TPP-based conjugates: potential targeting ligands.

Mitochondria are one of the major sources of energy as well as regulators of cancer cell metabolism. Thus, they are potential targets for the effective treatment and management of cancer. Research has explored triphenylphosphonium (TPP) derivatives as potent cancer-targeting ligands because of their lipophilic nature and mitochondrial affinity. In this review, we summarize the utility of TPP-based conjugates targeting mitochondria in different types of cancer and other diseases, such as neurodegenerative and cardiovascular disorders. Such conjugates offer versatile therapeutic potential by modulating membrane potential, influencing reactive oxygen species (ROS) production, and coupling of molecular modifications (such as ATP metabolism and energy metabolism). Thus, we highlight TPP conjugates as promising mitochondria-targeting agents for use in targeted drug delivery systems.

Polycationic phosphorous dendrimer potentiates multiple antibiotics against drug-resistant mycobacterial pathogens.

Mycobacterium tuberculosis (Mtb), causative agent of tuberculosis (TB) and non-tubercular mycobacterial (NTM) pathogens such as Mycobacterium abscessus are one of the most critical concerns worldwide due to increased drug-resistance resulting in increased morbidity and mortality. Therefore, focusing on developing novel therapeutics to minimize the treatment period and reducing the burden of drug-resistant Mtb and NTM infections are an urgent and pressing need. In our previous study, we identified anti-mycobacterial activity of orally bioavailable, non-cytotoxic, polycationic phosphorus dendrimer 2G0 against Mtb. In this study, we report ability of 2G0 to potentiate activity of multiple classes of antibiotics against drug-resistant mycobacterial strains. The observed synergy was confirmed using time-kill kinetics and revealed significantly potent activity of the combinations as compared to individual drugs alone. More importantly, no re-growth was observed in any tested combination. The identified combinations were further confirmed in intra-cellular killing assay as well as murine model of NTM infection, where 2G0 potentiated the activity of all tested antibiotics significantly better than individual drugs. Taken together, this nanoparticle with intrinsic antimycobacterial properties has the potential to represents an alternate drug candidate and/or a novel delivery agent for antibiotics of choice for enhancing the treatment of drug-resistant mycobacterial pathogens.

Fucoidan loaded PVA/Dextran blend electrospun nanofibers for the effective wound healing.

Chronic wounds have become a serious global health issue. In this study, we investigated the effect of increasing fucoidan (FD) concentration on the characteristics of nanofibers and their wound healing potential at in vitro as well as in vivo level. The results showed that increasing FD content (0.25 to 1 %) led to an significant increase in nanofiber diameter (487.7 ± 125.39 to 627.9 ± 149.78 nm), entrapment efficiency (64.26 ± 2.6 to 94.9 ± 3.1 %), and water uptake abilities (436.5 ± 1.2 to 679.7 ± 11.3 %). However, the in vitro biodegradation profile decreased with an increase in FD concentration. Water vapor transmission rate analysis showed that it was within the standard range for all FD concentrations. Nanofibers with 1 % PVA/DX/FD exhibited slow-release behavior, suggesting prolonged FD availability at the wound site. In vivo studies in rats with full-thickness wounds demonstrated that applying 1 % FD-enriched PVA/DEX nanofibers significantly (p < 0.0001) improved mean wound area closure. These findings suggest that FD-enriched nanofibers have immense potential as a wound dressing material in future if explored further.

Nur77 influences immunometabolism to regulate the release of proinflammatory cytokines and the formation of lipid bodies during Mycobacterium tuberculosis infection of macrophages.

Infection of macrophages with Mycobacterium tuberculosis induces innate immune responses designed to clear the invading bacterium. However, bacteria often survive within the intracellular environment by exploiting these responses triggered by macrophages. Here, the role of the orphan nuclear receptor Nur77 (Nr4a1) in regulating the response of macrophages infected with M. tuberculosis (Mtb) has been delineated. Nur77 is induced early during infection, regulates metabolism by binding directly at the promoter of the TCA cycle enzyme, isocitrate dehydrogenase 2 (IDH2), to act as its repressor, and shifts the balance from a proinflammatory to an anti-inflammatory phenotype. Depletion of Nur77 increased transcription of IDH2 and, consequently, the levels of intracellular succinate, leading to enhanced levels of the proinflammatory cytokine IL-1ß. Further, Nur77 inhibited the production of antibacterial nitric oxide and IL-1ß in a succinate dehydrogenase (SDH)-dependent manner, suggesting that its induction favors bacterial survival by suppressing bactericidal responses. Indeed, depletion of Nur77 inhibited the intracellular survival of Mtb. On the other hand, depletion of Nur77 enhanced lipid body formation, suggesting that the fall in Nur77 levels as infection progresses likely favors foamy macrophage formation and long-term survival of Mtb in the host milieu.

Clinicopathological Profile of Appendicular Disease in Children: A Tertiary Health Care Center Study.

Background Acute appendicitis (AA) is the most common surgical emergency worldwide. Delay in diagnosis of disease often leads to serious complications such as perforation appendicitis (PA) and gangrenous appendicitis (GA). Aims and objectives The purpose of the study is to document clinicopathological outcomes in pediatric age group patients in a tertiary health care center. Material and method This study was a prospective observation study of 50 patients with pediatric appendicitis who had undergone emergency appendectomy from January 2022 to December 2022. All pediatric patients below 15 years of age with a diagnosis of AA were included. Institute ethical permission was granted before the study, and parent consent was taken for the surgery and also for inclusion in the study. After proper resuscitation, all patients underwent appendectomy, and necessary specimens were sent for histological examination. Based on histopathology reports, all patients were classified into four groups: AA, PA, GA, and normal appendix (NA). Results Out of 50 patients, 33 (66%) patients were males and 17 (34%) patients were females. The mean age of the patients was 10.22 ± 2.73 years. The mean age of AA, PA, GA, and NA patients were 10.25 ± 2.6 years, 9.78 ± 2.99 years, 10.00 ± 4.6 years, and 12.00 ± 2.8 years, respectively. The mean duration of symptoms at the time of hospital admission was 2.42 ± 0.97 days for histopathologically proven AA patients, 4.67 ± 2.1 days for GA patients, 2.8 ± 0.83 for PA patients, and one day for NA patients. Overall clinical presentation was right iliac fossa (RIF) pain in 36 (72%) patients, migration of pain in 31 (62%) patients, anorexia in 37 (74%) patients, nausea and vomiting in 43 (86%) patients fever in 26 (52%) patients, RIF tenderness in 50 (100%) patients, rebound tenderness in 39 (78%) patients, guarding in 19 (38%) patients, Psoas's sign in nine (18% patients), and Rovsing's sign in 19 (38%) patients. On histopathological examination of the sent specimen, AA was found in 36 (72%) patients, PA was found in nine (18%) patients, GA was found in three (6%) patients, and NA was found in two (4%) patients. Wound infection was the most common complication and was found in five (10%) patients. The average duration of hospital stay for AA, PA, GA, and NA was 4.33 ± 1.04 days, 9.56 ± 4.2 days, 12.33 ± 8.5 days, and 3.50 ± 0.71 days, respectively. Conclusion The appendicular disease is common in teenage male children. Fever, dehydration, and rebound tenderness at the RIF are clinically significant findings. Duration of symptoms at the time of diagnosis, post-appendectomy complication, and duration of hospital stay significantly correlated with histopathological findings.

Sialic Acid Engineered Prodrug Nanoparticles for Codelivery of Bortezomib and Selenium in Tumor Bearing Mice.

Most cancer patients rarely benefit from monodrug therapy because of both cancer complexity and tumor environment. One of the main reasons for this failure is insufficient accumulation of the optimal dose at the tumorous site. Our investigation implies a promising strategy to engineer prodrug nanoparticles (NPs) of bortezomib (BTZ) and selenium (Se) using sialic acid (SAL) as a ligand to improve breast cancer therapy. BTZ was conjugated with SAL and HPMA (N-2-hydroxypropyl methacrylamide) to prepare a prodrug conjugate; BTZ-SAL-HPMA (BSAL-HP) and then fabricated into prodrug NPs with Se (Se_BSAL-HP prodrug NPs). The self-assembly of prodrug NPs functionalized with Se showed size (204.13 ± 0.02 nm) and zeta potential (-31.0 ± 0.11 mV) in dynamic light scattering (DLS) experiments and spherical shape in TEM and SEM analysis. Good stability and low pH drug release profile were characterized by Se_BSAL-HP prodrug NPs. The tumor-selective boronate-ester-based prodrug NPs of BTZ in combination with Se endowed a synergistic effect against cancer cells. Compared to prodrug conjugate, Se_BSAL-HP prodrug NPs exhibited higher cell cytotoxicity and enhanced cellular internalization with significant changes in mitochondria membrane potential (MMP). Elevated apoptosis was observed in the (G2/M) phase of the cell cycle for Se_BSAL-HP prodrug NPs (2.7-fold) higher than BTZ. In vivo studies were performed on Sprague-Dawley rats and resulted in positive trends. The increased therapeutic activity of Se_BSAL-HP prodrug NPs inhibited primary tumor growth and showed 43.05 fold decrease in tumor volume than the control in 4T1 tumor bearing mice. The surprising and remarkable outcomes for Se_BSAL-HP prodrug NPs were probably due to the ROS triggering effect of boronate ester and selenium given together.

Hepatocellular carcinoma: Preclinical and clinical applications of nanotechnology with the potential role of carbohydrate receptors.

Hepatocellular carcinoma (HCC) is one of the most common types of liver cancer; accounts for 75-85% of cases. The treatment and management of HCC involve different sanative options like surgery, chemotherapy, immunotherapy, etc. Recently, various advancements have been introduced for the diagnosis and targeting of hepatic tumor cells. Among these, biomarkers are considered the primary source for the diagnosis and differentiation of tumor cells. With the advancement in the field of nanotechnology, different types of nanocarriers have been witnessed in tumor targeting. Nanocarriers such as nanoparticles, liposomes, polymeric micelles, nanofibers, etc. are readily prepared for effective tumor targeting with minimal side-effects. The emergence of various approaches tends to improve the effectiveness of these nanocarriers as demonstrated in ample clinical trials. This review focuses on the significant role of carbohydrates such as mannose, galactose, fructose, etc. in the development, diagnosis, and therapy of HCC. Hence, the current focus of this review is to acknowledge various perspectives regarding the occurrence, diagnosis, treatment, and management of HCC.

An Evidence Base for Heart Disease Prevention using a Mediterranean Diet Comprised Primarily of Vegetarian Food.

Dietary patterns, nutrition, physical activity, air pollution, tobacco smoke, ethnicity and genetics affect heart disease. Vegetarian food diets are one of the important factors in its prevention and control. People living in the five blue zones, mostly consuming the Mediterranean diet (MedDiet), have the highest longevity in the world and the least incidence of heart disease. There are several forms of heart pathology, e.g., the most common coronary heart disease, myocardial infarction, congestive heart failure, heart valve disease and abnormal heart rhythms. Heart disease is the leading cause of death in the world and varies by race, where indigenous and people of color have a higher risk for its complications than the white population. The morbidity of cardiovascular pathology in the Afro-American community persists high and is a primary source of disparities in life expectancy between Afro-Americans and whites in the United States. Adherence to healthy diets higher in vegetable foods and lower in animal foods is correlated with a lower risk of cardiovascular disease, morbidity and mortality in the general population. A detailed literature review was performed of the Medline, EMBASE, and Ebsco databases to synthesize and compare evidence on this topic to produce a review of the importance of a Mediterranean diet in the prevention of heart disease. Consumption of a MedDiet consisting of fruits and vegetables (including berries due to their high fibre and antioxidant content), nuts, whole grains, leafy greens, beans like chickpeas, eggplants, Greek yogurt and extra virgin olive oil are associated with longer life and lower incidence of heart disease. The latter diet is superior to consuming large quantities of meat and refined carbohydrates, such as sucrose, high fructose corn syrup and grains that have had the fibrous and nutritious parts removed.

Angiopep-2 Grafted PAMAM Dendrimers for the Targeted Delivery of Temozolomide: In Vitro and In Vivo Effects of PEGylation in the Management of Glioblastoma Multiforme.

The present study was aimed to synthesize, characterize, and evaluate the angiopep-2 grafted PAMAM dendrimers (Den, G 3.0 NH2) with and without PEGylation for the targeted and better delivery approach of temozolomide (TMZ) for the management of glioblastoma multiforme (GBM). Den-ANG and Den-PEG2-ANG conjugates were synthesized and characterized by 1H NMR spectroscopy. The PEGylated (TMZ@Den-PEG2-ANG) and non-PEGylated (TMZ@Den-ANG) drug loaded formulations were prepared and characterized for particle size, zeta potential, entrapment efficiency, and drug loading. An in vitro release study at physiological (pH 7.4) and acidic pH (pH 5.0) was performed. Preliminary toxicity studies were performed through hemolytic assay in human RBCs. MTT assay, cell uptake, and cell cycle analysis were performed to evaluate the in vitro efficacy against GBM cell lines (U87MG). Finally, the formulations were evaluated in vivo in a Sprague-Dawley rat model for pharmacokinetics and organ distribution analysis. The 1H NMR spectra confirmed the conjugation of angiopep-2 to both PAMAM and PEGylated PAMAM dendrimers, as the characteristic chemical shifts were observed in the range of 2.1 to 3.9 ppm. AFM results revealed that the surface of Den-ANG and Den-PEG2-ANG conjugates were rough. The particle size and zeta potential of TMZ@Den-ANG were observed to be 229.0 ± 17.8 nm and 9.06 ± 0.4 mV, respectively, whereas the same for TMZ@Den-PEG2-ANG were found to be 249.6 ± 12.9 nm and 10.9 ± 0.6 mV, respectively. The entrapment efficiency of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were calculated to be 63.27 ± 5.1% and 71.48 ± 4.3%, respectively. Moreover, TMZ@Den-PEG2-ANG showed a better drug release profile with a controlled and sustained pattern at PBS pH 5.0 than at pH 7.4. The ex vivo hemolytic study revealed that TMZ@Den-PEG2-ANG was biocompatible in nature as it showed 2.78 ± 0.1% hemolysis compared to 4.12 ± 0.2% hemolysis displayed by TMZ@Den-ANG. The outcomes of the MTT assay inferred that TMZ@Den-PEG2-ANG possessed maximum cytotoxic effects against U87MG cells with IC50 values of 106.62 ± 11.43 µM (24 h) and 85.90 ± 9.12 µM (48 h). In the case of TMZ@Den-PEG2-ANG, the IC50 values were reduced by 2.23-fold (24 h) and 1.36-fold (48 h) in comparison to pure TMZ. The cytotoxicity findings were further confirmed by significantly higher cellular uptake of TMZ@Den-PEG2-ANG. Cell cycle analysis of the formulations suggested that the PEGylated formulation halts the cell cycle at G2/M phase with S-phase inhibition. In the in vivo studies, the half-life (t1/2) values of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were enhanced by 2.22 and 2.76 times, respectively, than the pure TMZ. After 4 h of administration, the brain uptake values of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were found to be 2.55 and 3.35 times, respectively, higher than that of pure TMZ. The outcomes of various in vitro and ex vivo experiments promoted the use of PEGylated nanocarriers for the management of GBM. Angiopep-2 grafted PEGylated PAMAM dendrimers can be potential and promising drug carriers for the targeted delivery of antiglioma drugs directly to the brain.

Lipid-Based Nanocarriers in the Treatment of Glioblastoma Multiforme (GBM): Challenges and Opportunities.

Glioblastoma multiforme (also known as glioblastoma; GBM) is one of the most malignant types of brain tumors that occurs in the CNS. Treatment strategies for glioblastoma are majorly comprised of surgical resection, radiotherapy, and chemotherapy along with combination therapy. Treatment of GBM is itself a tedious task but the involved barriers in GBM are one of the main impediments to move one step closer to the treatment of GBM. Basically, two of the barriers are of utmost importance in this regard, namely blood brain barrier (BBB) and blood brain tumor barrier (BBTB). This review will address different challenges and barriers in the treatment of GBM along with their etiology. The role and recent progress of lipid-based nanocarriers like liposomes, solid lipid nanocarriers (SLNs), nanostructured lipid carriers (NLCs), lipoplexes, and lipid hybrid carriers in the effective management of GBM will be discussed in detail.

N-2-Hydroxypropylmethacrylamide-Polycaprolactone Polymeric Micelles in Co-delivery of Proteasome Inhibitor and Polyphenol: Exploration of Synergism or Antagonism.

Breast cancer leads to the highest mortality among women resulting in a major clinical burden. Multidrug therapy is more efficient in such patients compared to monodrug therapy. Simultaneous combinatorial or co-delivery garnered significant interest in the past years. Caffeic acid (CFA) (a natural polyphenol) has received growing attention because of its anticarcinogenic and antioxidant potential. Bortezomib (BTZ) is a proteasome inhibitor and may be explored for treating breast cancer. Despite its high anticancer activity, the low water solubility and chemical instability restrict its efficacy against solid tumors. In the present study, we designed and investigated a HP-PCL (N-2-hydroxypropylmethacrylamide-polycaprolactone) polymeric micellar (PMCs) system for the simultaneous delivery of BTZ and CFA in the treatment of breast cancer. The designed BTZ+CFA-HP-PCL PMCs were fabricated, optimized, and characterized for size, zeta potential, surface morphology, and in vitro drug release. Developed nanosized (174.6 ± 0.24 nm) PMCs showed enhanced cellular internalization and cell cytotoxicity in both MCF-7 and MDA-MB-231 cells. ROS (reactive oxygen species) levels were highest in BTZ-HP-PCL PMCs, while CFA-HP-PCL PMCs significantly (p < 0.001) scavenged the ROS generated in 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. The mitochondrial membrane potential (MMP) assay revealed intense and significant green fluorescence in both types of cancer cells when treated with BTZ-HP-PCL PMCs (p < 0.001) indicating apoptosis or cell death. The pharmacokinetic studies revealed that BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs exhibited the highest bioavailability, enhanced plasma half-life, decreased volume of distribution, and lower clearance rate than the pure combination of drugs. In the organ biodistribution studies, the combination of BTZ+CFA showed higher distribution in the spleen and the heart. Overall findings of in vitro studies surprisingly resulted in better therapeutic efficiency of BTZ-HP-PCL PMCs than BTZ+CFA-HP-PCL PMCs. However, the in vivo tumor growth inhibition study performed in tumor-induced mice concluded that the tumor growth was inhibited by both BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs (p < 0.0001) more efficiently than pure BTZ and the combination (BTZ+CFA), which may be due to the conversion of boronate ester into boronic acid. Henceforth, the combination of BTZ and CFA provides further indications to be explored in the future to support the hypothesis that BTZ may work with polyphenol (CFA) in the acidic environment of the tumor.

Exploration of hemocompatibility and intratumoral accumulation of paclitaxel after loco-regional administration of thermoresponsive hydrogel composed of poloxamer and xanthan gum: An application to dose-dense chemotherapy.

Although paclitaxel is a front-line chemotherapeutic agent for the treatment of metastatic breast cancer, its intravenous therapy produces deleterious adverse effects. In an attempt to address the issue, the present study aimed to develop a paclitaxel loaded thermosensitive/thermoresponsive hydrogel (PTXNp-TGel) for loco-regional administration to breast tumors to provide dose-dense chemotherapy. Poloxamer and xanthan gum were used to prepare TGel by the cold method. In vitro and in vivo performance of PTXNp-TGel was compared with TGel, pure drug loaded TGel (PTX-TGel) and marketed formulation, Taxol®. The formulated PTXNp-TGel showed acceptable gelation temperature and time (37 °C and 57 s), lower viscosity at room temperature and higher viscosity at body temperature to support sol-gel transition with increasing temperature, and sustained drug release up to 21 days. Additionally, PTXNp-TGel showed negligible hemolytic toxicity as compared to PTX-TGel and Taxol®. Intratumoral administration of PTXNp-TGel produced significantly higher antitumor activity as indicated by lowest relative tumor volume (1.50) and relative antitumor proliferation rate (27.71 %) in comparison with PTX-TGel, Taxol®, and PTXNp (p < 0.05). Finally, insignificant body weight loss during the experimental period, lack of hematotoxicity, nephrotoxicity, and hepatotoxicity imply improved therapeutic performance of the locally administrated dose-dense therapy of PTXNp-TGel as compared to Taxol®.

Polymeric Nanoparticles: A Holistic Approach to Combat Tuberculosis.

The emergence of multidrug-resistant (MDR) and extremely drug resistant (XDR) forms of pulmonary tuberculosis (TB) remains a major health challenge in this advanced era of health science. The longer therapy and higher dose of anti-tubercular drugs (ATDs) increases the patient incompliance at its peak levels of intolerance as well as toxicity. In the recent decades, nanoparticulate drug delivery has emerged as an excellent venture for the effective treatment of cancer, infectious diseases, brain as well as TB. Currently, encapsulation and conjugation of therapeutics to polymeric nanoparticles (PNPs) is an attractive strategy to enhance the effectivity of chemotherapeutics and minimize the toxic effects associated with ATDs. Various characteristics of nanoparticles (NPs) such as high stability, high loading efficiency, and high carrying capacity gives preference to the NPs over other drug delivery systems. Multiple or dual drug delivery concept is continuously gaining attention as a strict and favourable requirement of anti-TB therapy. The ideal properties of NPs including controlled or sustained drug release from the matrix enhances drug bioavailability with dose reduction and also enhance compliance of TB patients. Natural and synthetic polymers are playing important role in curtailing the side effects of chemotherapeutics. This review extensively highlights the drug delivery approaches of ATDs and emphasized on the importance and application of PNPs to combat TB.

Surface Engineered Dendrimers: A Potential Nanocarrier for the Effective Management of Glioblastoma Multiforme.

Gliomas are the most prevailing intracranial tumors, which account for approximately 36% of the primary brain tumors of glial cells. Glioblastoma multiforme (GBM) possesses a higher degree of malignancy among different gliomas. The blood-brain barrier (BBB) protects the brain against infections and toxic substances by preventing foreign molecules or unwanted cells from entering the brain parenchyma. Nano-carriers such as liposomes, nanoparticles, dendrimers, etc. boost the brain permeability of various anticancer drugs or other drugs. The favorable properties like small size, better solubility, and the modifiable surface of dendrimers have proven their broad applicability in the better management of GBM. However, in vitro and in vivo toxicities caused by dendrimers have been a significant concern. The presence of multiple functionalities on the surface of dendrimers enables the grafting of target ligand and/or therapeutic moieties. Surface engineering improves certain properties like targeting efficiency, pharmacokinetic profile, therapeutic effect, and toxicity reduction. This review will be focused on the role of different surface-modified dendrimers in the effective management of GBM.

Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-D).

BACKGROUND: A phase 3 study to assess the efficacy and safety of the desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, against the epoetin alfa for the treatment of anemia in patients with chronic kidney disease (CKD) with dialysis dependency. METHODS: DREAM-D was a phase 3, multicenter, open-label, randomized, active-controlled clinical study conducted across 38 centers in India. A total of 392 patients with clinical diagnosis of anemia due to CKD with dialysis need (Erythrocyte Stimulating Agent [ESA] naïve or prior ESA users) and with baseline hemoglobin levels of 8.0-11.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either desidustat oral tablets (thrice a week) or epoetin alfa subcutaneous injection for 24 weeks to maintain a hemoglobin level of 10-12 g/dL. The primary endpoint was to assess the change in the hemoglobin level between the desidustat and the epoetin alfa groups from the baseline to evaluation period week 16-24. The key secondary efficacy endpoint was the number of patients with hemoglobin response. RESULTS: The least square mean (standard error) change in hemoglobin from the baseline to week 16-24 was 0.95 (0.09) g/dL in the desidustat group and 0.80 (0.09) g/dL in the epoetin alfa group (difference: 0.14 [0.14] g/dL; 95% confidence interval: -0.1304, 0.4202), which met the prespecified noninferiority margin. The number of hemoglobin responders was significantly higher in the desidustat group (106 [59.22%]) when compared to the epoetin alfa group (89 [48.37%]) (p = 0.0382). The safety profile of the desidustat oral tablet was comparable with the epoetin alfa injection. There were no new risks or no increased risks seen with the use of desidustat compared to epoetin alfa. CONCLUSION: In this study, desidustat was found to be noninferior to epoetin in the treatment of anemia in CKD patients on dialysis and it was well-tolerated. Clinical Trial Registry Identifier: CTRI/2019/12/022312 (India).

Unraveling novel roles of the Mycobacterium tuberculosis transcription factor Rv0081 in regulation of the nucleoid-associated proteins Lsr2 and EspR, cholesterol utilization, and subversion of lysosomal trafficking in macrophages.

The transcriptional network of Mycobacterium tuberculosis is designed to enable the organism to withstand host-associated stresses and to exploit the host milieu for its own survival and multiplication. Rv0081 (MT0088) is a transcriptional regulator whose interplay with other gene regulatory proteins and role in enabling M. tuberculosis to thrive within its host is incompletely understood. M. tuberculosis utilizes cholesterol within the granuloma. We show that deletion of Rv0081 compromises the ability of M. tuberculosis to utilize cholesterol as the sole carbon source, to subvert lysosomal trafficking, and to form granulomas in vitro. Rv0081 downregulates expression of the nucleoid-associated repressor Lsr2, leading to increased expression of the cholesterol catabolism-linked gene kshA and genes of the cholesterol importing operon, accounting for the requirement of Rv0081 in cholesterol utilization. Furthermore, Rv0081 activates EspR which is required for secretion of ESX-1 substrates, which in turn are involved in subversion of lysosomal trafficking of M. tuberculosis and granuloma expansion. These results provide new insight into the role of Rv0081 under conditions which resemble the environment encountered by M. tuberculosis within its host. Rv0081 emerges as a central regulator of genes linked to various pathways which are crucial for the survival of the bacterium in vivo.

Nose-to-brain drug delivery for the treatment of Alzheimer's disease: current advancements and challenges.

INTRODUCTION: The irreversible destruction of neurons, progressive loss of memory and cognitive behavior, high cost of therapy, and impact on society, desire a better, effective, and affordable treatment of AD. The nose-to-brain delivery approach holds great potential to access the brain without any hindrance of BBB and results in higher bioavailability and thus better therapeutic efficacy of anti-AD drugs. AREAS COVERED: The present review article highlights the current facts and worldwide statistics of AD and its detailed etiology. This is followed by barriers to brain delivery, nose-to-brain delivery, their limitations, and amalgamation with various novel carrier systems. We have emphasized recent advancements in nose-to-brain delivery using mucoadhesive, stimuli-responsive carriers, polymeric nanoparticles, lipid nanoparticles, and protein/peptide delivery for treatment of AD. EXPERT OPINION: The available therapies are symptomatic and mitigate the symptoms of AD at the initial stages. In lieu of this, nose-to-brain delivery has the ability to overcome these limitations and increase drug bioavailability in the brain. Various novel strategies including stimuli-responsive systems, nanoparticles, etc. enhance the nasal permeation, protect the drug, and enhance its therapeutic potency. However, successful preclinical data do not assure the clinical success of the therapy, and hence exhaustive clinical investigations are needed to make the therapy available for patients.

Theranostic Applications of Nanomaterials in the Field of Cardiovascular Diseases.

A large percentage of people are being exposed to mortality due to cardiovascular diseases. Convention approaches have not provided satisfactory outcomes in the management of these diseases. To overcome the limitations of conventional approaches, nanomaterials like nanoparticles, nanotubes, micelles, lipid-based nanocarriers, dendrimers, and carbon-based nanoformulations represent the new aspect of diagnosis and treatment of cardiovascular diseases. The unique inherent properties of the nanomaterials are the major reasons for their rapidly growing demand in the field of medicine. Profound knowledge in the field of nanotechnology and biomedicine is needed for the notable translation of nanomaterials into theranostic cardiovascular applications. In this review, the authors have summarized different nanomaterials which are being extensively used to diagnose and treat the diseases, such as coronary heart disease, myocardial infarction, atherosclerosis, stroke and thrombosis.