in regulating the expression of Erk-5 and ameliorating ED using in vitro and in vivo models. Primary human umbilical vein endothelial cells (pHUVECs) viability was measured by MTT assay; mRNA and protein expression by RT-qPCR and Western blotting; tube-formation assay was performed to examine endothelialness. In in-vivo experiments, normal chow-fed mice (control) or high-fat diet (HFD)-fed mice were administered Sym or Erk-5 inhibitor (BIX02189) and body weight, blood glucose, plasma-LDL, oxLDL levels, and expression of EC markers in the aorta were examined. Sym (5 µg/ml) maintained the viability and tube-formation ability of oxLDL exposed pHUVECs. Sym increased the expression of Erk-5, vWF, and eNOS and decreased ICAM-1 at transcription and translation levels in oxLDL-exposed pHUVECs. In HFD-fed mice, Sym reduced the body weight, blood glucose, LDL-cholesterol, and oxLDL levels, and increased the levels of vWF and eNOS along with Erk-5 and decreased the level of ICAM-1 in the aorta. These data suggest that Sym could be a potent anti-atherosclerotic agent that could elevate Erk-5 level in the ECs and prevent ED caused by oxidized LDL during HFD-induced obesity in mice.

Cancer Pathways Targeted by Berberine: Role of microRNAs.

Cancer is a complex and heterogeneous malignant disease. Due to its multifactorial nature, including progressive changes in genetic, epigenetic, transcript, and protein levels, conventional therapeutics fail to save cancer patients. Evidence indicates that dysregulation of microRNA (miRNA) expression plays a crucial role in tumorigenesis, metastasis, cell proliferation, differentiation, metabolism, and signaling pathways. Moreover, miRNAs can be used as diagnostic and prognostic markers and therapeutic targets in cancer. Berberine, a naturally occurring plant alkaloid, has a wide spectrum of biological activities in different types of cancers. Inhibition of cell proliferation, metastasis, migration, invasion, and angiogenesis, as well as induction of cell cycle arrest and apoptosis in cancer cells, is reported by berberine. Recent studies suggested that berberine regulates many oncogenic and tumor suppressor miRNAs implicated in different phases of cancer. This review discussed how berberine inhibits cancer growth and propagation and regulates miRNAs in cancer cells. And how berberine-mediated miRNA regulation changes the landscape of transcripts and proteins that promote or suppress cancer progression. Overall, the underlying molecular pathways altered by berberine and miRNA influencing the tumor pathophysiology will enhance our understanding to combat the malignancy.

Simulated microgravity induces DNA damage concurrent with impairment of DNA repair and activation of cell-type specific DNA damage response in microglial and glioblastoma cells.

Long-term spaceflights affect the structural changes in brain, alter motor or cognitive function and associated development of neuro-optic syndrome in astronauts. Studies addressing the impact of microgravity on brain cells are very limited. Herein, we employed microglial (CHME3) and glioblastoma (U87MG and A172) cells to study their molecular and functional adaptations under simulated microgravity (SMG) exposure. A reduction in cell viability and proliferation with decreased levels of PCNA were observed in these cells. SMG caused extensive DNA damage with an increase in γH2A.X (ser139) phosphorylation and differential activation/expression of DNA damage response (DDR) proteins including ATM, ATR, Chk1, Chk2 and p53 in all the three cell lines. Unlike CHME3, the ATM/Chk2-dependent DDR pathway was activated in glioblastoma cells suggesting a marked difference in the adaptation between normal and cancer cells to SMG. Five different classes of DNA repair pathways including BER, NER, MMR, NHEJ and HR were suppressed in both cell lines with the notable exception of NHEJ (Ku70/80 and DNA-PK) activation in U87MG cells. SMG induced mitochondrial apoptosis with increased expression of Bax, cleaved caspase-3 and cleaved poly-(ADP-ribose) polymerase, and reduced Bcl-2 level. SMG triggered apoptosis simultaneously via ERK1/2 and AKT activation, and inhibition of GSK3ß activity which was reversed by MEK1 and PI3K inhibitors. Taken together, our study revealed that microgravity is a strong stressor to trigger DNA damage and apoptosis through activation of ERK1/2 and AKT, and impairment of DNA repair capacity, albeit with a cell-type difference in DDR and NHEJ regulation, in microglial and glioblastoma cells.

Diallyl Trisulfide Induces ROS-Mediated Mitotic Arrest and Apoptosis and Inhibits HNSCC Tumor Growth and Cancer Stemness.

Despite advances in therapeutic approaches, the five-year survival rate for head and neck squamous cell carcinoma (HNSCC) patients is still less than fifty percent. Research has indicated that the consumption of Allium vegetables or processed garlic containing diallyl trisulfide (DATS) can lower the risk of multiple types of cancer. Nevertheless, the effectiveness and underlying mechanisms of DATS against HNSCC have not been thoroughly explored until the current study. In this research, it was found that DATS notably curtailed the growth and viability of HNSCC cells. Additionally, DATS triggered a significant G2/M cell cycle arrest in these cells, accumulating cyclin B1, Cip1/p21, and Ser-10 phospho-histone H3-this was indicative of mitotic arrest attenuated by NAC pretreatment, suggesting the role of reactive oxygen species (ROS) induction. The production of ROS induced by DATS led to DNA damage and apoptosis, a process associated with elevated levels of cleaved caspase-3 and cleaved PARP, along with reduced XIAP. When HNSCC cells were exposed to pharmacological concentrations of DATS, it resulted in the suppression of cancer stem cell (CSC) populations, as indicated by a decrease in the CD133high/CD44high cell fraction, reduced aldehyde dehydrogenase 1 (ALDH1) activity, inhibited spheroid formation and downregulated SOX2 and Oct4 expression. Furthermore, the administration of DATS to tumor xenografts demonstrated its in vivo capacity to hinder CSCs. Further, DATS treatment inhibited the growth of UMSCC-22B head and neck cancer tumor xenograft in immunocompromised mice. Overall, DATS inhibited cell proliferation; induced cell cycle mitotic arrest and apoptosis involving DNA damage through ROS generation; reduced the CSC fraction and spheroid formation; and downregulated SOX2 and Oct4 expression. More importantly, DATS inhibited HNSCC tumor growth and CSC fraction in vivo. Thus, DATS could be a potential anticancer agent that can be used against head and neck cancer.

Mechanism of synergistic inhibitory effect of benzyl isothiocyanate and zoledronic acid combination on breast cancer induction of osteoclast differentiation.

Bone is the most favored site for metastasis for each major subtype of breast cancer. Therapeutic modalities for alleviation of clinical symptoms associated with bone metastasis include surgical resection, radiation, and bone-targeted therapies, including bisphosphonates (e.g., zoledronic acid; ZA) and a humanized antibody against receptor activator of nuclear factor-κB ligand (denosumab). However, the bone-targeted therapies are expensive, and have poor pharmacokinetic attributes and/or serious adverse effects. Therefore, novel strategies are needed for treatment of bone metastasis or to increase effectiveness of existing bone-targeted therapies. We have shown previously that benzyl isothiocyanate (BITC) is a novel inhibitor of osteoclast differentiation in vitro and bone metastasis in vivo. The present study shows that BITC + ZA combination synergistically inhibits osteoclast differentiation induced by addition of conditioned media from breast cancer cells. These effects were associated with a significant increase in levels of several antiosteoclastogenic cytokines, including interferons, interleukin (IL)-3, IL-4, and IL-27. Kyoto Encyclopedia of Genes and Genomes pathway analysis of RNA-seq data from BITC and/or ZA-treated cells revealed downregulation of genes of many pathways (e.g., actin cytoskeleton, Hippo signaling, etc.) by treatment with BITC + ZA combination, but not by BITC alone or ZA alone. Confocal microscopy confirmed severe disruption of actin cytoskeleton upon treatment of MCF-7 and MDA-MB-231 cells with the BITC + ZA combination. This combination also decreased the nuclear level of yes-associated protein, a core component of Hippo signaling. In conclusion, the present study offers a novel combination for prevention or treatment of bone metastasis of breast cancer.

Rhizospheric Bacillus spp. Exhibit Miticidal Efficacy against Oligonychus coffeae (Acari: Tetranychidae) of Tea.

Oligonychus coffeae (Acari: Tetranychidae), popularly known as red spider mite (RSM) is one of the major pests of commercial tea (Camellia sinensis (L.) O. Kuntze) plantation world over. Many attempts have been made in the past to control this devastating pest using a variety of microbial bioagents, however, area-wise field success is very limited. We carried out an in vitro study to explore the potential of rhizospheric Bacillus spp. (B. amyloliquefaciens BAC1, B. subtilis LB22, and B. velezensis AB22) against O. coffeae through adulticidal and ovicidal activity. The 100% adult and egg mortality was observed with bacterial suspension (1 × 109 CFU/mL) by B. velezensis AB22, showing the lowest LC50 values for both adults and eggs of O. coffeae, i.e., 0.28 × 105 and 0.29 × 105, respectively. The study also throws some insights into the underlying mechanism through electron microscopy study and identification of some putative pesticidal metabolites from all the species. The three Bacillus species were observed to have four commonly secreted putative bioactive secondary metabolites, brevianamide A, heptadecanoic acid, thiolutin, and versimide responsible for their bio-efficacy against O. coffeae. The outcome of our study provides a strong possibility of introducing Bacillus spp. as a biological miticide and developing synthetic metabolites mimicking the mechanistic pathway involved in microbial bioefficacy.

Predictors of Escalation to Intensive Care Unit Level of Care Among Admissions for Alcohol Withdrawal.

According to the 2019 National Survey on Drug Use and Health, 14.5 million people ages 12 and older had alcohol abuse disorder. Alcohol withdrawal syndrome (AWS) can be defined as a collection of physical symptoms experienced due to abrupt cessation of alcohol after long-term dependence. In instances where regular inpatient management fails to control AWS symptoms, patients are shifted to intensive care units (ICUs) for closer monitoring and prevention of life-threatening complications like withdrawal seizures and delirium tremens (DTs), labeled as severe alcohol withdrawal syndrome (SAWS). Although this represents a significant healthcare burden, minimal studies have been conducted to determine objective predictors. In this study, we aim to determine the effect of patient demographics, socio-economic status, biochemical parameters, and clinical factors on the need for escalation to ICU level of care among admissions for AWS. Our study showed that factors such as a history of DTs or alcohol-related seizures, the initial protocol of management, degree of reported alcohol usage, activation of rapid response teams, mean corpuscular value, alcohol level on admission, highest Clinical Institute Withdrawal Assessment Alcohol Revised (CIWA-Ar) scored during the hospital stay, and the total amount of sedatives used were significantly associated with escalation to ICU level of care. Clinicians must use these objective parameters to identify high-risk patients and intervene early. We encourage further studies to establish a scoring algorithm incorporating biochemical parameters to tailor management algorithms that might better suit high-risk patients.

Circular Penile Skin Fasciocutaneous Ventral Onlay Flap Urethroplasty as an Alternative to Dorsal Onlay Buccal Mucosal Graft Urethroplasty in Complex Long-Segment Urethral Stricture: A Retrospective Study.

Background A urethral stricture is the narrowing of the urethra that results in symptoms of obstruction. It can appear anywhere along the male urethra's length and has a variety of causes. The circular penile fasciocutaneous flap is employed in the successful single-stage reconstruction of long-segment complex anterior urethral strictures especially when the buccal mucosa is unavailable due to various reasons. The study has tried to identify a surgical technique that is more beneficial for the treatment of urethral strictures. Objective The objective of this research was to evaluate the outcomes of circular penile skin fasciocutaneous ventral onlay flap urethroplasty (group A) and the outcomes of dorsal onlay buccal mucosal graft urethroplasty (group B) in the management of complex long-segment penile urethral stricture. Methods In this retrospective study between December 2012 and December 2022, 60 patients with long-segment complex penile urethral stricture who underwent urethroplasty at our center were evaluated. Patients were divided into two groups according to the flap used (dorsal onlay buccal mucosal graft urethroplasty was used in 30 patients (group B), and circular penile fasciocutaneous flap (single stage) was used in 30 patients (group A)). The success rate and the mean peak flow rate were also calculated post-operation to identify the effectiveness of the surgical procedure used for urethral strictures. Results The study consisted of 60 patients in total. Group A's mean age was determined to be 51.2±16.2 years, whereas group B's mean age was determined to be 40.7±16.8 years. Preoperatively, the median urethral stricture length was 69 mm in group A (range: 20-100 mm) and 56 mm in group B (range: 30-110 mm). The intraoperative median length of the urethral stricture was 82 mm in group A (range: 20-120 mm) and 65 mm in group B (range: 40-140 mm). The mean peak flow rate was 30.9±6.8 mL/s in group A compared to 18.1±4.9 mL/s in group B. The success rate for group A was 89.7%, while the success rate for group B was 75.9%. Conclusion For complex long-segment urethral strictures, circular penile skin fasciocutaneous ventral onlay flap urethroplasty has a higher rate of success and fewer complications than dorsal onlay buccal mucosal graft urethroplasty. Along with success rate, it has a better mean peak flow rate and lower complications.

Invasive Breast Cancer: miR-24-2 Targets Genes Associated with Survival and Sensitizes MDA-MB-231 Cells to Berberine.

MicroRNA aberrations including that of miR-24-2 have been reported in various cancers. However, the target genes for miR-24-2 are yet to be identified and validated in invasive breast cancer and the triple-negative breast cancer (TNBC). Using in silico approaches and gene expression analyses, we identified and validated the target genes of miR-24-2 in invasive breast cancer, majority of which were TNBC. We studied the translational potential of these target genes using berberine in a TNBC cell line. Differentially expressed genes targeted by miR-24-2 were identified and analyzed for their survival effects using the The Cancer Genome Atlas-Breast Invasive Carcinoma (-BRCA) samples. Furthermore, we carried out protein-protein interaction, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene expression, and Kaplan-Meier survival analyses using common targets of miR-24-2 in invasive breast cancer/TNBC. We identified 11 biomarker candidate genes as crucial targets of miR-24-2. The survival of breast cancer patients was significantly associated with the low expressions of nine genes, including RACGAP1, KIAA1199, TIMM17A, LYRM7, IL1R1, SLC1A3, DTX4, L1CAM, and SAP30-like (SAP30L), and high expressions of two genes, SOD2 and HLA-DQB2. These in silico findings were validated by overexpressing miR-24-2 and assessing the expression pattern of these target genes in the TNBC MDA-MB-231 cells. miR-24-2 overexpression inhibited (by 20%; p < 0.001) cell proliferation and sensitized the anticancer effect of berberine. In all, this study reports on the novel target genes of miR-24-2 in invasive breast cancer/TNBC, and that miR-24-2 sensitizes MDA-MB-231 cells to berberine. These data lend evidence for the translational potentials of miR-24-2 for invasive breast cancer diagnostic and therapeutic innovation.

A Polyherbal Formulation Habb-e-Ustukhuddus Induces Apoptosis and Inhibits Cell Migration in Lung and Breast Cancer Cells without Any Toxicity in Mice.

OBJECTIVE: A polyherbal medicine, Habb-e-Ustukhuddus (HU), is used for its anti-inflammatory properties. However, the anticancer and chemopreventive properties of HU were not known, and Therefore, investigated in  the  present study. METHODS: Cancer cells were treated with 50-400 µg/ml HU and MTT, trypan blue, and clonogenic assays were performed. Propidium iodide (PI) staining, annexin V-FITC assay, and JC-1 staining were done for cell cycle progression, apoptosis, and mitochondrial membrane potential, respectively, using flow cytometry. Immunoblotting, cell migration and invasion assays were performed. Chemical characterization of HU was done through GC-MS and HPLC analyses. C57BL/6 mice were used to assess the in vivo toxicity of HU. RESULTS: While evaluating the anticancer activity, the methanolic extract of HU (50-400 µg/ml) strongly inhibited the growth and survival (P<0.05-0.001) of lung and breast cancer cells and increased the cell population in the sub-G1 phase of the cell cycle. HU caused apoptotic death of cancer cells (P<0.05-0.001), which was associated with the depolarization of mitochondrial membrane potential (Δψ) (P<0.001) and an increase in Bax to Bcl-2 protein ratio. Further, HU inhibited the invasion and migration of cancer cells, which was accompanied by an increase in the epithelial marker, E-cadherin, and a decrease in the mesenchymal marker, vimentin. The HU characterization by GC-MS and HPLC analyses showed the abundance of bioactive compounds including flavonoids and alkaloids. In the chemopreventive study, the oral administration of methanolic extract of the formulation HU (50 and 100 mg/kg body weight) to mice did not cause any toxicity and significantly increased the specific activities of hepatic drug metabolizing phase I and phase II enzymes, which suggested for its detoxification potential of xenobiotic compounds. CONCLUSION: Together, these results demonstrated the anticancer potential HU, without any apparent toxicity in mice, and thus HU could be further explored for its clinical utility in cancer control.

A Study of Normal Renal Dimensions at Ultrasonography and Their Influencing Factors in an Indian Population.

Background: Kidney dimensions play one of the most vital roles in the diagnosis and identification of any renal disease. Renal dimensions are generally used in clinical practices to determine the size of the kidney as well as correlate with renal function to have a better understanding of acute and chronic renal diseases. This study aimed to find out the normal renal dimensions with the help of ultrasonography and their impact on the Indian population. Methods: Renal dimensions, which include parenchymatous thickness and length as well as the width of about 60 healthy adult Indian populations, were estimated with the help of sonography, and a detailed study has been performed on the difference observed based on age, sex, height, weight, body mass index, and body surface area. Results: There was no particular difference found on the basis of width and length between the left and right kidneys; however, the parenchymal thickness between the left and right has been shown to have a significant difference. The mean width, length, and parenchymal thickness were 4.6 ± 0.43, 9.64 ± 0.62, and 2.03 ± 0.1 cm, respectively. While doing estimation based on gender, it has been observed that there is a noticeable difference in width but no difference in height or parenchymal thickness. A significant diversity has been observed in patients in age groups above 49 compared to other age groups. A positive correlation with body weight, body height, and body mass index has also been observed in some cases. Conclusion: The given study has attempted to define the standard reference for renal dimension in the Indian census. The observations made in the given study demonstrated the possibility of renal dimensions being smaller in the Indian population in contrast to those of the Western population, which are much larger.

Targeting DNA repair for cancer treatment: Lessons from PARP inhibitor trials.

Ionizing radiation is frequently used to treat solid tumors, as it causes DNA damage and kill cancer cells. However, damaged DNA is repaired involving poly-(ADP-ribose) polymerase-1 (PARP-1) causing resistance to radiation therapy. Thus, PARP-1 represents an important target in multiple cancer types, including prostate cancer. PARP is a nuclear enzyme essential for single-strand DNA breaks repair. Inhibiting PARP-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair (HR) pathway. This article provides a concise and simplified overview of the development of PARP inhibitors in the laboratory and their clinical applications. We focused on the use of PARP inhibitors in various cancers, including prostate cancer. We also discussed some of the underlying principles and challenges that may affect the clinical efficacy of PARP inhibitors.

Tension pneumocephalus in a patient with NF1 following ventriculoperitoneal shunt-deciphering the cause and proposed management strategy.

INTRODUCTION: Spontaneous pneumocephalus following ventriculoperitoneal shunting is a very unique complication, seen in a handful of patients. Small bony defects form as a result of chronically raised intracranial pressure, which can later lead to pneumocephalus once intracranial pressure decreases following ventriculoperitoneal shunting. CASE REPORT: Here, we present a case of a 15-year-old girl with NF1 who presented to us with pneumocephalus 10 months following shunting and our management strategy along with a literature review of this condition. CONCLUSION: NF1 & hydrocephalus can lead to skull base erosion, which needs to be looked up before proceeding with VP shunting to avoid delayed onset pneumocephalus. SOKHA with the opening of LT is a minimally invasive approach suitable to tackle both problems simultaneously.

Meeting report: International Symposium on Mitochondria, Cell Death and Human Diseases: Jawaharlal Nehru University, New Delhi, India, February 18-19, 2023.

The School of Life Sciences at the Jawaharlal Nehru University in New Delhi, India held an International Symposium on Mitochondria, Cell Death and Human Diseases on February 18-19, 2023. The meeting provided a highly interactive forum for scientific discussion, cultural exchange, and collaborations between international scientists working in diverse areas of mitochondrial biology, cell death, and cancer. The two-day symposium attracted more than 180 delegates that included leading international scientists, early career researchers in India, as well as postdoctoral fellows and students. Several of the students, postdoctoral fellows, and junior faculty presented platform talks and had a chance to showcase the depth and emerging progress in biomedical research in India. The meeting will be instrumental for planning future congresses and symposium throughout India, not only to focus on mitochondrial biology, cell death and cancer but to foster continued ferment and collaborations in the biological sciences throughout India.

Acacetin induces sustained ERK1/2 activation and RIP1-dependent necroptotic death in breast cancer cells.

Acacetin (AC), a naturally occurring flavonoid has shown anticancer potential. Herein, we studied the mechanisms of cell death and growth inhibition by AC in breast carcinoma T-47D and MDA-MB-231 cells. AC (10-40 µM) significantly decreased the levels of G2/M phase cyclins and CDKs, simultaneously increasing the expression of CDK inhibitors including Cip1/p21. A concentration-dependent increase in cell death was noted in both breast cancer cell lines with no such considerable effects on MCF-10A non-tumorigenic breast cells. The cell death-inducing potential of AC was further confirmed using confocal microscopy and flow cytometry analysis. AC resulted in mitochondrial superoxide generation, DNA damage, and ROS generation. N-acetyl cysteine (NAC) pre-treatment inhibited ROS generation and partially reversed ERK1/2 activation as well as cell death by AC. Further, AC enhanced the expression of RIP1 and RIP3, which mediate necroptosis. RIP1-specific inhibitor Necrostatin-1 (NS-1) reversed the AC-induced DNA damage and cell death. Collectively, these findings, for the first time, suggested that AC exerts its antitumor potential through ROS induction and RIP1-dependent necroptosis in breast carcinoma cells.

Decursin inhibits EGFR-ERK1/2 signaling axis in advanced human prostate carcinoma cells.

We have shown that decursin, a coumarin compound, induces cell cycle arrest and apoptosis in human prostate cancer cells (PCa); however, its molecular mechanisms are largely unexplored. We studied the mechanisms associated with its anticancer activity in advanced human prostate carcinoma cells. We found that decursin inhibited epidermal growth factor receptor (EGFR) signaling by inhibiting its activating phosphorylation at tyrosine 1068 residue in DU145 and 22Rv1 cells. This inhibition of EGFR was associated with the downregulation of ERK1/2 phosphorylation. Both EGFR and ERK1/2 are known to be deregulated/activated in many human malignancies. Consistent with our earlier study, decursin (25-100 µM) treatment for 24-72 h inhibited DU145 cell proliferation by 49%-87% (p < 0.001) which was associated with strong G1 phase arrest and cell death. It also decreased (p < 0.001) the number of surviving colonies. Decursin moderately increased the expression of Rb-related proteins p107 and p130 but decreased the levels of E2F family transcription factors including E2F-3, E2F-4 and E2F-5. Further, decursin strongly inhibited the growth of androgen-dependent prostate carcinoma 22Rv1 cells from 61% to 79% (p < 0.001) and arrested these cells at G1 phase via induction of cyclin-dependent kinase inhibitor p27/Kip1 and downregulation of CDK2 and CDK4 protein expression. Additionally, EGFR inhibitor erlotinib- and EGF ligand-modulated EGFR activation validated EGFR signaling as a target of decursin-mediated cell growth inhibition and cytotoxicity. Decursin decreased EGF ligand-induced phosphorylation of EGFR (Y-1068) as well as activation of its downstream mediator, ERK1/2. Furthermore, inhibitory targeting of EGFR-ERK1/2 axis by combinatorial treatment of decursin and erlotinib further sensitized DU145 cells for the decursin-induced growth inhibition and cell death. Overall, these findings strongly suggest that anticancer efficacy of decursin against human PCa involves inhibitory targeting of EGFR-ERK1/2 signaling axis, a pathway constitutively active in advanced PCa.

Amino Acid Tracer PET MRI in Glioma Management: What a Neuroradiologist Needs to Know.

PET with amino acid tracers provides additional insight beyond MR imaging into the biology of gliomas that can be used for initial diagnosis, delineation of tumor margins, planning of surgical and radiation therapy, assessment of residual tumor, and evaluation of posttreatment response. Hybrid PET MR imaging allows the simultaneous acquisition of various PET and MR imaging parameters in a single investigation with reduced scanning time and improved anatomic localization. This review aimed to provide neuroradiologists with a concise overview of the various amino acid tracers and a practical understanding of the clinical applications of amino acid PET MR imaging in glioma management. Future perspectives in newer advances, novel radiotracers, radiomics, and cost-effectiveness are also outlined.

A novel 4'-brominated derivative of fisetin induces cell cycle arrest and apoptosis and inhibits EGFR/ERK1/2/STAT3 pathways in non-small-cell lung cancer without any adverse effects in mice.

The therapeutic toxicity and resistance to currently available treatment options are major clinical challenges for the management of lung cancer. As a novel strategy, we synthesized analogues of a known flavonol, fisetin, which has shown anti-tumorigenic potential against cancer in cell culture with no adverse effects in animal models. We studied the synthetic analogues of fisetin for their anti-cancer potential against lung cancer cells, toxicity in mice and efficacy in a xenograft model. Brominated fisetin analogues were screened for their effects on the viability of A549 and H1299 lung cancer cells, and three analogues (3a, 3b, 3c), showed improved activity compared to fisetin. These analogues were more effective in restricting lung cancer cell proliferation, inducing G2 M phase cell cycle arrest and apoptosis. The fisetin analogues also downregulated EGFR/ERK1/2/STAT3 pathways. Fisetin analogue-induced apoptosis was accompanied by a higher Bax to Bcl-2 expression ratio. Based on the in vitro studies, the most effective fisetin analogue 3b was evaluated for in vivo toxicity, wherein it did not show any hepatotoxicity or adverse health effects in mice. Furthermore, analogue 3b showed greater antitumor efficacy (p < .001) as compared to its parent compound fisetin in a human lung cancer cell xenograft study in athymic mice. Together, our data suggest that the novel fisetin analogue 3b is more effective in restricting lung cancer cell growth, both in vitro as well as in vivo, without any apparent toxicity, supporting its further development as a novel anti-lung cancer agent.