Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA.

Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.

SARS-CoV-2 cases reported from long-term residential facilities (care homes) in South Africa: a retrospective cohort study.

BACKGROUND: Globally, long-term care facilities (LTCFs) experienced a large burden of deaths during the COVID-19 pandemic. The study aimed to describe the temporal trends as well as the characteristics and risk factors for mortality among residents and staff who tested positive for SARS-CoV-2 in selected LTCFs across South Africa. METHOD: We analysed data reported to the DATCOV sentinel surveillance system by 45 LTCFs. Outbreaks in LTCFs were defined as large if more than one-third of residents and staff had been infected or there were more than 20 epidemiologically linked cases. Multivariable logistic regression was used to assess risk factors for mortality amongst LTCF residents. RESULTS: A total of 2324 SARS-CoV-2 cases were reported from 5 March 2020 through 31 July 2021; 1504 (65%) were residents and 820 (35%) staff. Among LTCFs, 6 reported sporadic cases and 39 experienced outbreaks. Of those reporting outbreaks, 10 (26%) reported one and 29 (74%) reported more than one outbreak. There were 48 (66.7%) small outbreaks and 24 (33.3%) large outbreaks reported. There were 30 outbreaks reported in the first wave, 21 in the second wave and 15 in the third wave, with 6 outbreaks reporting between waves. There were 1259 cases during the first COVID-19 wave, 362 during the second wave, and 299 during the current third wave. The case fatality ratio was 9% (138/1504) among residents and 0.5% (4/820) among staff. On multivariable analysis, factors associated with SARS-CoV-2 mortality among LTCF residents were age 40-59 years, 60-79 years and ≥ 80 years compared to < 40 years and being a resident in a LTCF in Free State or Northern Cape compared to Western Cape. Compared to pre-wave 1, there was a decreased risk of mortality in wave 1, post-wave 1, wave 2, post-wave 2 and wave 3. CONCLUSION: The analysis of SARS-CoV-2 cases in sentinel LTCFs in South Africa points to an encouraging trend of decreasing numbers of outbreaks, cases and risk for mortality since the first wave. LTCFs are likely to have learnt from international experience and adopted national protocols, which include improved measures to limit transmission and administer early and appropriate clinical care.

Non-coding RNAs: Regulators of valvular calcification.

There is currently a growing global burden of valvular heart diseases due to aging populations and changing lifestyles. Valvular heart diseases mainly include the malfunctioning of aortic and mitral valves and are characterized by extensive tissue remodeling, which includes calcification, endothelial dysfunction, and endothelial-mesenchymal transition. These valvular remodeling processes are known to be regulated by protein-coding genes as well as non-coding genes. Here, we have summarized studies highlighting the non-coding RNA mediated regulation of valvular tissue remodeling and their potential therapeutic benefits. Additionally, studies investigating the diagnostic capability of circulating non-coding RNA molecules in valvular diseases are also summarized. Overall, of the various candidates, several studies have highlighted miR-214 and miR-204 as central regulators of valvular calcification.

Extension of Azine-Triazole Synthesis to Azole-Triazoles Reduces Ligand Field, Leading to Spin Crossover in Tris-L Fe(II).

The first examples of azole-triazole Rat ligands, bidentate L4NMeIm(3-(1-methyl-1H-imidazol-4-yl)-5-phenyl-4-(p-tolyl)-4H-1,2,4-triazole) and L4SIm (4-(5-phenyl-4-(p-tolyl)-4H-1,2,4-triazol-3-yl)thiazole), have been prepared, by extension of the general synthesis used to access many examples of azine-triazoles. The tris-L FeII complexes of the azine-triazoles are consistently low spin (LS). As intended, these new azole-triazole ligands provide lower field strengths, resulting in high-spin (HS) [FeII(L4NMeIm)3](BF4)2 (1·4H2O) and spin crossover (SCO) active [FeII(L4SIm)3](BF4)2 (2·0.5H2O). Single-crystal structure determinations revealed that at 100 K 1·solvents is HS whereas 2·solvents is LS. Solid-state variable temperature magnetic studies of air-dried crystals showed that the methylimidazole-triazole complex 1·4H2O remains HS while the thiazole-triazole complex 2·0.5H2O undergoes a two-step gradual SCO (T1/2 approximately 275 and 350 K). Variable-temperature Evans method NMR studies of 2, in five different solvents (CD3NO2, CD3CN, CD3COCD3, CD2Cl2, and CDCl3) gave T1/2 values in a relatively narrow range, 214-259 K. These T1/2 values did not correlate with the solvent polarity index P' (R2 = 0.25) but did correlate with the solvent basicity parameter SB (R2 = 0.90). Variable-temperature UV-vis studies on a golden yellow CH3CN solution of 2, with monitoring of the d-d transition at 530 nm (ε = 39 L mol-1 cm-1 at 293 K) while the solution was heated from 253 to 303 K, showed that the high-spin fraction increased from 0.51 to 0.77. Cyclic voltammetry studies in CH3CN revealed a Fe(III)/Fe(II) redox process that was reversible for 1 and irreversible for 2, with significant tuning of the Epa value: the methylimidazole-triazole complex 1 is significantly easier to oxidize (0.46 V) than the thiazole-triazole complex 2 (0.68 V; both vs 0.01 M Ag/AgNO3).

Spin crossover in discrete polynuclear iron(ii) complexes.

Iron(ii) spin crossover (SCO) materials have been widely studied as molecular switches with a wide variety of potential applications, including as displays, sensors, actuators or memory components. Most SCO materials have been either monometallic or polymeric, and it is only relatively recently that chemists have really started to focus on linking multiple metal centres together within the one, discrete, molecule in an effort to enhance the SCO properties, such as abrupt, hysteretic, and multistep switching, as well as the potential for quantum cellular automata, whilst still being readily amenable to characterisation. Here we present a review of the ligand designs of the last two decades that have led to self assembly of discrete di- to poly-nuclear iron(ii) complexes of helicate, cage, cube, and other supramolecular architectures with rich SCO activity, and to an increased focus on host-guest interactions. Analysis of selected octahedral distortion parameters (Σ, CShM) reveals interesting differences between these structural types, for example that the iron(ii) centres in grids are generally significantly more distorted than those in squares or cages, yet are still SCO-active. Of the 127 complexes reviewed (79 published 2012-Feb. 2018), 54% are dinuclear, 10% trinuclear, 31% tetranuclear, and the remaining 5% are penta, hexa and octanuclear. Of the 93 designer ligands utilised in these polynuclear architectures: 60 feature azoles; 55 provide all donors to the Fe(ii) centres (no co-ligands coordinated) and form exclusively 5-membered chelate rings via either bidentate azole-imine/pyridine or tridentate heterocycle-imine/amine/thioether/pyridine-heterocycle binding pockets.

Dysbiosis Disrupts Gut Immune Homeostasis and Promotes Gastric Diseases.

Perturbation in the microbial population/colony index has harmful consequences on human health. Both biological and social factors influence the composition of the gut microbiota and also promote gastric diseases. Changes in the gut microbiota manifest in disease progression owing to epigenetic modification in the host, which in turn influences differentiation and function of immune cells adversely. Uncontrolled use of antibiotics, chemotherapeutic drugs, and any change in the diet pattern usually contribute to the changes in the colony index of sensitive strains known to release microbial content in the tissue micromilieu. Ligands released from dying microbes induce Toll-like receptor (TLR) mimicry, skew hypoxia, and cause sterile inflammation, which further contributes to the severity of inflammatory, autoimmune, and tumorous diseases. The major aim and scope of this review is both to discuss various modalities/interventions across the globe and to utilize microbiota-based therapeutic approaches for mitigating the disease burden.

Low dose radiation primed iNOS + M1macrophages modulate angiogenic programming of tumor derived endothelium.

Solid tumors are covered by stroma, which is hypoxic in nature and composed of various non-malignant components such as endothelial cells, fibroblasts, and pericytes that support tumor growth. Tumor stroma represents a mechanical barrier for tumor infiltration of CD8+ effector T cells in particular. In this context, our previous studies have demonstrated the therapeutic impact of Low-Dose Radiation (LDR)-primed and M1-retuned (iNOS+) peritumoral macrophages that produce inducible nitric oxide, have immunological roles on tumor infiltration of effector T cells, cancer-related inflammation, and subsequent tumor immune rejection in a mouse model of pancreatic cancer. These findings suggested a possible modification of tumor endothelium by LDR-primed macrophages. In line with these observations, here we demonstrate the influence of LDR in down-modulating HIF-1 in irradiated tumors in the course of polarization of irradiated tumor-associated macrophages toward an M1 phenotype. Furthermore, we demonstrate that M1 macrophages which are primed by LDR can directly influence angiogenic responses in eNOS+ endothelial cells which produce nitric oxide having both vascular and physiological roles. Furthermore, we demonstrate that naïve macrophages, upon differentiating to an M1 phenotype either by Th1 stimuli or LDR, potentially modify sphingosine-1-phosphate/VEGF-induced angiogenic signaling in tumor-derived endothelial cells with tumorigenic potential, thus indicating the significance of iNOS+ macrophages in modulating signaling in eNOS+ tumor-derived endothelium. Our study suggests that iNOS+ macrophages can activate tumor endothelium which may contribute to cancer-directed immunotherapy in particular.

Gonadotropin and tumorigenesis: Direct and indirect effects on inflammatory and immunosuppressive mediators and invasion.

Human chorionic gonadotropin (hCG), a hormone essential for pregnancy, is also ectopically expressed by a variety of cancers and is associated with poor prognosis; molecular mechanisms which may contribute to tumor progression remain ill-defined. Exogenous hCG enhanced the viability of human colorectal and lung cancer cells and promoted the growth of syngeneic tumors in mice. It induced the synthesis of VEGF, IL-8, matrix metalloprotease (MMP)-2 and MMP-9, and increased invasiveness in an MMP-dependent manner. While inducing the secretion of the tumor-associated extra-cellular matrix proteoglycan versican from tumor cells, hCG consequently caused the TLR-2-mediated generation of the inflammatory, tumor-associated cytokines TNF-α and IL-6 from peripheral blood adherent cells. The molecule up-modulated the Treg-associated transcription factor FOXP3 in tumor cells and increased the secretion of TGFß and IL-10, thereby inhibiting T cell proliferation and inducing the differentiation FOXP3- CD4+ CD25- cells into functional FOXP3+ CD4+ CD25+ suppressor cells. Co-culture of hCG-treated tumor cells with mature bone-marrow derived dendritic cells induced the generation of active indoleamine deoxygenase. While anti-hCG antibodies restricted the growth of implanted tumor cells in nude mice, immunization of immune competent mice with a ßhCG-TT conjugate supplemented with Mycobacterium indicus pranii provided synergistic survival benefit in animals implanted with syngeneic, hCG-responsive tumor cells. These studies elucidate the pathways by which hCG can promote tumorigenesis, providing further rationale for anti-hCG vaccination in the treatment of gonadotropin-sensitive tumors. © 2016 Wiley Periodicals, Inc.

HIF-1 mediated metabolic reprogramming in cancer: Mechanisms and therapeutic implications.

Cancer cells undergo metabolic reprogramming to survive in hypoxic conditions and meet the elevated energy demands of the cancer microenvironment. This metabolic alteration is orchestrated by hypoxia-inducible factor 1 (HIF-1), regulating various processes within cancer cells. The intricate metabolic modifications induced by hypoxia underscore the significance of HIF-1-induced metabolic reprogramming in promoting each aspect of cancer progression. The complex interactions between HIF-1 signalling and cellular metabolic processes in response to hypoxia are examined in this study, focusing on the metabolism of carbohydrates, nucleotides, lipids, and amino acids. Comprehending the various regulatory mechanisms controlled by HIF-1 in cellular metabolism sheds light on the intricate biology of cancer growth and offers useful insights for developing targeted treatments.

Silver-doped hydroxyapatite laden chitosan-gelatin nanocomposite scaffolds for bone tissue engineering: an in-vitro and in-ovo evaluation.

Despite the advancements in bone tissue engineering, the majority of implant failures are caused due to microbial contamination. So, efforts are being made to develop biomaterial with antimicrobial property enhancing the regeneration of damaged bone tissue. In the present study, chitosan-gelatin (CG) scaffolds containing silver-doped hydroxyapatite (AgHAP) nanoparticles at 0.5%, 1.0% and 1.5% (w/v) were fabricated by lyophilization technique. The results confirmed the synthesis of AgHAP nanoparticles and showed interconnected porous structure of the nanocomposite scaffolds with 89%-75% porosity. Similarly, the swelling percentage, degradation behavior and compressive modulus of CG-AgHAP nanocomposite scaffolds were 1666%, 40% and 0.7 MPa, respectively. The developed nanocomposite scaffolds revealed better antimicrobial properties and bioactivity. The cell culture studies showed favorable viability of Wharton's jelly stem cells on CG-AgHAP nanocomposite scaffolds. CAM (chorioallantoic membrane) assay determined the angiogenic potential with better visualization of blood vessels in the CAM area. Hence, the obtained results confirmed that CG-AgHAP3 nanocomposite scaffold was the most suitable for bone tissue engineering applications among all scaffolds.

Determinants of sub-optimal glycemic control among patients enrolled in a medicine dispensing programme in KwaZulu-Natal: A cohort study, 2018-2021.

BACKGROUND:  The Central Chronic Medicines Dispensing and Distribution (CCMDD) programme facilitates clinically stable patients to collect their chronic medication from community-based pick-up points. AIM:  We determined baseline glycaemic control and rates and predictors of becoming sub-optimally controlled for type 2 diabetes mellitus (T2DM) CCMDD-enrolled patients. SETTING:  The setting of the study was eThekwini, KwaZulu-Natal, South Africa. METHODS:  We performed a cohort study (April 2018- December 2021). We linked T2DM CCMDD-enrolled patients to glycated haemoglobin (HbA1c) data from the National Health Laboratory Service. We selected patients optimally controlled at their baseline HbA1c, with ≥ 1 repeat-test available. We used Kaplan-Meier analysis to assess survival rates and extended Cox regression to determine associations between time to sub-optimal control (HbA1c 7%) and predictors. Adjusted hazard ratios (aHRs), 95% confidence interval (CI), and p-values are reported. RESULTS:  Of the 41145 T2DM patients enrolled in the CCMDD programme, 7960 (19%) had a HbA1c result available. Twenty-seven percent (2147/7960) were optimally controlled at their baseline HbA1c. Of those controlled at baseline, 695 (32%) patients had a repeat test available, with 35% (242/695) changing to sub-optimal status. The HbA1c testing frequency as per national guidelines was associated with a lower hazard of sub-optimal glycaemic control (aHR: 0.46; 95% CI: 0.24-0.91; p-value = 0.024). Patients prescribed dual-therapy had a higher hazard of sub-optimal glycaemic control (aHR: 1.50; 95% CI: 1.16-1.95; p-value = 0.002) versus monotherapy. CONCLUSIONS:  The HbA1c monitoring, in-line with testing frequency guidelines, is needed to alert the CCMDD programme of patients who become ineligible for enrolment. Patients receiving dual-therapy require special consideration.Contribution: Addressing identified shortfalls can assist programme implementation.

Application of thermosonication for guava juice processing: Impacts on bioactive, microbial, enzymatic and quality attributes.

The present work explores different conditions of thermosonication (TS) processing that would ensure microbiological and enzymatic safety for guava juice while simultaneously maximizing the preservation of its quality attributes. The guava juice was subjected to TS treatment (frequency: 40 kHz; power: 200 W; Temperature: 40, 60, and 80 °C; Time: 2, 6 and 10 min) and was compared with fresh and pasteurized (90 °C/60 s) juice samples. The objectives of the research work were to determine the effect of thermosonication on the quality attributes such as total soluble solids (TSS), pH, titratable acidity, cloud value, color attributes, total phenolic contents, total flavonoid contents, antioxidant activity, ascorbic acid levels, enzymatic, microbiological, and sensory properties. The thermosonicated and pasteurized samples showed no significant (p > 0.05) changes in pH, total soluble solids, and titratable acidity. TS improved the cloud value and color attributes. Furthermore, TS enhanced total phenols (10 to17%), flavonoids (5 to 25%), antioxidant activity (10.45% to 14.55%) and retention of ascorbic acid (61.98-83.32%) relative to control. Thermosonicated sample at 80 °C/10 min gives the maximum inactivation of Pectin methyl esterase (PME), Peroxidase (POD) and Polyphenol oxidase (PPO) enzymes. While both thermosonication and pasteurization drastically decreased the microbial count to undetectable levels, only TS exhibited modest improvement in sensory qualities. The results demonstrated that TS can enhance the overall safety, quality, and commercial viability of guava juice as a practical substitute to pasteurization.

Predictors of Neonatal Mortality: A Retrospective Cross-Sectional Study From the Special Newborn Care Unit of a Tertiary Care Hospital.

Background In India, a significant number of newborns die each year, with Madhya Pradesh having the highest neonatal mortality rate. However, there is a lack of information on factors that can predict neonatal mortality. Objective This study aimed to examine the factors influencing neonatal mortality among neonates admitted to a tertiary care centre's special newborn care unit (SNCU). Methods This retrospective record-based observational study was done at a tertiary care centre, where data from the special newborn care unit (SNCU) from 1st January 2021 to 31st December 2021 was used. We included data of all newborns who were treated in SNCU during the said period and excluded those who got referred or left against medical advice. We abstracted data on age at admission, gender, category, maturity status, birth weight, place of delivery, mode of transport, type of admission, indication of admission, duration of stay and outcome. Qualitative variables were described using frequency and percentage. The chi-square test was used to find out the association of different variables with the outcome, while multivariate logistic regression was conducted to identify risk factors of neonatal mortality. A p-value of <0.05 was considered significant. Results We finalized data of 1052 neonates for analysis. Among them, 846 neonates were successfully discharged while 206 neonates were deceased. The major cause of admission was perinatal asphyxia followed by prematurity. The major cause of mortality in this study was sepsis followed by respiratory distress syndrome, birth asphyxia, and prematurity. Mortality of neonates was significantly associated with maturity status, birth weight, place of delivery, age during admission and duration of stay. Prematurity (OR=3.762, 95% CI:1.93-7.33), birth weight 1000-1499g (OR=4.78, 95% CI:2.21-10.32), birth weight <1000g (OR=25.11, 95% CI:5.71-110.24), age at admission <1-day (OR=2.312, 95% CI:1.03-5.19), duration of stay 1-3-days (OR=12.98, 95% CI:7.48-22.52) and <1-day (OR=1271.88, 95% CI:121.39-13325.69) were significant predictors of mortality in our study. Conclusion Our study emphasizes monitoring and addressing risk factors like maturity status, birth weight, and age at admission to reduce neonatal mortality, with a focus on early management of preterm births and low birth weight.

Cerium oxide nanoparticles disseminated chitosan gelatin scaffold for bone tissue engineering applications.

Cell-free and cell-loaded constructs are used to bridge the critical-sized bone defect. Oxidative stress at the site of the bone defects is a major interference that slows bone healing. Recently, there has been an increase in interest in enhancing the properties of three-dimensional scaffolds with free radical scavenging materials. Cerium oxide nanoparticles (CNPs) can scavenge free radicals due to their redox-modulating property. In this study, freeze-drying was used to fabricate CG-CNPs nanocomposite scaffolds using gelatin (G), chitosan (C), and cerium oxide nanoparticles. Physico-chemical, mechanical, and biological characterization of CG-CNPs scaffolds were studied. CG-CNPs scaffolds demonstrated better results in terms of physicochemical, mechanical, and biological properties as compared to CG-scaffold. CG-CNPs scaffolds were cyto-friendly to MC3T3-E1 cells studied by performing in-vitro and in-ovo studies. The scaffold's antimicrobial study revealed high inhibition zones against Gram-positive and Gram-negative bacteria. With 79 % porosity, 45.99 % weight loss, 178.25 kPa compressive modulus, and 1.83 Ca/P ratio, the CG-CNP2 scaffold displays the best characteristics. As a result, the CG-CNP2 scaffolds are highly biocompatible and could be applied to repair bone defects.

Surgical cotton microfibers loaded with proteins and apatite: A potential platform for bone tissue engineering.

Tissue engineering has emerged as the best alternative to replacing damaged tissue/organs. However, the cost of scaffold materials continues to be a significant obstacle; thus, developing inexpensive scaffolds is strongly encouraged. In this study, cellulose microfibers (C), gelatin (G), egg white (EW), and nanohydroxyapatite (nHA) were assembled into a quaternary scaffold using EDC-NHS crosslinking, followed by freeze-drying method. Cellulose microfibers as a scaffold have only received a limited amount of research due to the absence of an intrinsic three-dimensional structure. Gelatin, more likely to interact chemically with collagen, was used to provide a stable structure to the cellulose microfibers. EW was supposed to provide the scaffold with numerous cell attachment sites. nHA was chosen to enhance the scaffold's bone-bonding properties. Physico-chemical, mechanical, and biological characterization of scaffolds were studied. In-vitro using MG-63 cells and in-ovo studies revealed that all scaffolds were biocompatible. The results of the DPPH assay demonstrate the ability of CGEWnHA to reduce free radicals. The CGEWnHA scaffold exhibits the best properties with 56.84 ± 28.45 µm average pore size, 75 ± 1.4 % porosity, 39.23 % weight loss, 109.19 ± 0.98 kPa compressive modulus, and 1.72 Ca/P ratio. As a result, the constructed CGEWnHA scaffold appears to be a viable choice for BTE applications.

African Control of Hypertension through Innovative Epidemiology and a Vibrant Ecosystem (ACHIEVE): novel strategies for accelerating hypertension control in Africa.

Hypertension is a leading preventable and controllable risk factor for cardiovascular and cerebrovascular diseases and the leading preventable risk for death globally. With a prevalence of nearly 50% and 93% of cases uncontrolled, very little progress has been made in detecting, treating, and controlling hypertension in Africa over the past thirty years. We propose the African Control of Hypertension through Innovative Epidemiology and a Vibrant Ecosystem (ACHIEVE) to implement the HEARTS package for improved surveillance, prevention, treatment/acute care of hypertension, and rehabilitation of those with hypertension complications across the life course. The ecosystem will apply the principles of an iterative implementation cycle by developing and deploying pragmatic solutions through the contextualization of interventions tailored to navigate barriers and enhance facilitators to deliver maximum impact through effective communication and active participation of all stakeholders in the implementation environment. Ten key strategic actions are proposed for implementation to reduce the burden of hypertension in Africa.

Phytochemicals targeting NF-κB signaling: Potential anti-cancer interventions.

Nuclear factor κB (NF-κB) is a ubiquitous regulator of the signalome and is indispensable for various biological cell functions. NF-κB consists of five transcription factors that execute both cytoplasmic and nuclear signaling processes in cells. NF-κB is the only signaling molecule that governs both pro- and anti-apoptotic, and pro- and anti-inflammatory responses. This is due to the canonical and non-canonical components of the NF-κB signaling pathway. Together, these pathways orchestrate cancer-related inflammation, hyperplasia, neoplasia, and metastasis. Non-canonical NF-κB pathways are particularly involved in the chemoresistance of cancer cells. In view of its pivotal role in cancer progression, NF-κB represents a potentially significant therapeutic target for modifying tumor cell behavior. Several phytochemicals are known to modulate NF-κB pathways through the stabilization of its inhibitor, IκB, by inhibiting phosphorylation and ubiquitination thereof. Several natural pharmacophores are known to inhibit the nuclear translocation of NF-κB and associated pro-inflammatory responses and cell survival pathways. In view of this and the high degree of specificity exhibited by various phytochemicals for the NF-κB component, we herein present an in-depth overview of these phytochemicals and discuss their mode of interaction with the NF-κB signaling pathways for controlling the fate of tumor cells for cancer-directed interventions.

Cutting the umbilical cord: Cancer stem cell-targeted therapeutics.

Cancer Stem Cells (CSCs) are a notoriously quiescent subpopulation of cells within heterogeneous tumors exhibiting self-renewal, differentiation and drug-resistant capabilities leading to tumor relapse. Heterogeneous cell populations in tumor microenvironment develop an elaborate network of signalling and factors supporting the CSC population within a niche. Identification of specific biomarkers for CSCs facilitates their isolation. CSCs demonstrate abilities that bypass immune surveillance, exhibit resistance to therapy, and induce cancer recurrence while promoting altered metabolism of the bulk tumor, thereby encouraging metastasis. The fight against cancer is prone to relapse without discussing the issue of CSCs, making it imperative for encapsulation of current studies. In this review, we provide extensive knowledge of recent therapeutics developed that target CSCs via multiple signalling cascades, altered metabolism and the tumor microenvironment. Thorough understanding of the functioning of CSCs, their interaction with different cells in the tumor microenvironment as well as current gaps in knowledge are addressed. We present possible strategies to disrupt the cellular and molecular interplay within the tumor microenvironment and make it less conducive for CSCs, which may aid in their eradication with subsequently better treatment outcomes. In conclusion, we discuss a brief yet functional idea of emerging concepts in CSC biology to develop efficient therapeutics acting on cancer recurrence and metastasis.

Yin and yang of immunological memory in controlling infections: Overriding self defence mechanisms.

Immunological memory is critical for host immunity and decisive for individual to respond exponentially to previously encountered infection. Both T and B cell memory are known to orchestrate immunological memory with their central and effector memory arms contributing in prolonged immunity/defence mechanisms of host. While central memory helps in maintaining prolonged immunity for a particular infection, effector memory helps in keeping local/seasonal infection in control. In addition to this, generation of long-lived plasma cells is pivotal for generating neutralizing antibodies which can enhance recall and B cell memory to control re-infection. In view of this, scaling up memory response is one of the major objectives for the expected outcome of vaccination. In this line, this review deals with the significance of memory cells, molecular pathways of their development, maintenance, epigenetic regulation and negative regulation in various infections. We have also highlighted the significance of both T and B cell memory responses in the vaccination approaches against range of infections which is not fully explored so far.[Box: see text].

Scaffold Fabrication Techniques of Biomaterials for Bone Tissue Engineering: A Critical Review.

Bone tissue engineering (BTE) is a promising alternative to repair bone defects using biomaterial scaffolds, cells, and growth factors to attain satisfactory outcomes. This review targets the fabrication of bone scaffolds, such as the conventional and electrohydrodynamic techniques, for the treatment of bone defects as an alternative to autograft, allograft, and xenograft sources. Additionally, the modern approaches to fabricating bone constructs by additive manufacturing, injection molding, microsphere-based sintering, and 4D printing techniques, providing a favorable environment for bone regeneration, function, and viability, are thoroughly discussed. The polymers used, fabrication methods, advantages, and limitations in bone tissue engineering application are also emphasized. This review also provides a future outlook regarding the potential of BTE as well as its possibilities in clinical trials.