Cortisol affects macrophage polarization by inducing miR-143/145 cluster to reprogram glucose metabolism and by promoting TCA cycle anaplerosis.

Chronic stress can have adverse consequences on human health by disrupting the hormonal balance in our body. Earlier, we observed elevated levels of cortisol, a primary stress hormone, and some exosomal microRNAs in the serum of patients with breast cancer. Here, we investigated the role of cortisol in microRNA induction and its functional consequences. We found that cortisol induced the expression of miR-143/145 cluster in human monocyte (THP1 and U937)-derived macrophages but not in breast cancer cells. In silico analysis identified glucocorticoid-response element in the upstream CARMN promoter utilized by the miR-143/145 cluster. Enhanced binding of glucocorticoid-receptor (GR) upon cortisol exposure and its regulatory significance was confirmed by chromatin-immunoprecipitation and promoter-reporter assays. Further, cortisol inhibited IFNγ-induced M1 polarization and promoted M2 polarization, and these effects were suppressed by miR-143-3p and miR-145-5p inhibitors pretreatment. Cortisol-treated macrophages exhibited increased oxygen-consumption rate (OCR) to extracellular-acidification rate (ECAR) ratio, and this change was neutralized by functional inhibition of miR-143-3p and miR-145-5p. HK2 and ADPGK were confirmed as the direct targets of miR-143-3p and miR-145-5p, respectively. Interestingly, silencing of HK2 and ADPGK inhibited IFNγ-induced M1 polarization but failed to induce M2 polarization, since it suppressed both ECAR and OCR, while OCR was largely sustained in cortisol-treated M2-polarized macrophages. We found that cortisol treatment sustained OCR by enhancing fatty acid and glutamine metabolism through upregulation of CPT2 and GLS, respectively, to support M2 polarization. Thus, our findings unfold a novel mechanism of immune suppression by cortisol and open avenues for preventive and therapeutic interventions.

From modulation of cellular plasticity to potentiation of therapeutic resistance: new and emerging roles of MYB transcription factors in human malignancies.

MYB transcription factors are encoded by a large family of highly conserved genes from plants to vertebrates. There are three members of the MYB gene family in human, namely, MYB, MYBL1, and MYBL2 that encode MYB/c-MYB, MYBL1/A-MYB, and MYBL2/B-MYB, respectively. MYB was the first member to be identified as a cellular homolog of the v-myb oncogene carried by the avian myeloblastosis virus (AMV) causing leukemia in chickens. Under the normal scenario, MYB is predominantly expressed in hematopoietic tissues, colonic crypts, and neural stem cells and plays a role in maintaining the undifferentiated state of the cells. Over the years, aberrant expression of MYB genes has been reported in several malignancies and recent years have witnessed tremendous progress in understanding of their roles in processes associated with cancer development. Here, we review various MYB alterations reported in cancer along with the roles of MYB family proteins in tumor cell plasticity, therapy resistance, and other hallmarks of cancer. We also discuss studies that provide mechanistic insights into the oncogenic functions of MYB transcription factors to identify potential therapeutic vulnerabilities.

MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming.

Extensive desmoplasia and poor vasculature renders pancreatic tumors severely hypoxic, contributing to their aggressiveness and therapy resistance. Here, we identify the HuR/MYB/HIF1α axis as a critical regulator of the metabolic plasticity and hypoxic survival of pancreatic cancer cells. HuR undergoes nuclear-to-cytoplasmic translocation under hypoxia and stabilizes MYB transcripts, while MYB transcriptionally upregulates HIF1α. Upon MYB silencing, pancreatic cancer cells fail to survive and adapt metabolically under hypoxia, despite forced overexpression of HIF1α. MYB induces the transcription of several HIF1α-regulated glycolytic genes by directly binding to their promoters, thus enhancing the recruitment of HIF1α to hypoxia-responsive elements through its interaction with p300-dependent histone acetylation. MYB-depleted pancreatic cancer cells exhibit a dramatic reduction in tumorigenic ability, glucose-uptake and metabolism in orthotopic mouse model, even after HIF1α restoration. Together, our findings reveal an essential role of MYB in metabolic reprogramming that supports pancreatic cancer cell survival under hypoxia.

Prevalence of steatotic liver disease, advanced fibrosis and cirrhosis among community-dwelling overweight and obese individuals in the USA.

BACKGROUND: There are limited prospective data among overweight and obese individuals on the prevalence of advanced fibrosis, and cirrhosis using advanced MRI-based methods in the USA. The aim of this study was to fill that gap in knowledge by prospectively determining the MRI-based prevalence of steatotic liver disease (SLD) and its subcategories, advanced fibrosis and cirrhosis among overweight and obese individuals residing in the USA. METHODS: This is a cross-sectional analysis of prospectively enrolled overweight or obese adults aged 40-75 years from primary care and community-based settings in Southern California. Participants were classified as having SLD if MRI proton density fat fraction ≥5%, and subclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-related liver disease (ALD) consistently with the new nomenclature guidance per AASLD-EASL-ALEH. Advanced fibrosis and cirrhosis were defined as magnetic resonance elastography (MRE) ≥3.63 kPa and MRE ≥4.67 kPa, respectively. RESULTS: The cohort included 539 participants with mean (±SD) age of 51.5 (±13.1) years and body mass index of 32.6 (±6.2) kg/m2, respectively. The prevalence of SLD, advanced fibrosis and cirrhosis was 75%, 10.8% and 4.5%, respectively. The prevalence of MASLD, MetALD and ALD was 67.3%, 4.8% and 2.6%, respectively. There was no difference in prevalence of advanced fibrosis and cirrhosis among subcategories. CONCLUSIONS: Using advanced MRI methods among community-dwelling overweight and obese adults, the prevalence of cirrhosis was 4.5%. Most common SLD subcategory was MASLD with 67% of individuals, whereas MetALD and ALD were less common. Systematic screening for advanced fibrosis among overweight/obese adults may be considered.

Biphasic transcriptional and posttranscriptional regulation of MYB by androgen signaling mediates its growth control in prostate cancer.

MYB, a proto-oncogene, is overexpressed in prostate cancer (PCa) and promotes its growth, aggressiveness, and resistance to androgen-deprivation therapy. Here, we examined the effect of androgen signaling on MYB expression and delineated the underlying molecular mechanisms. Paralleling a dichotomous effect on growth, low-dose androgen induced MYB expression at both transcript and protein levels, whereas it was suppressed in high-dose androgen-treated PCa cells. Interestingly, treatment with both low- and high-dose androgen transcriptionally upregulated MYB by increasing the binding of androgen receptor to the MYB promoter. In a time-course assay, androgen induced MYB expression at early time points followed by a sharp decline in high-dose androgen-treated cells due to decreased stability of MYB mRNA. Additionally, profiling of MYB-targeted miRNAs demonstrated significant induction of miR-150 in high-dose androgen-treated PCa cells. We observed a differential binding of androgen receptor on miR-150 promoter with significantly greater occupancy recorded in high-dose androgen-treated cells than those treated with low-dose androgen. Functional inhibition of miR-150 relieved MYB suppression by high-dose androgen, while miR-150 mimic abolished MYB induction by low-dose androgen. Furthermore, MYB-silencing or miR-150 mimic transfection suppressed PCa cell growth induced by low-dose androgen, whereas miR-150 inhibition rescued PCa cells from growth repression by high-dose androgen. Similarly, we observed that MYB silencing suppressed the expression of androgen-responsive, cell cycle-related genes in low-dose androgen-treated cells, while miR-150 inhibition increased their expression in cells treated with high-dose androgen. Overall, these findings reveal novel androgen-mediated mechanisms of MYB regulation that support its biphasic growth control in PCa cells.

Clinicopathological significance of unraveling mitochondrial pathway alterations in non-small-cell lung cancer.

Early detection, accurate monitoring, and therapeutics are major problems in non-small-cell lung cancer (NSCLC) patients. We identified genomic copy number variation of a unique panel of 40 mitochondria-targeted genes in NSCLCs (GEOGSE #29365). Validation of mRNA expression of these molecules revealed an altered panel of 34 genes in lung adenocarcinomas (LUAD) and 36 genes in lung squamous cell carcinomas (LUSC). In the LUAD subtype (n = 533), we identified 29 upregulated and 5 downregulated genes, while in the LUSC subtype (n = 502), a panel of 30 upregulated and 6 downregulated genes were discovered. The majority of these genes are associated with mitochondrial protein transport, ferroptosis, calcium signaling, metabolism, OXPHOS function, TCA cycle, apoptosis, and MARylation. Altered mRNA expression of SLC25A4, ACSF2, MACROD1, and GCAT was associated with poor survival of the NSCLC patients. Progressive loss of SLC25A4 protein expression was confirmed in NSCLC tissues (n = 59), predicting poor survival of the patients. Forced overexpression of SLC25A4 in two LUAD cell lines inhibited their growth, viability, and migration. A significant association of the altered mitochondrial pathway genes with LC subtype-specific classical molecular signatures was observed, implicating the existence of nuclear-mitochondrial cross-talks. Key alteration signatures shared between LUAD and LUSC subtypes including SLC25A4, ACSF2, MACROD1, MDH2, LONP1, MTHFD2, and CA5A could be helpful in developing new biomarkers and therapeutics.

Building public-private research partnerships in troubled times.

The Indian government is launching a series of new initiatives to boost public-private research partnerships and to jumpstart science-driven economic growth. But will the current global economic downturn hamper these efforts?

Axillary arch muscle and pectoralis quartus: an unusual combination of two variant supernumerary muscles in the axillary region - a case report.

Variant anatomy in the axillary region is of great clinical significance. It is one of the most frequently accessed regions for radical dissection surgery. During routine dissection of embalmed cadavers, we found a rare case of two accessory muscular slips emerging from the lateral border of latissimus dorsi (LD) and the inferolateral border of pectoralis major (PM), crossing the neurovascular structures in the axilla and merging distally together to the brachial fascia at the upper end of humerus below the bicipital groove. The accessory slip from LD is commonly referred to as the "axillary arch" in literature. We identified the accessory slip from the PM crossing over the axilla as pectoralis quartus. These aberrant slips can cause neurovascular compression in the axilla and can have clinical implications. Prior knowledge of the variant anatomy is the key to successful surgery in the axilla, thereby avoiding inadvertent injuries and post-operative complications.

Unusual branch of the saphenous nerve to the sartorius muscle in a female cadaver.

PURPOSE: The saphenous nerve is a predominantly sensory nerve. It is the longest nerve of the body which supplies the skin of the medial side of the leg and foot as far as the ball of the great toe. We present here an unusual motor branch of the saphenous nerve to the sartorius muscle. METHOD: Institutional guidelines for use of human cadaver were followed. Routine dissection of the lower limbs for undergraduate medical teaching was performed in a 67 years old female cadaver employing standard methods. Relevant gross features of the variations were photographed. H&E staining of relevant structure was done and photomicrographed. RESULTS: The unusual motor branch to Sartorius was observed in the right thigh. The branch was given off in the lower third of the thigh after the saphenous nerve exited the adductor canal. The branch was distinctly seen entering the substance of the sartorius. The structure was confirmed to be a peripheral nerve by histological examination. The saphenous nerve then descended between the sartorius and gracilis tendons, pierced the fascia lata and became cutaneous. CONCLUSION: The motor branch to the sartorius muscle is a very rare branch whose knowledge is important for clinicians as it can get damaged during arthroscopy and other knee surgery or during adductor canal block.

Is it time for anatomists to enter the OT? Their role in clinical anatomy education of residents: A pre-trial survey research among surgeons.

OBJECTIVE: This study aimed to assess the perceived need among surgical residents to revisit their anatomical knowledge and evaluate their attitude towards integrating clinical anatomists into surgical residency program curriculum. BACKGROUND: While medical students learn human anatomy during undergraduate years, the practical application of clinically oriented anatomy becomes vital in surgical specialties. However, this aspect has not been adequately addressed in Indian surgical residency programs. METHODS: An 11-item questionnaire, including closed-ended and Likert-scale questions, was administered to 153 surgical residents. Consent was obtained, and responses were collected via Google Forms. RESULTS: Half of the respondents (50%) felt confident in their self-directed anatomy learning, but 87% believed integrating clinical anatomists would enhance their surgical expertise. Additionally, 88% saw value in revisiting cadaveric dissection. Third-year residents showed a significantly higher inclination towards cadaveric dissection. Deficiencies in the curriculum and time constraints were identified as major barriers. CONCLUSION: The study highlights a perceived need among surgical residents to augment their anatomical knowledge, advocating for the integration of clinical anatomists and cadaveric dissection into training. A collaborative approach, emphasizing both horizontal and vertical integration of anatomy, is recommended to enhance surgical education and practice. (Tab. 4, Fig. 1, Ref. 25).

Origin of median sacral artery with fourth pair of lumbar artery - an alert for spine surgeons and interventionalists: A case report and mini literature review.

The median sacral artery (MSA) is the single unpaired dorsal branch of the abdominal aorta. The present case describes the relatively unusual origin of the median sacral artery in common with the fourth pair of lumbar arteries via a common trunk in a 74-year-old males' cadaver. Unusual common trunk is prone for iatrogenic injury in surgeries of the lumbar and pelvic region. Owing to the deep seated nature of MSA close to the periosteum of lumbar vertebrae and sacrum, detection of accidental rupture of MSA and ligation thereof becomes a difficult task. MSA is also increasingly being utilized for intra-arterial embolization of pelvic tumours. The proximal portion of the common origin may at times undergo cone shaped dilatation which is referred to as infundibulum or infundibular dilatation and can also transform into aneurysm later. Knowledge of this variation is imperative for spine and pelvic surgeons to avoid unwanted complications.

Modulation of the tumor microenvironment by natural agents: implications for cancer prevention and therapy.

The development of cancer is not just the growth and proliferation of a single transformed cell, but its surrounding environment also coevolves with it. Indeed, successful cancer progression depends on the ability of the tumor cells to develop a supportive tumor microenvironment consisting of various types of stromal cells. The interactions between the tumor and stromal cells are bidirectional and mediated through a variety of growth factors, cytokines, metabolites, and other biomolecules secreted by these cells. Tumor-stromal crosstalk creates optimal conditions for the tumor growth, metastasis, evasion of immune surveillance, and therapy resistance, and its targeting is being explored for clinical management of cancer. Natural agents from plants and marine life have been at the forefront of traditional medicine. Numerous epidemiological studies have reported the health benefits imparted on the consumption of certain fruits, vegetables, and their derived products. Indeed, a significant majority of anti-cancer drugs in clinical use are either naturally occurring compounds or their derivatives. In this review, we describe fundamental cellular and non-cellular components of the tumor microenvironment and discuss the significance of natural compounds in their targeting. Existing literature provides hope that novel prevention and therapeutic approaches will emerge from ongoing scientific efforts leading to the reduced tumor burden and improve clinical outcomes in cancer patients.

Opioid abuse and SIV infection in non-human primates.

Human immunodeficiency virus (HIV) and drug abuse are intertwined epidemics, leading to compromised adherence to combined antiretroviral therapy (cART) and exacerbation of NeuroHIV. As opioid abuse causes increased viral replication and load, leading to a further compromised immune system in people living with HIV (PLWH), it is paramount to address this comorbidity to reduce the NeuroHIV pathogenesis. Non-human primates are well-suited models to study mechanisms involved in HIV neuropathogenesis and provide a better understanding of the underlying mechanisms involved in the comorbidity of HIV and drug abuse, leading to the development of more effective treatments for PLWH. Additionally, using broader behavioral tests in these models can mimic mild NeuroHIV and aid in studying other neurocognitive diseases without encephalitis. The simian immunodeficiency virus (SIV)-infected rhesus macaque model is instrumental in studying the effects of opioid abuse on PLWH due to its similarity to HIV infection. The review highlights the importance of using non-human primate models to study the comorbidity of opioid abuse and HIV infection. It also emphasizes the need to consider modifiable risk factors such as gut homeostasis and pulmonary pathogenesis associated with SIV infection and opioid abuse in this model. Moreover, the review suggests that these non-human primate models can also be used in developing effective treatment strategies for NeuroHIV and opioid addiction. Therefore, non-human primate models can significantly contribute to understanding the complex interplay between HIV infection, opioid abuse, and associated comorbidities.

Funneled Depolymerization of Ionic Liquid-Based Biorefinery "Heterogeneous" Lignin into Guaiacols over Reusable Palladium Catalyst.

The efficient utilization of lignin, the direct source of renewable aromatics, into value-added renewable chemicals is an important step towards sustainable biorefinery practices. Nevertheless, owing to the random heterogeneous structure and limited solubility, lignin utilization has been primarily limited to burning for energy. The catalytic depolymerization of lignin has been proposed and demonstrated as a viable route to sustainable biorefinery, however, low yields and poor selectivity of products, high char formation, and limited to no recycling of transition-metal-based catalyst involved in lignin depolymerization demands attention to enable practical-scale lignocellulosic biorefineries. In this study, we demonstrate the catalytic depolymerization of ionic liquid-based biorefinery poplar lignin into guaiacols over a reusable zirconium phosphate supported palladium catalyst. The essence of the study lies in the high conversion (>80 %), minimum char formation (7-16 %), high yields of guaiacols (up to 200 mg / g of lignin), and catalyst reusability. Both solid residue, liquid stream, and gaseous products were thoroughly characterized using ICP-OES, PXRD, CHN analysis, GC-MS, GPC, and 2D NMR to understand the hydrogenolysis pathway.

India takes an open source approach to drug discovery.

Open source software may have been around for 17 years, but using an open source model to speed up drug discovery is a relatively new idea. This month, India is launching a new open source initiative for developing drugs to treat diseases such as tuberculosis, malaria, and HIV.

The Journey of Mitochondrial Protein Import and the Roadmap to Follow.

Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the oxidative phosphorylation system (OXPHOS). The rest of the proteins (99%) that function in mitochondria in the various pathways described above are nuclear-transcribed and synthesized as precursors in the cytosol. These proteins are imported into the mitochondria by the unique mitochondrial protein import system that consists of seven machineries. Proper functioning of the mitochondrial protein import system is crucial for optimal mitochondrial deliverables, as well as mitochondrial and cellular homeostasis. Impaired mitochondrial protein import leads to proteotoxic stress in both mitochondria and cytosol, inducing mitochondrial unfolded protein response (UPRmt). Altered UPRmt is associated with the development of various disease conditions including neurodegenerative and cardiovascular diseases, as well as cancer. This review sheds light on the molecular mechanisms underlying the import of nuclear-encoded mitochondrial proteins, the consequences of defective mitochondrial protein import, and the pathological conditions that arise due to altered UPRmt.

Cardiovascular Complications in Patients with Prostate Cancer: Potential Molecular Connections.

Cardiovascular diseases (CVDs) and complications are often seen in patients with prostate cancer (PCa) and affect their clinical management. Despite acceptable safety profiles and patient compliance, androgen deprivation therapy (ADT), the mainstay of PCa treatment and chemotherapy, has increased cardiovascular risks and metabolic syndromes in patients. A growing body of evidence also suggests that patients with pre-existing cardiovascular conditions show an increased incidence of PCa and present with fatal forms of the disease. Therefore, it is possible that a molecular link exists between the two diseases, which has not yet been unraveled. This article provides insight into the connection between PCa and CVDs. In this context, we present our findings linking PCa progression with patients' cardiovascular health by performing a comprehensive gene expression study, gene set enrichment (GSEA) and biological pathway analysis using publicly available data extracted from patients with advanced metastatic PCa. We also discuss the common androgen deprivation strategies and CVDs most frequently reported in PCa patients and present evidence from various clinical trials that suggest that therapy induces CVD in PCa patients.

Mitochondrial Alterations in Prostate Cancer: Roles in Pathobiology and Racial Disparities.

Prostate cancer (PCa) affects millions of men worldwide and is a major cause of cancer-related mortality. Race-associated PCa health disparities are also common and are of both social and clinical concern. Most PCa is diagnosed early due to PSA-based screening, but it fails to discern between indolent and aggressive PCa. Androgen or androgen receptor-targeted therapies are standard care of treatment for locally advanced and metastatic disease, but therapy resistance is common. Mitochondria, the powerhouse of cells, are unique subcellular organelles that have their own genome. A large majority of mitochondrial proteins are, however, nuclear-encoded and imported after cytoplasmic translation. Mitochondrial alterations are common in cancer, including PCa, leading to their altered functions. Aberrant mitochondrial function affects nuclear gene expression in retrograde signaling and promotes tumor-supportive stromal remodeling. In this article, we discuss mitochondrial alterations that have been reported in PCa and review the literature related to their roles in PCa pathobiology, therapy resistance, and racial disparities. We also discuss the translational potential of mitochondrial alterations as prognostic biomarkers and as effective targets for PCa therapy.

Involvement of lncRNA TUG1 in HIV-1 Tat-Induced Astrocyte Senescence.

HIV-1 infection in the era of combined antiretroviral therapy has been associated with premature aging. Among the various features of HIV-1 associated neurocognitive disorders, astrocyte senescence has been surmised as a potential cause contributing to HIV-1-induced brain aging and neurocognitive impairments. Recently, lncRNAs have also been implicated to play essential roles in the onset of cellular senescence. Herein, using human primary astrocytes (HPAs), we investigated the role of lncRNA TUG1 in HIV-1 Tat-mediated onset of astrocyte senescence. We found that HPAs exposed to HIV-1 Tat resulted in significant upregulation of lncRNA TUG1 expression that was accompanied by elevated expression of p16 and p21, respectively. Additionally, HIV-1 Tat-exposed HPAs demonstrated increased expression of senescence-associated (SA) markers-SA-ß-galactosidase (SA-ß-gal) activity and SA-heterochromatin foci-cell-cycle arrest, and increased production of reactive oxygen species and proinflammatory cytokines. Intriguingly, gene silencing of lncRNA TUG1 in HPAs also reversed HIV-1 Tat-induced upregulation of p21, p16, SA-ß gal activity, cellular activation, and proinflammatory cytokines. Furthermore, increased expression of astrocytic p16 and p21, lncRNA TUG1, and proinflammatory cytokines were observed in the prefrontal cortices of HIV-1 transgenic rats, thereby suggesting the occurrence of senescence activation in vivo. Overall, our data indicate that HIV-1 Tat-induced astrocyte senescence involves the lncRNA TUG1 and could serve as a potential therapeutic target for dampening accelerated aging associated with HIV-1/HIV-1 proteins.

Chemical characterization and the intrusion through elicitation and Agrobacterium rhizogenes mediated hairy root transformation in Saussurea costus C.B. Clarke.

Saussurea costus (Asteraceae) commonly known as kuth, is an important medicinal plant with a rich repository of medicinally valuable compounds. During the present study, pharmacologically important sesquiterpene lactones namely costunolide, dehydrocostus lactone, betulinic acid and syringin were isolated from different plant extracts. Furthermore, the elicitation effect of jasmonic acid (JA) and different light regiments on the accumulation of secondary metabolites (costunolide and dehydrocostus lactone) was evaluated using HPLC. There was an increase in amount of costunolide and dehydrocostus lactone compared to control after 96 h of treatment with JA and continuous light. The amount of costunolide after 96 h was maximum 6.47 mg/g DW in response to JA as compared to control which was found to be 1.7 mg/g DW. Similarly, the concentration of dehydrocostus lactone after 96 h showed maximum accumulation of compound 4.7 mg/g DW in response to continuous light. The in vitro response in MS medium augmented with BAP (4 mg/l) produces friable and creamish coloured callus, however, number of days increased from 10 to 22 days with 70% culture response. Also, Agrobacterium rhizogenes strain LBA9402 was found to be most effective strain for the establishment of hairy root cultures among all the strains used. The genomic DNA was used as template in PCR to amplify rolB gene which confirmed the efficient transformation of the roots. Additionally, total metabolite content of in vitro raised hairy roots of S. costus was significantly higher than the field grown plants. The production of secondary metabolites through elicitation and hairy roots can serve as a potential tool for the conservation action programme in S. costus. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01270-9.