Involvement of Endolysosomes and Aurora Kinase A in the Regulation of Amyloid ß Protein Levels in Neurons.

Aurora kinase A (AURKA) is a serine/threonine-protein kinase that regulates microtubule organization during neuron migration and neurite formation. Decreased activity of AURKA was found in Alzheimer's disease (AD) brain samples, but little is known about the role of AURKA in AD pathogenesis. Here, we demonstrate that AURKA is expressed in primary cultured rat neurons, neurons from adult mouse brains, and neurons in postmortem human AD brains. AURKA phosphorylation, which positively correlates with its activity, is reduced in human AD brains. In SH-SY5Y cells, pharmacological activation of AURKA increased AURKA phosphorylation, acidified endolysosomes, decreased the activity of amyloid beta protein (Aß) generating enzyme ß-site amyloid precursor protein cleaving enzyme (BACE-1), increased the activity of the Aß degrading enzyme cathepsin D, and decreased the intracellular and secreted levels of Aß. Conversely, pharmacological inhibition of AURKA decreased AURKA phosphorylation, de-acidified endolysosomes, decreased the activity of cathepsin D, and increased intracellular and secreted levels of Aß. Thus, reduced AURKA activity in AD may contribute to the development of intraneuronal accumulations of Aß and extracellular amyloid plaque formation.

HIV-1 Tat endocytosis and retention in endolysosomes affects HIV-1 Tat-induced LTR transactivation in astrocytes.

The presence of latent HIV-1 reservoirs in the periphery and brain represents a major obstacle to curing HIV-1 infection. As an essential protein for HIV-1 viral replication, HIV-1 Tat, mostly intracellular, has been implicated in latent HIV-1 infection. From HIV-1 infected cells, HIV-1 Tat is actively secreted and bystander cells uptake the released Tat whereupon it is endocytosed and internalized into endolysosomes. However, to activate the HIV-1 LTR promoter and increase HIV-1 replication, HIV-1 Tat must first escape from the endolysosomes and then enter the nucleus. Here, we tested the hypothesis that HIV-1 Tat can accumulate in endolysosomes and contribute to the activation of latent HIV-1 in astrocytes. Using U87MG astrocytoma cells expressing HIV-1 LTR-driven luciferase and primary human astrocytes we found that exogenous HIV-1 Tat enters endolysosomes, resides in endolysosomes for extended periods of time, and induces endolysosome de-acidification as well as enlargement. The weak base chloroquine promoted the release of HIV-1 Tat from endolysosomes and induced HIV-1 LTR transactivation. Similar results were observed by activating endolysosome Toll-like receptor 3 (TLR3) and TLR7/8. Conversely, pharmacological block of TLRs and knocking down expression levels of TLR3 and TLR7, but not TLR8, prevented endolysosome leakage and attenuated HIV-1 Tat-mediated HIV-1 LTR transactivation. Our findings suggest that HIV-1 Tat accumulation in endolysosomes may play an important role in controlling HIV-1 transactivation.

Heterogeneity of ferrous iron-containing endolysosomes and effects of endolysosome iron on endolysosome numbers, sizes, and localization patterns.

Endolysosomes are key regulators of iron metabolism and are central to iron trafficking and redox signaling. Iron homeostasis is linked to endolysosome acidity and inhibition of endolysosome acidity triggers iron dysregulation. Because of the physiological importance and pathological relevance of ferrous iron (Fe2+ ), we determined levels of Fe2+ specifically and quantitatively in endolysosomes as well as the effects of Fe2+ on endolysosome morphology, distribution patterns, and function. The fluorescence dye FeRhoNox-1 was specific for Fe2+ and localized to endolysosomes in U87MG astrocytoma cells and primary rat cortical neurons; in U87MG cells the endolysosome concentration of Fe2+ ([Fe2+ ]el ) was 50.4 µM in control cells, 73.6 µM in ferric ammonium citrate (FAC) treated cells, and 12.4 µM in cells treated with the iron chelator deferoxamine (DFO). Under control conditions, in primary rat cortical neurons, [Fe2+ ]el was 32.7 µM. Endolysosomes containing the highest levels of Fe2+ were located perinuclearly. Treatment of cells with FAC resulted in endolysosomes that were less acidic, increased in numbers and sizes, and located further from the nucleus; opposite effects were observed for treatments with DFO. Thus, FeRhoNox-1 is a useful probe for the study of endolysosome Fe2+ , and much more work is needed to understand better the physiological significance and pathological relevance of endolysosomes classified according to their heterogeneous iron content Cover Image for this issue: https://doi.org/10.1111/jnc.15396.

Endolysosome iron restricts Tat-mediated HIV-1 LTR transactivation by increasing HIV-1 Tat oligomerization and ß-catenin expression.

HIV-1 transactivator of transcription (Tat) protein is required for HIV-1 replication, and it has been implicated in the pathogenesis of HIV-1-associated neurocognitive disorder (HAND). HIV-1 Tat can enter cells via receptor-mediated endocytosis where it can reside in endolysosomes; upon its escape from these acidic organelles, HIV-1 Tat can enter the cytosol and nucleus where it activates the HIV-1 LTR promoter. Although it is known that HIV-1 replication is affected by the iron status of people living with HIV-1 (PLWH), very little is known about how iron affects HIV-1 Tat activation of the HIV-1 LTR promoter. Because HIV-1 proteins de-acidify endolysosomes and endolysosome de-acidification affects subcellular levels and actions of iron, we tested the hypothesis that the endolysosome pool of iron is sufficient to affect Tat-induced HIV-1 LTR transactivation. Ferric (Fe3+) and ferrous (Fe2+) iron both restricted Tat-mediated HIV-1 LTR transactivation. Chelation of endolysosome iron with deferoxamine (DFO) and 2-2 bipyridyl, but not chelation of cytosolic iron with deferiprone and deferasirox, significantly enhanced Tat-mediated HIV-1 LTR transactivation. In the presence of iron, HIV-1 Tat increasingly oligomerized and DFO prevented the oligomerization. DFO also reduced protein expression levels of the HIV-1 restriction agent beta-catenin in the cytosol and nucleus. These findings suggest that DFO increases HIV-1 LTR transactivation by increasing levels of the more active dimeric form of Tat relative to the less active oligomerized form of Tat, increasing the escape of dimeric Tat from endolysosomes, and/or reducing beta-catenin protein expression levels. Thus, intracellular iron might play a significant role in regulating HIV-1 replication, and these findings raise cautionary notes for chelation therapies in PLWH.

Two-pore channels regulate Tat endolysosome escape and Tat-mediated HIV-1 LTR transactivation.

HIV-1 Tat is essential for HIV-1 replication and appears to play an important role in the pathogenesis of HIV-associated neurological complications. Secreted from infected or transfected cells, Tat has the extraordinary ability to cross the plasma membrane. In the brain, Tat can be taken up by CNS cells via receptor-mediated endocytosis. Following endocytosis and its internalization into endolysosomes, Tat must be released in order for it to activate the HIV-1 LTR promoter and facilitate HIV-1 viral replication in the nucleus. However, the underlying mechanisms whereby Tat escapes endolysosomes remain unclear. Because Tat disrupts intracellular calcium homeostasis, we investigated the involvement of calcium in Tat endolysosome escape and subsequent LTR transactivation. We demonstrated that chelating endolysosome calcium with high-affinity rhodamine-dextran or chelating cytosolic calcium with BAPTA-AM attenuated Tat endolysosome escape and LTR transactivation. Significantly, we demonstrated that pharmacologically blocking and knocking down the endolysosome-resident two-pore channels (TPCs) attenuated Tat endolysosome escape and LTR transactivation. This calcium-mediated effect appears to be selective for TPCs because knocking down TRPML1 calcium channels was without effect. Our findings suggest that calcium released from TPCs is involved in Tat endolysosome escape and subsequent LTR transactivation. TPCs might represent a novel therapeutic target against HIV-1 infection and HIV-associated neurological complications.

Apolipoprotein E isoform dependently affects Tat-mediated HIV-1 LTR transactivation.

BACKGROUND: Apolipoprotein E (ApoE) is the major carrier protein that mediates the transport and delivery of cholesterol and other lipids in the brain. Three isoforms of ApoE (ApoE2, ApoE3, ApoE4) exist in humans, and their relative expression levels impact HIV-1 infection, HIV-1/AIDS disease progression, and cognitive decline associated with HIV-1-associated neurocognitive disorder. Because HIV-1 Tat, a viral protein essential for HIV-1 replication, can bind to low-density lipoprotein receptor-related protein 1 (LRP1) that controls ApoE uptake in the brain, we determined the extent to which different isoforms of ApoE affected Tat-mediated HIV-1 LTR transactivation. METHODS: Using U87MG glioblastoma cells expressing LTR-driven luciferase, we determined the extent to which LRP1 as well as ApoE2, ApoE3, and ApoE4 affected Tat-mediated HIV-1 LTR transactivation. RESULTS: A specific LRP1 antagonist and siRNA knockdown of LRP1 both restricted significantly Tat-mediated LTR transactivation. Of the three ApoEs, ApoE4 was the least potent and effective at preventing HIV-1 Tat internalization and at decreasing Tat-mediated HIV-1 LTR transactivation. Further, Tat-mediated LTR transactivation was attenuated by an ApoE mimetic peptide, and ApoE4-induced restriction of Tat-mediated LTR transactivation was potentiated by an ApoE4 structure modulator that changes ApoE4 into an ApoE3-like phenotype. CONCLUSIONS: These findings help explain observed differential effects of ApoEs on HIV-1 infectivity and the prevalence of HAND in people living with HIV-1 infection and suggest that ApoE mimetic peptides and ApoE4 structure modulator might be used as a therapeutic strategy against HIV-1 infection and associated neurocognitive disorders.

The dawning era of oral thin films for nutraceutical delivery: From laboratory to clinic.

Oral thin films (OTFs) are innovative dosage forms that have gained tremendous attention for the delivery of nutraceuticals. They are ultra-thin, flexible sheets that can be easily placed on the tongue, sublingual or buccal mucosa (inner lining of the cheek). These thin films possess several advantages for nutraceutical delivery including ease of administration, rapid disintegration, fast absorption, rapid onset of action, bypass first-pass hepatic metabolism, accurate dosing, enhanced stability, portability, discreetness, dose flexibility and most importantly consumer acceptance. This review highlights the utilization OTFs for nutraceutical delivery, their composition, criteria for excipient selection, methods of development and quality-based design (QbD) approach to achieve quality product. We have also provided recent case studies representing OTFs as promising platform in delivery of nutraceuticals (plant extracts, bioactive molecules, vitamins, minerals and protein/peptides) and probiotics. Finally, we provided advancement in technologies, recent patents, market analysis, challenges and future perspectives associated with this unique dosage form.

Phacoemulsification in phacomorphic angle closure: Our experience.

PURPOSE: To evaluate intraocular pressure (IOP) control, visual prognosis, and complications following phacoemulsification in eyes with phacomorphic angle closure of <10 days' duration. METHODS: Prospective, nonrandomized interventional consecutive case series included all patients with phacomorphic glaucoma who presented between November 2020 and November 2021. All patients underwent slit-lamp biomicroscopy, applanation tonometry, and gonioscopy of the other eye. Phacoemulsification with IOL implantation under topical anesthesia was performed in all cases. A complete ophthalmic examination was done at each follow-up visit. RESULTS: A total of 50 eyes with phacomorphic glaucoma were included in this study. The preoperative mean IOP was 41.12 ± 8.20 mmHg and the mean IOP at last visit was 13.84 ± 2.08 mmHg. There was a statistically significant difference between IOP at presentation and IOP at last follow-up (P < 0.001) (Wilcoxon Signed-Ranks Test). There was no requirement of long-term anti-glaucoma medications in any patients. No significant intraoperative complications were noted. The final postoperative best-corrected visual acuity was 6/12 or better in 32 patients. Sixteen eyes had corneal edema and 20 eyes had anterior chamber inflammation on postoperative day one that resolved with standard medical therapy. CONCLUSION: Phacoemulsification is safe and effective in controlling IOP and achieving good functional visual acuity with minimal complications in the management of phacomorphic glaucoma in expert hands. Our study also lays emphasis on public awareness, early detection, and management of advanced cataract, so that the incidence of this potentially blinding entity can be reduced.

Preparation, Characterization, and Antioxidant Activity of L-Ascorbic Acid/HP-ß-Cyclodextrin Inclusion Complex-Incorporated Electrospun Nanofibers.

L-Ascorbic acid (LAA) is a key vitamin, implicated in a variety of physiological processes in humans. Due to its free radical scavenging activity, it is extensively employed as an excipient in pharmaceutical products and food supplements. However, its application is greatly impeded by poor thermal and aqueous stability. Herein, to improve the stability and inhibit oxidative degradation, we prepared LAA-cyclodextrin inclusion complex-incorporated nanofibers (NFs). The continuous variation method (Job plot) demonstrated that LAA forms inclusions with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) at a 2:1 molar stoichiometric ratio. The NFs were prepared via the single step electrospinning technique, without using any polymer matrix. The solid-state characterizations of LAA/HP-ß-CD-NF via powder x-ray diffractometry (PXRD), Fourier-transform infrared (FT-IR) analysis, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and nuclear magnetic resonance (1H NMR and 2D-NOESY) spectroscopy, reveal the effective encapsulation of the LAA (guest molecule) inside the HP-ß-CD (host) cavity. The SEM micrograph reveals an average fiber diameter of ~339 nm. The outcomes of the thermal investigations demonstrated that encapsulation of LAA within HP-ß-CD cavities provides improved thermal stability of LAA (by increasing the thermal degradation temperature). The radical scavenging assay demonstrated the enhanced antioxidant potential of LAA/HP-ß-CD-NF, as compared to native LAA. Overall, the study shows that cyclodextrin inclusion complex-incorporated NFs, are an effective approach for improving the limitations associated with LAA, and provide promising avenues in its therapeutic and food applications.

Recent progress in covalent organic frameworks for cancer therapy.

Covalent organic frameworks (COFs) have gained tremendous interest in cancer therapy owing to their multifunctional properties, such as biocompatibility, tunable cavities, excellent crystallinity, ease of modification/functionalization, and high flexibility. These unique properties offer multiple benefits, such as high loading capacity, prevention from premature leakage, targeted delivery to the tumor microenvironment (TME), and release of therapeutic agents in a controlled manner, which makes them effective and excellent nanoplatforms for cancer therapeutics. In this review, we outline recent advances in using COFs as delivery system for chemotherapeutic agents, photodynamic therapy (PDT), photothermal therapy (PTT), sonodynamic therapy (SDT), cancer diagnostics, and combinatorial therapy for cancer therapeutics. We also summarize current challenges and future directions of this unique research field.

Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death.

Objectives: Opioids including morphine and DAMGO activate mu-opioid receptors (MOR), increase intracellular reactive oxygen species (ROS) levels, and induce cell death. Ferrous iron (Fe2+) through Fenton-like chemistry increases ROS levels and endolysosomes are "master regulators of iron metabolism" and contain readily-releasable Fe2+ stores. However, mechanisms underlying opioid-induced changes in endolysosome iron homeostasis and downstream-signaling events remain unclear. Methods: We used SH-SY5Y neuroblastoma cells, flow cytometry, and confocal microscopy to measure Fe2+ and ROS levels and cell death. Results: Morphine and DAMGO de-acidified endolysosomes, decreased endolysosome Fe2+ levels, increased cytosol and mitochondria Fe2+ and ROS levels, depolarized mitochondrial membrane potential, and induced cell death; effects blocked by the nonselective MOR antagonist naloxone and the selective MOR antagonist ß-funaltrexamine (ß-FNA). Deferoxamine, an endolysosome-iron chelator, inhibited opioid agonist-induced increases in cytosolic and mitochondrial Fe2+ and ROS. Opioid-induced efflux of endolysosome Fe2+ and subsequent Fe2+ accumulation in mitochondria were blocked by the endolysosome-resident two-pore channel inhibitor NED-19 and the mitochondrial permeability transition pore inhibitor TRO. Conclusions: Opioid agonist-induced increases in cytosolic and mitochondrial Fe2+ and ROS as well as cell death appear downstream of endolysosome de-acidification and Fe2+ efflux from the endolysosome iron pool that is sufficient to affect other organelles.

Orbital Mucormycosis: Understanding the Deadly Fungus Sweeping the Globe.

Introduction Mucormycosis (black fungus) is a rare opportunistic fungal infection commonly affecting immunocompromised individuals. There has been a surge in the number of these cases during the second wave of the coronavirus disease 2019 (COVID-19) in India. Mucormycosis has been reported to occur within a week or a few weeks post-recovery from COVID-19. The most common clinical manifestation of mucormycosis is rhino-orbital-cerebral mucormycosis (ROCM). At our tertiary care center, we initiated a prospective study to identify risk factors, study ocular manifestations, and explore medical and surgical management of orbital mucormycosis patients in the post-COVID-19 era. Material and methods This is a detailed description of a prospective observational hospital-based study. The study included 148 patients who presented with ROCM. A detailed history was taken regarding the complaint, duration, and associated risk factors. Systemic, local, and complete ophthalmic examinations were done that included assessment of extraocular movements, visual acuity, slit-lamp examination, and fundus examination. All data were recorded separately for each patient in a pre-decided proforma. Result The study group consisted of 148 patients. In our study, the highest association was with COVID-19-positive status (68.24%), out of which 57 (56.43%) were on oxygen support. Diabetes mellitus contributed next to COVID-19 with 86 (58.10%) patients with a positive history of diabetes. Seventy-one (47.97%) patients were on steroids, out of which 68 (67.32%) were COVID-19-positive and the rest (23%) were on steroids due to various systemic reasons. Rhinomaxillary involvement was present (51%). Out of 63 patients with orbital involvement, 16 (25.39%) presented bilaterally and 47 showed unilateral orbital involvement more on the right side (42.85%). The predominant location of orbital involvement was the orbital apex. The most common symptom seen in our study was nasal discharge (86.5%), and ophthalmoplegia was the most common sign. Conclusion Corticosteroids should be used with caution to prevent negative impact and potential ROCM. Good glycemic and metabolic control is crucial for treatment. Management of mucormycosis involves surgical debridement, antifungal agents, and retrobulbar amphotericin B injections. Early diagnosis and aggressive treatment are essential for success. Orbital exenteration may be necessary for advanced stages, while conservative approaches may work for earlier stages. Patient counseling is needed for cosmetic rehabilitation. A multidisciplinary approach involving various specialists is necessary.

Recent advances in dual-ligand targeted nanocarriers for cancer therapy.

Nanocarriers (NCs) containing targeting ligands have received significant attention in recent years because of their ability to enhance cancer cell recognition, which in turn improves both their accuracy and the therapeutic efficacy of their payloads. A promising approach in this area is the use of dual ligands, in which NCs are functionalized with two different targeting ligands, enabling them to specifically recognize and interact with two different biomarkers present on cancer cells for more efficient targeting compared with single-ligand targeted nanocarriers. Herein, we highlight recent advances in dual-ligand targeted NCs with particular emphasis on their potential for improving therapeutic outcomes for cancer therapy.

HIV-1 gp120-Induced Endolysosome de-Acidification Leads to Efflux of Endolysosome Iron, and Increases in Mitochondrial Iron and Reactive Oxygen Species.

The HIV-1 coat protein gp120 continues to be implicated in the pathogenesis of HIV-1 associated neurocognitive disorder (HAND); a condition known to affect ~50% of people living with HIV-1 (PLWH). Autopsy brain tissues of HAND individuals display morphological changes to mitochondria and endolysosomes, and HIV-1 gp120 causes mitochondrial dysfunction including increased levels of reactive oxygen species (ROS) and de-acidification of endolysosomes. Ferrous iron is linked directly to ROS production, ferrous iron is contained in and released from endolysosomes, and PLWH have elevated iron and ROS levels. Based on those findings, we tested the hypothesis that HIV-1 gp120-induced endolysosome de-acidification and subsequent iron efflux from endolysosomes is responsible for increased levels of ROS. In U87MG glioblastoma cells, HIV-1 gp120 de-acidified endolysosomes, reduced endolysosome iron levels, increased levels of cytosolic and mitochondrial iron, and increased levels of cytosolic and mitochondrial ROS. These effects were all attenuated significantly by the endolysosome-specific iron chelator deferoxamine, by inhibitors of endolysosome-resident two-pore channels and divalent metal transporter-1 (DMT-1), and by inhibitors of mitochondria-resident DMT-1 and mitochondrial permeability transition pores. These results suggest that oxidative stress commonly observed with HIV-1 gp120 is downstream of its ability to de-acidify endolysosomes, to increase the release of iron from endolysosomes, and to increase the uptake of iron into mitochondria. Thus, endolysosomes might represent early and upstream targets for therapeutic strategies against HAND.

Role of Viral Protein U (Vpu) in HIV-1 Infection and Pathogenesis.

Human immunodeficiency virus (HIV)-1 and HIV-2 originated from cross-species transmission of simian immunodeficiency viruses (SIVs). Most of these transfers resulted in limited spread of these viruses to humans. However, one transmission event involving SIVcpz from chimpanzees gave rise to group M HIV-1, with M being the principal strain of HIV-1 responsible for the AIDS pandemic. Vpu is an HIV-1 accessory protein generated from Env/Vpu encoded bicistronic mRNA and localized in cytosolic and membrane regions of cells capable of being infected by HIV-1 and that regulate HIV-1 infection and transmission by downregulating BST-2, CD4 proteins levels, and immune evasion. This review will focus of critical aspects of Vpu including its zoonosis, the adaptive hurdles to cross-species transmission, and future perspectives and broad implications of Vpu in HIV-1 infection and dissemination.

Possible Therapeutic Use of Natural Compounds Against COVID-19.

The outbreak of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to coronavirus disease-19 (COVID-19); a pandemic disease that has resulted in devastating social, economic, morbidity and mortality burdens. SARS-CoV-2 infects cells following receptor-mediated endocytosis and priming by cellular proteases. Following uptake, SARS-CoV-2 replicates in autophagosome-like structures in the cytosol following its escape from endolysosomes. Accordingly, the greater endolysosome pathway including autophagosomes and the mTOR sensor may be targets for therapeutic interventions against SARS-CoV-2 infection and COVID-19 pathogenesis. Naturally existing compounds (phytochemicals) through their actions on endolysosomes and mTOR signaling pathways might provide therapeutic relief against COVID-19. Here, we discuss evidence that some natural compounds through actions on the greater endolysosome system can inhibit SARS-CoV-2 infectivity and thereby might be repurposed for use against COVID-19.

Possible therapeutic targets for SARS-CoV-2 infection and COVID-19.

SARS-CoV-2 infection causes COVID-19, which has emerged as a health emergency worldwide. SARS-CoV-2 infects cells by binding to ACE2 receptors and enters into the cytoplasm following its escape from endolysosomes. Once in the cytoplasm, the virus replicates and eventually causes various pathological conditions including acute respiratory distress syndrome (ARDS) that is caused by pro-inflammatory cytokine storms. Thus, endolysosomes and cytokine storms are important therapeutic targets to suppress SARS-CoV-2 infection and COVID-19. Here, we discuss therapeutic targets of SARS-CoV-2 infection and available drugs that could be helpful in the suppression of the SARS-CoV-2 infection and pathological condition COVID-19. The urgency of the COVID-19 pandemic precludes the development of new drugs and increased focus on drug repurposing might provide the quickest way to finding effective medicines.

Aptamer-based sensing of breast cancer biomarkers: a comprehensive review of analytical figures of merit.

INTRODUCTION: Accurate determination of the aberrantly expressed biomarkers such as human epidermal growth factor receptor 2 (HER2), carcinoembryonic antigen (CEA), platelet-derived growth factor (PDGF), mucin 1 (MUC1), and vascular endothelial growth factor VEGF165 have played an essential role in the clinical management of the breast cancer. Assessment of these cancer-specific biomarkers has conventionally relied on time-taking methods like the enzyme-linked immunosorbent assay and immunohistochemistry. However, recent development in the aptamer-based diagnostics has allowed developing tools that may substitute the conventional means of biomarker assessment in breast cancer. Adopting the aptamer-based diagnostic tools (aptasensors) to clinical practices will depend on their analytical performance on clinical samples. AREAS COVERED: In this review, we provide an overview of the analytical merits of HER2, CEA, PDGF, MUC1, and VEGF165 aptasensors. Scopus and Pubmed databases were searched for studies reporting aptasensor development for the listed breast cancer biomarkers in the past one decade. Linearity, detection limit, and response time are emphasized. EXPERT OPINION: In our opinion, aptasensors have proven to be on a par with the antibody-based methods for detection of various breast cancer biomarkers. Though robust validation of the aptasensors on significant sample size is required, their ability to detect pathophysiological range of biomarkers suggest the possibility of future clinical adoption.

A common approach for fighting tuberculosis and leprosy: controlling endoplasmic reticulum stress in myeloid-derived suppressor cells.

Leprosy and tuberculosis are infectious diseases that are caused by bacteria, and both share primary risk factors. Mediators of these diseases are regulated by a heterogeneous immature population of myeloid cells called myeloid-derived suppressor cells (MDSCs) that exhibit immunosuppressive activity against innate and adaptive immunity. During pathological conditions, endoplasmic reticulum (ER) stress occurs in MDSCs, and high levels of ER stress affect MDSC-linked immunosuppressive activity. Investigating the role of ER stress in regulating immunosuppressive functions of MDSCs in leprosy and tuberculosis may lead to new approaches to treating these diseases. Here the authors discuss the immunoregulatory effects of ER stress in MDSCs as well as the possibility of targeting unfolded protein response elements of ER stress to diminish the immunosuppressive activity of MDSCs and reinvigorate diminished adaptive immune system responses that occur in leprosy and tuberculosis.

Lysosomal Stress Response (LSR): Physiological Importance and Pathological Relevance.

Extensive work has characterized endoplasmic reticulum (ER) and mitochondrial stress responses. In contrast, very little has been published about stress responses in lysosomes; subcellular acidic organelles that are physiologically important and are of pathological relevance. The greater lysosomal system is dynamic and is comprised of endosomes, lysosomes, multivesicular bodies, autophagosomes, and autophagolysosomes. They are important regulators of cellular physiology, they represent about 5% of the total cellular volume, they are heterogeneous in their sizes and distribution patterns, they are electron dense, and their subcellular positioning within cells varies in response to stimuli, insults and pH. These organelles are also integral to the pathogenesis of lysosomal storage diseases and it is increasingly recognized that lysosomes play important roles in the pathogenesis of such diverse conditions as neurodegenerative disorders and cancer. The purpose of this review is to focus attention on lysosomal stress responses (LSR), compare LSR with better characterized stress responses in ER and mitochondria, and form a framework for future characterizations of LSR. We synthesized data into the concept of LSR and present it here such that the definition of LSR can be modified as new knowledge is added and specific therapeutics are developed.