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Curcumin is a nutraceutical known to have numerous medicinal effects including anticancer activity. However, due to its poor water solubility and bioavailability, the therapeutic impact of curcumin against cancer, including breast cancer, has been constrained. Encapsulating curcumin into chitosan nanoparticles (CHNPs) is an effective method to increase its bioavailability as well as antitumorigenic activity. In the current study, the effects of curcumin-encapsulated CHNPs (Cur-CHNPs) on cell migration, targeted homing and tumor growth were examined using in vitro and in vivo breast cancer models. Cur-CHNPs possessed a monodispersed nature with long-term colloidal stability, and demonstrated significant inhibition of cell viability in vitro, which was potentiated by 5-Fluorouracil (5-FU). Outcomes of the in vivo imaging studies confirmed effective tumor targeting and retention ability of Cur-CHNPs, thereby suppressing breast tumor growth in mice models. Overall, the results demonstrated that Cur-CHNPs could be an effective candidate drug formulation for management of breast cancer.

Chronic kidney disease (CKD) impacts over 10% of the global population. Adults with CKD face significant morbidity and mortality. As kidney disease progresses, the risk of adverse outcomes increases. Here, we present an overview of strategies to care for adults with advanced CKD (stage 4-5 CKD, not receiving kidney replacement therapy). We aim to guide clinicians through several aspects of CKD care, ranging from recommended laboratory assessments to interdisciplinary support for patients as they plan for kidney replacement therapy (dialysis, transplantation, or conservative management). We incorporate considerations of health equity and person-centered care, empowering clinicians to deliver high-quality care to people with CKD.

The tumor microenvironment (TME) is composed of various cellular components such as tumor cells, stromal cells including fibroblasts, adipocytes, mast cells, lymphatic vascular cells and infiltrating immune cells, macrophages, dendritic cells and lymphocytes. The intricate interplay between these cells influences tumor growth, metastasis and therapy failure. Significant advancements in breast cancer therapy have resulted in a substantial decrease in mortality. However, existing cancer treatments frequently result in toxicity and nonspecific side effects. Therefore, improving targeted drug delivery and increasing the efficacy of drugs is crucial for enhancing treatment outcome and reducing the burden of toxicity. In this review, we have provided an overview of how tumor and stroma-derived osteopontin (OPN) plays a key role in regulating the oncogenic potential of various cancers including breast. Next, we dissected the signaling network by which OPN regulates tumor progression through interaction with selective integrins and CD44 receptors. This review addresses the latest advancements in the roles of splice variants of OPN in cancer progression and OPN-mediated tumor-stromal interaction, EMT, CSC enhancement, immunomodulation, metastasis, chemoresistance and metabolic reprogramming, and further suggests that OPN might be a potential therapeutic target and prognostic biomarker for the evolving landscape of cancer management.

With increasing knowledge of immunologic factors and with the advent of potent immunosuppressive agents, the last several decades have seen significantly improved kidney allograft survival. However, despite overall improved short to medium-term allograft survival, long-term allograft outcomes remain unsatisfactory. A large body of literature implicates acute and chronic rejection as independent risk factors for graft loss. In this article, we review measures taken at various stages in the kidney transplant process to minimize the risk of rejection. In the pre-transplant phase, it is imperative to minimize the risk of sensitization, aim for better HLA matching including eplet matching and use desensitization in carefully selected high-risk patients. The peri-transplant phase involves strategies to minimize cold ischemia times, individualize induction immunosuppression and make all efforts for better HLA matching. In the post-transplant phase, the focus should move towards individualizing maintenance immunosuppression and using innovative strategies to increase compliance. Acute rejection episodes are risk factors for significant graft injury and development of chronic rejection thus one should strive for early detection and aggressive treatment. Monitoring for DSA development, especially in high-risk populations, should be made part of transplant follow-up protocols. A host of new biomarkers are now commercially available, and these should be used for early detection of rejection, immunosuppression modulation, prevention of unnecessary biopsies and monitoring response to rejection treatment. There is a strong push needed for the development of new drugs, especially for the management of chronic or resistant rejections, to prolong graft survival. Prevention of rejection is key for the longevity of kidney allografts. This requires a multipronged approach and significant effort on the part of the recipients and transplant centers.

Introduction and Objective: Previously, various stretching techniques were compared to study their effects on the different physiological parameters of hamstring muscles in the elderly population. There is no research that compares the immediate and long-term effects of proprioceptive neuromuscular facilitation-contract-relax (PNF-CR) and static stretching (SS) techniques on knee range of motion (ROM), hamstring flexibility, and knee flexor muscle EMG activity in the elderly. This study intends to compare the same. Methods: A total of 30 males aged 55-75 years were randomly assigned into the PNF-CR group ( n = 10), SS group ( n = 10), and control group ( n = 10). The PNF-CR group received four trials of the contract-relax technique, the SS group received passive stretching of an 80 s duration by the therapist, and the control group received no intervention. A total of 12 sessions were given during the four-week period. Knee range of motion, electromyographic activity of the biceps femoris, and the sit-and-reach test were taken for the dominant side thrice: pre-intervention, immediately after stretching, and after the training period. Results: A statistically significant difference was observed in the maximum voluntary isometric contraction (MVIC) of biceps femoris between the PNF and the control groups ( p = 0.01) after four weeks of intervention. The knee ROM and hamstring flexibility for the PNF group showed significant improvement immediately post-test ( p = 0.01) and after four weeks of training ( p = 0.07 and p = 0.001). SS showed significant results for both ROM and flexibility after four weeks of intervention ( p = 0.001), and significant immediate post-test improvements were seen for ROM only ( p = 0.007). Conclusions: PNF stretching has an immediate, as well as long-term, effect on knee ROM and hamstring flexibility, whereas it has only a long-term effect on muscle electromyographic activity. SS has an immediate, as well as long-term, effect on knee ROM and only a long-term effect on hamstring flexibility, without any immediate or long-term effects on muscle electromyographic activity.

Increasing emphasis is placed on physical functional measures to examine treatments for chronic low back pain (CLBP). The Quebec Back Pain Disability Scale (Hindi version) (QBPDS-H) has never been evaluated for responsiveness. The objectives of this study were to (1) examine the internal and external responsiveness of the Quebec Back Pain Disability Scale (Hindi version) (QBPDS-H) and (2) find out the minimal clinically important difference (MCID) and minimal detectable change (MDC) in the functional ability of patients with chronic low back pain (CLBP) undergoing multimodal physical therapy treatment. In this prospective cohort study, QBPDS-H responses were recorded at the baseline and after eight weeks from 156 CLBP patients undergoing multimodal physiotherapy treatment. To differentiate between the clinically unimproved (n = 65, age: 44.16 ± 11.8 years) and clinically improved (n = 91, age: 43.28 ± 10.7 years) scores of patients from the initial assessment to the last follow-up, the Hindi version of the Patient's Global Impression of Change (H-PGIC) scale was utilized. Internal responsiveness was large (E.S. (pooled S.D.) (n = 91): 0.98 (95% CI = 1.14-0.85) and Standardized Response Mean (S.R.M.) (n = 91): 2.57 (95% CI = 3.05-2.17)). In addition, the correlation coefficient and receiver operative characteristics (R.O.C.) curve were used to assess the QBPDS-H external responsiveness. MCID and MDC were detected by the R.O.C. curve and standard error of measurements (S.E.M.), respectively. The H-PGIC scale showed moderate responsiveness (ρ = 0.514 and area under the curve (A.U.C.) = 0.658; 95% CI, 0.596-0.874), while the MDC achieved 13.68 points, and the MCID was found have 6 points (A.U.C. = 0.82; 95% CI: 0.74-0.88, sensitivity = 90%, specificity = 61%). This study shows that QBPDS-H has moderate levels of responsiveness in CLBP patients receiving multimodal physical therapy treatment, so it can be used to measure the changes in disability scores. MCID and MDC changes were also reported with QBPDS-H.

Background: This study aims to determine the effects of kinesio tape (KT) application on acute-onset muscle soreness and the extensibility of the calf muscles in endurance athletes., Methods: A one-arm repeated-measures randomized cross-over controlled study design investigated 55 endurance athletes, including 10 cyclists, 30 badminton players, and 15 long-distance runners (mean age 16.40 ± 2.69) from different stadia in Delhi NCR, India. KT and sham tapes (ST) were applied randomly to right and left legs (prone position) in a cross-over manner with a gap of 72 h. Ankle dorsiflexion range of motion (ADFROM) and pain due to acute-onset muscle soreness were assessed immediately and 10 min and 30 min after treadmill running, using a universal goniometer and numeric pain rating scale (NPRS), respectively, along with the time to fatigue., Results: A statistically significant difference was observed for the NPRS when the mean scores obtained for the KT and ST groups were compared immediately after cessation of running; however, the difference was not statistically significant in the NPRS score that was recorded ten or thirty minutes after. The range of motion increased significantly after the application of both the KT and the ST. After running on a treadmill, the range of motion decreased significantly with both the KT and ST, and the decrease was similar., Conclusion: KT was more effective in reducing the pain intensity immediately after running and increased the time spent running on the treadmill before fatigue set in among endurance athletes. In addition, the two taping methods (KT or ST) were equally effective in enhancing calf muscle extensibility (for both right and left legs) immediately after application. However, both taping methods failed in limiting the decrease in ankle ADFROM after treadmill running.

Paraoxonase-1 (PON-1) is a hydrolytic enzyme associated with HDL, contributing to its anti-inflammatory, antioxidant, and anti-atherogenic properties. Deficiencies in PON-1 activity result in oxidative stress and detrimental clinical outcomes in the context of chronic kidney disease (CKD). However, it is unclear if a decrease in PON-1 activity is mechanistically linked to adverse cardiovascular events in CKD. We investigated the hypothesis that PON-1 is cardioprotective in a Dahl salt-sensitive model of hypertensive renal disease. Experiments were performed on control Dahl salt-sensitive rats (SS Mcwi , hereafter designated SS-WT rats) and mutant PON-1 rats (SS-Pon1 em1Mcwi , hereafter designated SS-PON-1 KO rats) generated using CRISPR gene editing technology. Age-matched 10-week-old SS and SS-PON-1 KO male rats were maintained on high-salt diets (8% NaCl) for five weeks to induce hypertensive renal disease. Echocardiography showed that SS-PON-1 KO rats but not SS-WT rats developed compensated left ventricular hypertrophy after only 4 weeks on the high-salt diet. RT-PCR analysis demonstrated a significant increase in the expression of genes linked to cardiac hypertrophy, inflammation, and fibrosis, as well as a significant decrease in genes essential to left ventricular function in SS-PON-1 KO rats compared to SS-WT rats. A histological examination also revealed a significant increase in cardiac fibrosis and immune cell infiltration in SS-PON-1 KO rats, consistent with their cardiac hypertrophy phenotype. Our data suggest that a loss of PON-1 in the salt-sensitive hypertensive model of CKD leads to increased cardiac inflammation and fibrosis as well as a molecular and functional cardiac phenotype consistent with compensated left ventricular hypertrophy.

We have previously shown in a murine model of Non-alcoholic Fatty Liver Disease (NAFLD) that chronic, low-dose exposure to the Harmful Algal Bloom cyanotoxin microcystin-LR (MC-LR), resulted in significant hepatotoxicity including micro-vesicular lipid accumulation, impaired toxin metabolism as well as dysregulation of the key signaling pathways involved in inflammation, immune response and oxidative stress. On this background we hypothesized that augmentation of hepatic drug metabolism pathways with targeted antioxidant therapies would improve MC-LR metabolism and reduce hepatic injury in NAFLD mice exposed to MC-LR. We chose N-acetylcysteine (NAC, 40 mM), a known antioxidant that augments the glutathione detoxification pathway and a novel peptide (pNaKtide, 25 mg/kg) which is targeted to interrupting a specific Src-kinase mediated pro-oxidant amplification mechanism. Histological analysis showed significant increase in hepatic inflammation in NAFLD mice exposed to MC-LR which was attenuated on treatment with both NAC and pNaKtide (both p ≤ 0.05). Oxidative stress, as measured by 8-OHDG levels in urine and protein carbonylation in liver sections, was also significantly downregulated upon treatment with both antioxidants after MC-LR exposure. Genetic analysis of key drug transporters including Abcb1a , Phase I enzyme- Cyp3a11 and Phase II metabolic enzymes- Pkm (Pyruvate kinase, muscle), Pklr (Pyruvate kinase, liver, and red blood cell) and Gad1 (Glutamic acid decarboxylase) was significantly altered by MC-LR exposure as compared to the non-exposed control group (all p ≤ 0.05). These changes were significantly attenuated with both pNaKtide and NAC treatment. These results suggest that MC-LR metabolism and detoxification is significantly impaired in the setting of NAFLD, and that these pathways can potentially be reversed with targeted antioxidant treatment.

Cardiovascular disease (CVD) is one of the greatest public health concerns and is the leading cause of morbidity and mortality in the United States and worldwide. CVD is a broad yet complex term referring to numerous heart and vascular conditions, all with varying pathologies. Macrophages are one of the key factors in the development of these conditions. Macrophages play diverse roles in the maintenance of cardiovascular homeostasis, and an imbalance of these mechanisms contributes to the development of CVD. In the current review, we provide an in-depth analysis of the diversity of macrophages, their roles in maintaining tissue homeostasis within the heart and vasculature, and the mechanisms through which imbalances in homeostasis may lead to CVD. Through this review, we aim to highlight the potential importance of macrophages in the identification of preventative, diagnostic, and therapeutic strategies for patients with CVD.

Papraoxonase-1 (PON1) is a hydrolytic lactonase enzyme that is synthesized in the liver and circulates attached to high-density lipoproteins (HDL). Clinical studies have demonstrated an association between diminished PON-1 and the progression of chronic kidney disease (CKD). However, whether decreased PON-1 is mechanistically linked to renal injury is unknown. We tested the hypothesis that the absence of PON-1 is mechanistically linked to the progression of renal inflammation and injury in CKD. Experiments were performed on control Dahl salt-sensitive rats (SSMcwi, hereafter designated SS rats) and Pon1 knock-out rats (designated SS-Pon1em1Mcwi, hereafter designated SS-PON-1 KO rats) generated by injecting a CRISPR targeting the sequence into SSMcwi rat embryos. The resulting mutation is a 7 bp frameshift insertion in exon 4 of the PON-1 gene. First, to examine the renal protective role of PON-1 in settings of CKD, ten-week-old, age-matched male rats were maintained on a high-salt diet (8% NaCl) for up to 5 weeks to initiate the salt-sensitive hypertensive renal disease characteristic of this model. We found that SS-PON-1 KO rats demonstrated several hallmarks of increased renal injury vs. SS rats including increased renal fibrosis, sclerosis, and tubular injury. SS-PON-1 KO also demonstrated increased recruitment of immune cells in the renal interstitium, as well as increased expression of inflammatory genes compared to SS rats (all p < 0.05). SS-PON-1 KO rats also showed a significant (p < 0.05) decline in renal function and increased renal oxidative stress compared to SS rats, despite no differences in blood pressure between the two groups. These findings suggest a new role for PON-1 in regulating renal inflammation and fibrosis in the setting of chronic renal disease independent of blood pressure.

Injection treatment is one of the most widely used methods for the conservative management of patellar tendinopathy. The objective of this systematic review was to synthesise data from randomised control trails on the effectiveness of various injections used in the management of patellar tendinopathy. An electronic search was conducted in the Web of Science, Scopus, PubMed, and SPORTDiscus databases. To be included in the current systematic review, the study had to be an RCT conducted on human participants that investigated the effect of at least one injection treatment on the management of patellar tendinopathy. Selected studies were required to report either patient-reported outcomes or biological and clinical markers of the tendon healing. The methodological quality of the studies was appraised using the revised Cochrane risk of bias tool for RCTs (RoB 2.0). Nine RCTs on seven types of injections were included in this review, with an overall positive outcome. Pain intensity was measured in all the studies. The VISA P score was the most used outcome measure ( n = 8). A wide variety of interventions were compared with injection therapy, including eccentric training, extracorporeal shockwave, and arthroscopy. It can be concluded that the injection treatments can produce promising results in the management of patellar tendinopathy. However, because of the limited number of studies and the disparities in the study populations and protocols, it is not possible to make a firm conclusion on the efficacy of these injection methods, and these results should be inferred with care.

Paraoxonases (PONs) are a family of hydrolytic enzymes consisting of three members, PON1, PON2, and PON3, located on human chromosome 7. Identifying the physiological substrates of these enzymes is necessary for the elucidation of their biological roles and to establish their applications in the biomedical field. PON substrates are classified as organophosphates, aryl esters, and lactones based on their structure. While the established native physiological activity of PONs is its lactonase activity, the enzymes' exact physiological substrates continue to be elucidated. All three PONs have antioxidant potential and play an important anti-atherosclerotic role in several diseases including cardiovascular diseases. PON3 is the last member of the family to be discovered and is also the least studied of the three genes. Unlike the other isoforms that have been reviewed extensively, there is a paucity of knowledge regarding PON3. Thus, the current review focuses on PON3 and summarizes the PON substrates, specific activities, kinetic parameters, and their association with cardiovascular as well as other diseases such as HIV and cancer.

Vascular calcification (VC) is one of the major causes of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). VC is a complex process expressing similarity to bone metabolism in onset and progression. VC in CKD is promoted by various factors not limited to hyperphosphatemia, Ca/Pi imbalance, uremic toxins, chronic inflammation, oxidative stress, and activation of multiple signaling pathways in different cell types, including vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells. In the current review, we provide an in-depth analysis of the various kinds of VC, the clinical significance and available therapies, significant contributions from multiple cell types, and the associated cellular and molecular mechanisms for the VC process in the setting of CKD. Thus, we seek to highlight the key factors and cell types driving the pathology of VC in CKD in order to assist in the identification of preventative, diagnostic, and therapeutic strategies for patients burdened with this disease.

Viral entry mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an important aspect of virulence. Proposed mechanisms involve host cell membrane-bound angiotensin-converting enzyme 2 (ACE2), type II transmembrane serine proteases (TTSPs), such as transmembrane serine protease isoform 2 (TMPRSS2), lysosomal endopeptidase Cathepsin L (CTSL), subtilisin-like proprotein peptidase furin (FURIN), and even potentially membrane bound heparan sulfate proteoglycans. The distribution and expression of many of these genes across cell types representing multiple organ systems in healthy individuals has recently been demonstrated. However, comorbidities such as diabetes and cardiovascular disease are highly prevalent in patients with Coronavirus Disease 2019 (COVID-19) and are associated with worse outcomes. Whether these conditions contribute directly to SARS-CoV-2 virulence remains unclear. Here, we show that the expression levels of ACE2, TMPRSS2 and other viral entry-related genes, as well as potential downstream effector genes such as bradykinin receptors, are modulated in the target organs of select disease states. In tissues, such as the heart, which normally express ACE2 but minimal TMPRSS2, we found that TMPRSS2 as well as other TTSPs are elevated in individuals with comorbidities compared to healthy individuals. Additionally, we found the increased expression of viral entry-related genes in the settings of hypertension, cancer, or smoking across target organ systems. Our results demonstrate that common comorbidities may contribute directly to SARS-CoV-2 virulence and we suggest new therapeutic targets to improve outcomes in vulnerable patient populations.

Inflammatory Bowel Disease (IBD) is one of the most common gastrointestinal (GI) disorders around the world, and includes diagnoses such as Crohn's disease and ulcerative colitis. The etiology of IBD is influenced by genetic and environmental factors. One environmental perturbagen that is not well studied within the intestines is microcystin-leucine arginine (MC-LR), which is a toxin produced by cyanobacteria in freshwater environments around the world. We recently reported that MC-LR has limited effects within the intestines of healthy mice, yet interestingly has significant toxicity within the intestines of mice with pre-existing colitis induced by dextran sulfate sodium (DSS). MC-LR was found to prolong DSS-induced weight loss, prolong DSS-induced bloody stools, exacerbate DSS-induced colonic shortening, exacerbate DSS-induced colonic ulceration, and exacerbate DSS-induced inflammatory cytokine upregulation. In addition, we previously reported a significant increase in expression of the pro-inflammatory receptor CD40 in the colons of these mice, along with downstream products of CD40 activation, including plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1). In the current study, we demonstrate that knocking out CD40 attenuates the effects of MC-LR in mice with pre-existing colitis by decreasing the severity of weight loss, allowing a full recovery in bloody stools, preventing the exacerbation of colonic shortening, preventing the exacerbation of colonic ulceration, and preventing the upregulation of the pro-inflammatory and pro-fibrotic cytokines IL-1β, MCP-1, and PAI-1. We also demonstrate the promising efficacy of a CD40 receptor blocking peptide to ameliorate the effects of MC-LR exposure in a proof-of-concept study. Our findings suggest for the first time that MC-LR acts through a CD40-dependent mechanism to exacerbate colitis.

The burden of cardiovascular disease and death in chronic kidney disease (CKD) outpaces that of the other diseases and is not adequately described by traditional risk factors alone. Diminished activity of paraoxonase (PON)-1 is associated with increased oxidant stress, a common feature underlying the pathogenesis of CKD. We aimed to assess the prognostic value of circulating PON-1 protein and PON lactonase activity on adverse clinical outcomes across various stages and etiologies of CKD. Circulating PON-1 protein levels and PON lactonase activity were measured simultaneously in patients with CKD as well as a cohort of apparently healthy non-CKD subjects. Both circulating PON-1 protein levels and PON lactonase activity were significantly lower in CKD patients compared to the non-CKD subjects. Similarly, across all stages of CKD, circulating PON-1 protein and PON lactonase activity were significantly lower in patients with CKD compared to the non-CKD controls. Circulating PON lactonase activity, but not protein levels, predicted future adverse clinical outcomes, even after adjustment for traditional risk factors. The combination of lower circulating protein levels and higher activity within the CKD subjects were associated with the best survival outcomes. These findings demonstrate that diminished circulating PON lactonase activity, but not protein levels, predicts higher risk of future adverse clinical outcomes in patients with CKD.