Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons. Unfortunately, effective therapeutics against this disease is still not available. Almost 20% of ...familial ALS (fALS) is suggested to be associated with pathological deposition of superoxide dismutase (SOD1). Evidences suggest that SOD1-containing pathological inclusions in ALS exhibit amyloid like properties. An effective strategy to combat ALS may be to inhibit amyloid formation of SOD1 using small molecules. In the present study, we observed the fibrillation of one of the premature forms of SOD1 (SOD1 with reduced disulfide) in the presence of curcumin. Using ThT binding assay, AFM, TEM images and FTIR, we demonstrate that curcumin inhibits the DTT-induced fibrillation of SOD1 and favors the formation of smaller and disordered aggregates of SOD1. The enhancement in curcumin fluorescence on the addition of oligomers and pre-fibrillar aggregates of SOD1 suggests binding of these species to curcumin. Docking studies indicate that putative binding site of curcumin may be the amyloidogenic regions of SOD1. Further, there is a significant increase in SOD1 mediated toxicity in the regime of pre-fibrillar and fibrillar aggregates which is not evident in curcumin containing samples. All these data suggest that curcumin reduces toxicity by binding to the amyloidogenic regions of the species on the aggregation pathway and blocking the formation of the toxic species. Nanoparticles of curcumin with higher aqueous solubility show similar aggregation control as that of curcumin bulk. This suggests a potential role for curcumin in the treatment of ALS.
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•Curcumin inhibits the fibrillation of reduced SOD1 at physiological pH and temperature.•Curcumin binds to aggregation prone regions of SOD1.•Curcumin strongly binds to prefibrillar aggregates and moderately to reduced SOD1.•Disordered and less toxic aggregates of SOD1 are formed in presence of curcumin.
Despite significant advances in understanding breast cancer pathogenesis and prognosis, it remains one of the most common causes of death for women worldwide. To develop a more selective and specific ...treatment strategy, the drug must be efficiently targeted to breast sites with a minimum amount of drug accumulation at other sites. A possible solution to this problem has been explored extensively in recent years using aptamers (chemical antibodies). Aptamers have a higher level of specificity and biocompatibility, making them an excellent candidate for the development of cancer-targeted therapies. In addition to their extraordinary benefits, aptamers are also reported to address tumor resistance as a result of their high specificity and minimal toxicity. Thus, aptamers are expected to play an important role in the development of new therapeutics in the future. This review summarizes recent advances in aptamer-based targeted nanoliposomes for the treatment of breast cancer. A market analysis of the global aptamer market is presented as part of an effort to understand the growing use of aptamers in academic and industrial research. In addition, we discuss the challenges and future potential associated with the use of nanoliposomes as an effective anti-breast cancer therapy.
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The breast cancer is one of the most common cancer affecting millions of lives worldwide. Though the prevalence of breast cancer is worldwide; however, the developing nations are having a ...comparatively higher percentage of breast cancer cases and associated complications. The molecular etiology behind breast cancer is complex and involves several regulatory molecules and their downstream signaling. Studies have demonstrated that the CD44 remains one of the major molecule associated not only in breast cancer but also several other kinds of tumors. The complex structure and functioning of CD44 posed a challenge to develop and deliver precise anti-cancerous drugs against targeted tissue. There are more than 20 isoforms of CD44 reported till date associated with several kinds of tumor in the using breast cancer. The success of any anti-cancerous therapy largely depends on the precise drug delivery system, and in modern days nanotechnology-based drug delivery vehicles are the first choice not only for cancer but several other chronic diseases as well. The Carbon nanotubes (CNTs) have shown tremendous scope in delivering the drug by targeting a particular receptor and molecules. Functionalized CNTs including both SWCNTs and MWCNTs are a pioneer in drug delivery with higher efficacy. The present work emphasized mainly on the potential of CNTs including both SWCNTs and MWCNTs in drug delivery for anti-cancerous therapy. The review provides a comprehensive overview of the development of various CNTs and their validation for effective drug delivery. The work focus on drug delivery approaches for breast cancer, precisely targeting CD44 molecule.
Exaggerated inflammatory responses during influenza A virus (IAV) infection are typically associated with severe disease. Neutrophils are among the immune cells that can drive this excessive and ...detrimental inflammation. In moderation, however, neutrophils are necessary for optimal viral control. In this study, we explore the role of the nucleotide-binding domain leucine-rich repeat containing receptor family member Nlrp12 in modulating neutrophilic responses during lethal IAV infection.
mice are protected from lethality during IAV infection and show decreased vascular permeability, fewer pulmonary neutrophils, and a reduction in levels of neutrophil chemoattractant CXCL1 in their lungs compared with wild-type mice.
neutrophils and dendritic cells within the IAV-infected lungs produce less CXCL1 than their wild-type counterparts. Decreased CXCL1 production by
dendritic cells was not due to a difference in CXCL1 protein stability, but instead to a decrease in
mRNA stability. Together, these data demonstrate a previously unappreciated role for Nlrp12 in exacerbating the pathogenesis of IAV infection through the regulation of CXCL1-mediated neutrophilic responses.
•Progressive resistance exercise leads to long-term cognitive benefits in MCI.•Resistance exercise slows post-training CA1, subiculum and dentate atrophy.•Within-training preservation of PCC predicts ...long-term hippocampal preservation.•Neuroprotection of AD-vulnerable hippocampal subfields mediate long-term cognition.•Long-term neuroprotection is not mediated by post-training fitness adaptations.
Dementia affects 47 million individuals worldwide, and assuming the status quo is projected to rise to 150 million by 2050. Prevention of age-related cognitive impairment in older persons with lifestyle interventions continues to garner evidence but whether this can combat underlying neurodegeneration is unknown. The Study of Mental Activity and Resistance Training (SMART) trial has previously reported within-training findings; the aim of this study was to investigate the long-term neurostructural and cognitive impact of resistance exercise in Mild Cognitive Impairment (MCI). For the first time we show that hippocampal subareas particularly susceptible to volume loss in Alzheimer's disease (AD) are protected by resistance exercise for up to one year after training.
One hundred MCI participants were randomised to one of four training groups: (1) Combined high intensity progressive resistance and computerised cognitive training (PRT+CCT), (2) PRT+Sham CCT, (3) CCT+Sham PRT, (4) Sham physical+sham cognitive training (SHAM+SHAM). Physical, neuropsychological and MRI assessments were carried out at baseline, 6 months (directly after training) and 18 months from baseline (12 months after intervention cessation). Here we report neuro-structural and functional changes over the 18-month trial period and the association with global cognitive and executive function measures.
PRT but not CCT or PRT+CCT led to global long-term cognitive improvements above SHAM intervention at 18-month follow-up. Furthermore, hippocampal subfields susceptible to atrophy in AD were protected by PRT revealing an elimination of long-term atrophy in the left subiculum, and attenuation of atrophy in left CA1 and dentate gyrus when compared to SHAM+SHAM (p = 0.023, p = 0.020 and p = 0.027). These neuroprotective effects mediated a significant portion of long-term cognitive benefits. By contrast, within-training posterior cingulate plasticity decayed after training cessation and was unrelated to long term cognitive benefits. Neither general physical activity levels nor fitness change over the 18-month period mediated hippocampal trajectory, demonstrating that enduring hippocampal subfield plasticity is not a simple reflection of post-training changes in fitness or physical activity participation. Notably, resting-state fMRI analysis revealed that both the hippocampus and posterior cingulate participate in a functional network that continued to be upregulated following intervention cessation.
Multiple structural mechanisms may contribute to the long-term global cognitive benefit of resistance exercise, developing along different time courses but functionally linked. For the first time we show that 6 months of high intensity resistance exercise is capable of not only promoting better cognition in those with MCI, but also protecting AD-vulnerable hippocampal subfields from degeneration for at least 12 months post-intervention. These findings emphasise the therapeutic potential of resistance exercise; however, future work will need to establish just how long-lived these outcomes are and whether they are sufficient to delay dementia.
The present study explored the role of continuous erector spinae plane (ESP) block for analgesia as well as its impact on pulmonary functions in patients with multiple rib fractures.
Ten patients ...with multiple rib fractures were enrolled after getting informed and written consent. Ultrasound-guided ESP block was performed at the level midway between the fractured ribs followed by the insertion of the catheter. Pre- and post-block VAS score, hemodynamics, respiratory rate (RR), peripheral oxygen saturation (SpO2), inspiratory capacity (IC), blood gases (PaO2 and PCO2), and complications were compared.
Pain scores at rest as well as on movement showed a significant reduction from 5.9 and 7.5 pre block to 1.6 and 2.5 respectively at 96.ßhours (p.ß<.ß0.0001). Similarly, RR, SpO2, IC, and PaO2 were significantly better after the block placement (p.ß<.ß0.001).
Continuous ESP block provide adequate analgesia with better respiratory functions in patients with multiple rib fractures.
Women are liable to stress-related disorders as female sex hormone, estrogen has been indicated to be protective against stress disorders. The hormone level varies with different phases of menstrual ...cycle. Moreover, postmenopausal women are at risk for stress-related disorders. So this study was done to correlate the different phases of menstrual cycle with the perceived stress in different phases of monthly cycle.
This study was conducted in the Department of Physiology, Shri Guru Ram Rai Institute of Medical and Health Sciences (SGRRIMHS), Dehradun. Four hundred girls in the age group of 18-26 years were selected for the study. The Perceived Stress Scale (PSS) questionnaire was circulated via Google forms after briefing them about the study. Informed consent was also taken. The menstrual history of the subjects was enquired by one-to-one interaction. The participants completed the PSS questionnaire twice in the same cycle. Data collected were statistically analyzed, using Independent
-test and Chi-square test and point biserial correlation test.
The analysis showed strong statistical association of PSS with two phases of menstrual cycle. The PSS score was higher in the late luteal and menstrual phase, while it was less in the late follicular phase (
< 0.05). Conclusion: The decreased oestrogen levels in the late luteal & menstrual phase are strongly associated with perceived stress in our study. Hormonal changes in the monthly cycles are related with stress, behavioral shift and many other physical changes in females. This information to the family physicians would be beneficial in counseling the females regarding various changes occurring during the menstrual cycle.
The inbred mouse strain C57BL/6J is widely used in models of immunological and infectious diseases. Here we show that C57BL/6J mice have a defect in neutrophil recruitment to a range of inflammatory ...stimuli compared with the related C57BL/6N substrain. This immune perturbation is associated with a missense mutation in Nlrp12 in C57BL/6J mice. Both C57BL/6J and NLRP12-deficient mice have increased susceptibility to bacterial infection that correlates with defective neutrophil migration. C57BL/6J and NLRP12-deficient macrophages have impaired CXCL1 production and the neutrophil defect observed in C57BL/6J and NLRP12-deficient mice is rescued by restoration of macrophage NLRP12. These results demonstrate that C57BL/6J mice have a functional defect in NLRP12 and that macrophages require NLRP12 expression for effective recruitment of neutrophils to inflammatory sites.
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