Improving In Vivo Tumor Accumulation and Efficacy of Platinum Antitumor Agents by Electronic Tuning of the Kinetic Lability.

The impact of kinetic lability or reactivity on in vitro cytotoxicity, stability in plasma, in vivo tumor and tissue accumulation, and antitumor efficacy of functional platinum(II) (Pt) anticancer agents containing a O˄O ß-diketonate leaving ligand remain largely unexplored. To investigate this, we synthesized Pt complexes [(NH3 )2 Pt(L1-H)]NO3 and [(DACH)Pt(L1-H)]NO3 (L1=4,4,4-trifluoro-1-ferrocenylbutane-1,3-dione, DACH=1R,2R-cyclohexane-1,2-diamine) containing an electron deficient [L1-H]- O˄O leaving ligand and [(NH3 )2 Pt(L2-H)]NO3 and [(DACH)Pt(L2-H)]NO3 (L2=1-ferrocenylbutane-1,3-dione) containing an electron-rich [L2-H]- O˄O leaving ligand. While all four complexes have comparable lipophilicity, the presence of the electron-withdrawing CF3 group was found to dramatically enhance the reactivity of these complexes toward nucleophilic biomolecules. In vitro cellular assays revealed that the more reactive complexes have higher cellular uptake and higher anticancer potency as compared to their less reactive analogs. But the scenario is opposite in vivo, where the less reactive complex showed improved tissue and tumor accumulation and better anticancer efficacy in mice bearing ovarian xenograft when compared to its more reactive analog. Finally, in addition to demonstrating the profound but contrasting impact of kinetic lability on in vitro and in vivo antitumor potencies, we also described the impact of kinetic lability on the mechanism of action of this class of promising antitumor agents.

Metabolic transitions regulate global protein fatty acylation.

Intermediary metabolites and flux through various pathways have emerged as key determinants of post-translational modifications. Independently, dynamic fluctuations in their concentrations are known to drive cellular energetics in a bi-directional manner. Notably, intracellular fatty acid pools that drastically change during fed and fasted states act as precursors for both ATP production and fatty acylation of proteins. Protein fatty acylation is well regarded for its role in regulating structure and functions of diverse proteins; however, the effect of intracellular concentrations of fatty acids on protein modification is less understood. In this regard, we unequivocally demonstrate that metabolic contexts, viz. fed and fasted states, dictate the extent of global fatty acylation. Moreover, we show that presence or absence of glucose that influences cellular and mitochondrial uptake/utilization of fatty acids and affects palmitoylation and oleoylation, which is consistent with their intracellular abundance in fed and fasted states. Employing complementary approaches including click-chemistry, lipidomics, and imaging, we show the top-down control of cellular metabolic state. Importantly, our results establish the crucial role of mitochondria and retrograde signaling components like SIRT4, AMPK, and mTOR in orchestrating protein fatty acylation at a whole cell level. Specifically, pharmacogenetic perturbations that alter either mitochondrial functions and/or retrograde signaling affect protein fatty acylation. Besides illustrating the cross-talk between carbohydrate and lipid metabolism in mediating bulk post-translational modification, our findings also highlight the involvement of mitochondrial energetics.

Metabolic regulation of CTCF expression and chromatin association dictates starvation response in mice and flies.

Coordinated temporal control of gene expression is essential for physiological homeostasis, especially during metabolic transitions. However, the interplay between chromatin architectural proteins and metabolism in regulating transcription is less understood. Here, we demonstrate a conserved bidirectional interplay between CTCF (CCCTC-binding factor) expression/function and metabolic inputs during feed-fast cycles. Our results indicate that its loci-specific functional diversity is associated with physiological plasticity in mouse hepatocytes. CTCF differential expression and long non-coding RNA-Jpx mediated changes in chromatin occupancy, unraveled its paradoxical yet tuneable functions, which are governed by metabolic inputs. We illustrate the key role of CTCF in controlling temporal cascade of transcriptional response, with effects on hepatic mitochondrial energetics and lipidome. Underscoring the evolutionary conservation of CTCF-dependent metabolic homeostasis, CTCF knockdown in flies abrogated starvation resistance. In summary, we demonstrate the interplay between CTCF and metabolic inputs that highlights the coupled plasticity of physiological responses and chromatin function.

Shaping mitochondria through fed-fast and circadian cycles.

Energy and metabolic homeostasis at the level of the whole body are dictated by the balance between nutrient intake/utilization, bioenergetic potential, and energy expenditure, which are tightly coupled with fed/fast cycles and circadian oscillation. Emerging literature has highlighted the importance of each of these mechanisms that are essential to maintain physiological homeostasis. Lifestyle changes predominantly associated with altered fed-fast and circadian cycles are well established to affect systemic metabolism and energetics, and hence contribute to pathophysiological states. Therefore, it is not surprising that mitochondria have emerged as being pivotal in maintaining physiological homeostasis through daily oscillations/fluctuations in nutrient inputs and light-dark/sleep-wake cycles. Moreover, given the inherent association between mitochondrial dynamics/morphology and functions, it is important to understand the phenomenological and mechanistic underpinnings of fed-fast and circadian cycles dependent remodeling of mitochondria. In this regard, we have summarized the current status of the field in addition to providing a perspective vis-a-vis the complexity of cell-autonomous and non-cell-autonomous signals that dictate mitochondrial dynamics. We also highlight the lacunae besides speculating on prospective efforts that will possibly redefine our insights into the diurnal orchestration of fission/fusion events, which are ultimately coupled to the mitochondrial output.

Case report: A case of undiagnosed cannabinoid hyperemesis syndrome in rural part of Nepal.

Introduction: and importance: Cannabinoid, a widely used recreational drug worldwide. In Nepal, it is found easily and has multiple used as well as misused as a psychoactive substance. Despite having anti emetic property of Marijuana, chronic use of the substance can lead to cyclic vomiting syndrome due to effect in central nervous system and gastrointestinal system. Case: we present a case of 28 year old man presented frequently with severe vomiting and abdominal pain which improved with hot showers and stopping use of cannabinoid. Clinical findings and investigation: Patient abdomen was tender but all other physical examinations were within normal limits. His lab investigations were within normal limit except of Total leukocyte count and urine analysis. Intervention and outcome: The patient was hospitalized and treated for dehydration, nausea and vomiting, and abdominal pain. The patient was diagnosed with cannabinoid hyperemesis syndrome and was discharged from the hospital two days later with the advice to stop using cannabis completely.

Approaches to osteoarthritis: a qualitative study among physical therapists in Maharashtra, India.

BACKGROUND AND OBJECTIVE: Osteoarthritis (OA) is a major and growing problem in India. Better knowledge dissemination and implementation of evidence-based practice in Indian physical therapy require a better understanding of approaches to OA (i.e. perceptions of the condition and its management by Indian physical therapists (PTs)) which was the aim of our study. DESIGN AND METHOD: We used qualitative content analysis to analyze semi-structured interviews with 19 PTs from Maharashtra state, purposefully selected to represent both sexes, different ages and different educational and professional backgrounds. FINDINGS: We identified a main overarching theme of meaning, OA as a degenerative and irreversible condition with the four descriptive themes Assessment, Standardized treatment protocol, Leadership and Patient compliance as PTs' approaches to OA. The descriptive themes indicate that much focus seems to be on pain, physical impairments and biomechanics, with initial treatments being mainly passive. Communication appears to be mainly unidirectional with the PTs instructing the patients, who are expected to comply with PTs instructions. Clinical practice guidelines (CPGs) were not mentioned. CONCLUSIONS: Our findings can inform the design of awareness campaigns on evidence-based OA management and increase the understanding of the educational needs of students and PTs in non-Western countries. It is important to recognize that CPGs are mainly based on studies carried out in Western countries and that there are context-specific barriers to implementation in other parts of the world that have large populations.

A Rationally Designed Bimetallic Platinum (II)-Ferrocene Antitumor Agent Induces Non-Apoptotic Cell Death and Exerts in Vivo Efficacy.

Despite phenomenal clinical success, the efficacy of platinum anticancer drugs is often compromised due to inherent and acquired drug resistant phenotypes in cancers. To circumvent this issue, we designed two heterobimetallic platinum (II)-ferrocene hybrids that display multi-pronged anticancer action. In cancer cells, our best compound, 2, platinates DNA, produces reactive oxygen species, and has nucleus, mitochondria, and endoplasmic reticulum as potential targets. The multi-modal mechanism of action of these hybrid agents lead to non-apoptotic cell death induction which enables circumventing apoptosis resistance and significant improvement in platinum cross resistance profile. Finally, in addition to describing detail mechanistic insights, we also assessed its stability in plasma and demonstrate anticancer efficacy in an in vivo A2780 xenograft model. Strikingly, compared to oxaliplatin, our compound displays better tolerability, safety profile and efficacy in vivo.

Approaches to osteoarthritis - A qualitative study among patients in a rural setting in Central Western India.

BACKGROUND: Osteoarthritis (OA) represents a major cause of disability in India. For implementation of best practice management, it is important to consider the views of people in India since they might deviate from those expressed in previous studies by people with OA in the Western world. OBJECTIVE: The purpose of this study was to explore and describe approaches toward OA and its management among patients in a rural setting in Central Western India. DESIGN AND METHOD: Conventional content analysis was used to analyze semi-structured interviews with 24 patients diagnosed with OA from the target area of Pravara University Hospital and ten adjacent primary health care centers in Maharashtra, India. RESULTS: Four categories; lack of power, active ambivalence, taking control and a constant struggle were identified as patients' approaches to OA. The categories were further elaborated on in seven subcategories. CONCLUSION: Daily challenges and efforts, of which some may be unique to patients in a rural setting in India, underlie passive and active approaches to OA and its management. Understanding these may enhance Indian physiotherapists' implementation of evidence-based self-management programs adapted to Indian conditions and reduce the distress of their patients.

Epiphytic Orchid Diversity along an Altitudinal Gradient in Central Nepal.

Epiphytic orchids are common in subtropical forests, but little is known about the factors that determine their diversity. We surveyed two sites (north-facing Phulchowki and south-facing Shivapuri hills), in the sub-tropical forest in the Kathmandu valley, central Nepal. Along five transects per site, spanning an altitudinal gradient of 1525-2606 m a.s.l., we recorded all epiphytic orchids and the host species on which they were growing. The data were analyzed using a generalized linear model (GLM) and redundancy analysis (RDA). Species richness significantly decreased with increasing altitude and was higher in larger hosts and in places with high temperature. Species composition was affected by altitude, distance from the forest edge, host type, and precipitation. This study indicates that the most important factors affecting epiphytic orchid diversity was altitude, even if other factors were associated with patterns in composition. The low-altitude habitats with high species diversity are the best places for epiphytic orchids in this region. The altitudinal species richness and patterns in composition revealed by this study provide a baseline for further studies on epiphytic orchids.

Anabolic SIRT4 Exerts Retrograde Control over TORC1 Signaling by Glutamine Sparing in the Mitochondria.

Anabolic and catabolic signaling mediated via mTOR and AMPK (AMP-activated kinase) have to be intrinsically coupled to mitochondrial functions for maintaining homeostasis and mitigate cellular/organismal stress. Although glutamine is known to activate mTOR, whether and how differential mitochondrial utilization of glutamine impinges on mTOR signaling has been less explored. Mitochondrial SIRT4, which unlike other sirtuins is induced in a fed state, is known to inhibit catabolic signaling/pathways through the AMPK-PGC1α/SIRT1-peroxisome proliferator-activated receptor α (PPARα) axis and negatively regulate glutamine metabolism via the tricarboxylic acid cycle. However, physiological significance of SIRT4 functions during a fed state is still unknown. Here, we establish SIRT4 as key anabolic factor that activates TORC1 signaling and regulates lipogenesis, autophagy, and cell proliferation. Mechanistically, we demonstrate that the ability of SIRT4 to inhibit anaplerotic conversion of glutamine to α-ketoglutarate potentiates TORC1. Interestingly, we also show that mitochondrial glutamine sparing or utilization is critical for differentially regulating TORC1 under fed and fasted conditions. Moreover, we conclusively show that differential expression of SIRT4 during fed and fasted states is vital for coupling mitochondrial energetics and glutamine utilization with anabolic pathways. These significant findings also illustrate that SIRT4 integrates nutrient inputs with mitochondrial retrograde signals to maintain a balance between anabolic and catabolic pathways.

Immediate effect of scapular repositioning with active cervical rotation in acute spasmodic torticollis.

OBJECTIVES: The aim of this preliminary study was to investigate the immediate effects on pain and pressure pain threshold (PPT) of a scapular repositioning technique in patients with acute spasmodic torticollis. METHODS: A randomized, single blind pilot study was conducted. The subjects were 23 individuals (age 20-40 years) with a clinical diagnosis of spasmodic torticollis. Visual analog scale pain score, cervical active ranges of motion, and PPT were assessed before and after the intervention. The comparison group was treated with only conventional physiotherapy (microwave diathermy, submaximal isometrics, and ergonomic advice). The intervention group was given scapular repositioning with active cervical rotation technique, in addition to conventional physiotherapy treatment. RESULTS: There were significant improvements in intensity of pain (P < .01), cervical rotation to the ipsilateral side (P < .01), cervical side flexion to the contralateral side (P < .01), and PPT (P < .01) immediately after the treatment of the scapular repositioning and conventional therapy compared with the conventional therapy alone. CONCLUSION: The present pilot study demonstrated that scapular repositioning may have an immediate hypoalgesic effect on individuals with spasmodic torticollis in terms of pain severity, PPT, and cervical range of motion. Therefore, further controlled trials are warranted.

Effectiveness of transcutaneous electrical nerve stimulation and microcurrent electrical nerve stimulation in bruxism associated with masticatory muscle pain--a comparative study.

OBJECTIVES: To compare the effectiveness of transcutaneous electrical nerve stimulation (TENS) and microcurrent electrical nerve stimulation (MENS) on masticatory muscles pain bruxism patient. MATERIALS AND METHODS: A total of 60 subjects with the clinical diagnosis of bruxism were randomly allocated to two study groups. Group A received TENS (50 Hz, pulse width 0.5 mSec, intensity 0-60 mA for 20 minutes for a period of seven days) and Group B received MENS (0.5 Hz, intensity 1,000 muA for 20 minutes for a period of seven days). The outcome measures were assessed in term of Visual Analog Scale (VAS) and digital pressometer of 2 Kgf. RESULTS: The study showed significant change in intensity of pain as per VAS score ( P

An ergonomic study of women workers in a woolen textile factory for identification of health-related problems.

The observational cross-sectional study conducted on a sample of 100 women workers who volunteered, outlines their cardio-respiratory and musculo-skeletal profile before, during and at end of work. In addition, information on their health status in general was collected in advance.Contrary to expectation, there was no significant change in respiratory function. However, the musculo-skeletal problems were found to be abundantly present with pain in 91% of the subjects. Region-wise mapping of pain revealed that postural pain in low back was present in 47% while in neck was 19%. Scapular muscles on the right side were involved in stabilizing shoulder, which never went overhead. On the contrary, left shoulder was raised as high (>90 degrees) in spinning action, while pulling thread. This muscle work involved trapezius, deltoid and triceps action concentrically in lifting and while coming to starting position slowly, eccentrically. There was no pause since the wheel continued to spin the thread continuously, unless a worker opted to stop the work. Accordingly, left wrist and hand were in holding contraction while the right wrist and hand holding the handle were also in a fixed position with wrist in flexion with supinated forearm. Though the overall job was light as per peak HR, there was pain due to fatigue and grip strength weakened by around 10%, at the end of the day's work. In conclusion, pain and fatigue were found to be the main problems for women in the spinning section of the small-scale industry under this study. Women have to take up dual responsibility of a full-time job as well as the domestic work. It was considered that ergonomic factors such as provision of a backrest and frequent rest periods could remediate the musculo-skeletal symptoms.