Rice A20/AN1 protein, OsSAP10, confers water-deficit stress tolerance via proteasome pathway and positive regulation of ABA signaling in Arabidopsis.

KEY MESSAGE: Overexpression of rice A20/AN1 zinc-finger protein, OsSAP10, improves water-deficit stress tolerance in Arabidopsis via interaction with multiple proteins. Stress-associated proteins (SAPs) constitute a class of A20/AN1 zinc-finger domain containing proteins and their genes are induced in response to multiple abiotic stresses. The role of certain SAP genes in conferring abiotic stress tolerance is well established, but their mechanism of action is poorly understood. To improve our understanding of SAP gene functions, OsSAP10, a stress-inducible rice gene, was chosen for the functional and molecular characterization. To elucidate its role in water-deficit stress (WDS) response, we aimed to functionally characterize its roles in transgenic Arabidopsis, overexpressing OsSAP10. OsSAP10 transgenics showed improved tolerance to water-deficit stress at seed germination, seedling and mature plant stages. At physiological and biochemical levels, OsSAP10 transgenics exhibited a higher survival rate, increased relative water content, high osmolyte accumulation (proline and soluble sugar), reduced water loss, low ROS production, low MDA content and protected yield loss under WDS relative to wild type (WT). Moreover, transgenics were hypersensitive to ABA treatment with enhanced ABA signaling and stress-responsive genes expression. The protein-protein interaction studies revealed that OsSAP10 interacts with proteins involved in proteasomal pathway, such as OsRAD23, polyubiquitin and with negative and positive regulators of stress signaling, i.e., OsMBP1.2, OsDRIP2, OsSCP and OsAMTR1. The A20 domain was found to be crucial for most interactions but insufficient for all interactions tested. Overall, our investigations suggest that OsSAP10 is an important candidate for improving water-deficit stress tolerance in plants, and positively regulates ABA and WDS signaling via protein-protein interactions and modulation of endogenous genes expression in ABA-dependent manner.

From orphan to oncogene: The role of GPR35 in cancer and immune modulation.

G protein-coupled receptors (GPCRs) are well-studied and the most traceable cell surface receptors for drug discovery. One of the intriguing members of this family is G protein-coupled receptors 35 (GPR35), which belongs to the class A rhodopsin-like family of GPCRs identified over two decades ago. GPR35 presents interesting features such as ubiquitous expression and distinct isoforms. Moreover, functional and genome-wide association studies on its widespread expression have linked GPR35 with pathophysiological disease progression. Various pieces of evidence have been accumulated regarding the independent or endogenous ligand-dependent role of GPR35 in cancer progression and metastasis. In the current scenario, the relationship of this versatile receptor and its putative endogenous ligands for the activation of oncogenic signal transduction pathways at the cellular level is an active area of research. These intriguing features offered by GPR35 make it an oncological target, justifying its uniqueness at the physiological and pathophysiological levels concerning other GPCRs. For pharmacologically targeting receptor-induced signaling, few potential competitive antagonists have been discovered that offer high selectivity at a human level. In addition to its fascinating features, targeting GPR35 at rodent and human orthologue levels is distinct, thus contributing to the sub-species selectivity. Strategies to modulate these issues will help us understand and truly target GPR35 at the therapeutic level. In this article, we have provided prospects on each topic mentioned above and suggestions to overcome the challenges. This review discusses the molecular mechanism and signal transduction pathways activated by endogenous ligands or spontaneous auto-activation of GPR35 that contributes towards disease progression. Furthermore, we have highlighted the GPR35 structure, ubiquitous expression, its role in immunomodulation, and at the pathophysiological level, especially in cancer, indicating its status as a versatile receptor. Subsequently, we discussed the various proposed ligands and their mechanism of interaction with GPR35. Additionally, we have summarized the GPR35 antagonist that provides insights into the opportunities for therapeutically targeting this receptor.

Pt-doped Ru nanoparticles loaded on 'black gold' plasmonic nanoreactors as air stable reduction catalysts.

This study introduces a plasmonic reduction catalyst, stable only in the presence of air, achieved by integrating Pt-doped Ru nanoparticles on black gold. This innovative black gold/RuPt catalyst showcases good efficiency in acetylene semi-hydrogenation, attaining over 90% selectivity with an ethene production rate of 320 mmol g-1 h-1. Its stability, evident in 100 h of operation with continuous air flow, is attributed to the synergy of co-existing metal oxide and metal phases. The catalyst's stability is further enhanced by plasmon-mediated concurrent reduction and oxidation of the active sites. Finite-difference time-domain simulations reveal a five-fold electric field intensification near the RuPt nanoparticles, crucial for activating acetylene and hydrogen. Kinetic isotope effect analysis indicates the contribution from the plasmonic non-thermal effects along with the photothermal. Spectroscopic and in-situ Fourier transform infrared studies, combined with quantum chemical calculations, elucidate the molecular reaction mechanism, emphasizing the cooperative interaction between Ru and Pt in optimizing ethene production and selectivity.

Copper metabolism and cuproptosis in human malignancies: Unraveling the complex interplay for therapeutic insights.

Copper, a vital trace element, orchestrates diverse cellular processes ranging from energy production to antioxidant defense and angiogenesis. Copper metabolism and cuproptosis are closely linked in the context of human diseases, with a particular focus on cancer. Cuproptosis refers to a specific type of copper-mediated cell death or copper toxicity triggered by disruptions in copper metabolism within the cells. This phenomenon encompasses a spectrum of mechanisms, such as oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and perturbations in metal ion equilibrium. Mechanistically, cuproptosis is driven by copper binding to the lipoylated enzymes within the tricarboxylic acid (TCA) cycle. This interaction participates in protein aggregation and proteotoxic stress, ultimately culminating in cell death. Targeting copper metabolism and its associated pathways in cancer cells hold therapeutic potential by selectively targeting and eliminating cancerous cells. Strategies to modulate copper levels, enhance copper excretion, or interfere with cuproptotic pathways are being explored to identify novel therapeutic targets for cancer therapy and improve patient outcomes. Understanding the relationship between cuproptosis and copper metabolism in human malignancies remains an active area of research. This review provides a comprehensive overview of the association among copper metabolism, copper homeostasis, and carcinogenesis, explicitly emphasizing the cuproptosis mechanism and its implications for cancer pathogenesis. Additionally, we emphasize the therapeutic aspects of targeting copper and cuproptosis for cancer treatment.

Hydroxychloroquine interaction with phosphoinositide 3-kinase modulates prostate cancer growth in bone microenvironment: In vitro and molecular dynamics based approach.

Patients with advanced prostate cancer (PCa) are more likely to develop bone metastases. Tumor cells thrive in the bone microenvironment, interacting with osteoblasts and osteoclasts. Given the PI3K/AKT pathway's metastatic potential and signal integration's ability to modulate cell fates in PCa development, drugs targeting this system have great therapeutic promise. Hydroxychloroquine (HCQ) is an anti-malarial medication commonly used to treat clinical conditions such as rheumatology and infectious disorders. We explored the anti-neoplastic effect of HCQ on PC3 and C4-2B cell lines in the bone microenvironment. Interestingly, HCQ treatment substantially decreases the viability, proliferation, and migration potential of PCa cells in the bone microenvironment. HCQ induces apoptosis and cell cycle arrest, even in the presence of osteoblast-secreted factors. Mechanistically, HCQ inhibited the activity of the PI3K/AKT signaling pathway, which ultimately regulates the proliferation and migration of PCa cells in the bone. The binding energy for docking HCQ with PI3K was -6.7 kcal/mol, and the complex was stabilized by hydrogen bonds, hydrophobic forces, and van der Waals forces. Molecular simulations further validated the structural integrity of the HCQ-PI3K complex without altering PI3K's secondary structure. Our findings underscore the efficacy of HCQ as a potential therapeutic agent in treating PCa.

The olfactory diary: Tracking awareness and consciousness of the sense of smell throughout the day.

Objectives: The aim of the present study was to follow the daily course of patients with olfactory dysfunction and healthy controls and to assess (i) how many times a day, (ii) at which time, and (iii) in which aspect of daily life participants are conscious about their sense of smell. Methods: In this longitudinal study, 49 patients with smell loss and 30 healthy participants were enrolled. Olfactory function was assessed using the Sniffin' Sticks. All participants received paper diaries designed for a 14-day period, featuring 12 rows representing 12 daily hours and six columns for various daily life aspects. They were instructed to mark their awareness of smell by indicating the relevant row and column in the diary. Following the return of the diaries, a second olfactory test was conducted within the patient group. Results: On average, patients were consciously aware of their sense of smell around 8 times daily, while healthy participants noted it about 6.5 times a day. Both groups primarily focused on their sense of smell during activities related to "eating," followed by considerations in "social life" and "personal hygiene." Interestingly, distinct patterns emerged: patients peaked in awareness at 8 a.m. and 7 p.m., whereas healthy individuals showed peaks at 6 a.m., 12 p.m., and 7 p.m. Despite regular diary use, we observed no improvement in patients' olfactory function or related quality of life. Conclusion: The olfactory diary is a valuable tool unveiling individual smell awareness patterns in patients with smell loss, aiding in counseling and patient management. Level of Evidence: 4.

α-lipoic acid modulates prostate cancer cell growth and bone cell differentiation.

Prostate cancer (PCa) progression leads to bone modulation in approximately 70% of affected men. A nutraceutical, namely, α-lipoic acid (α-LA), is known for its potent anti-cancer properties towards various cancers and has been implicated in treating and promoting bone health. Our study aimed to explore the molecular mechanism behind the role of α-LA as therapeutics in preventing PCa and its associated bone modulation. Notably, α-LA treatment significantly reduced the cell viability, migration, and invasion of PCa cell lines in a dose-dependent manner. In addition, α-LA supplementation dramatically increased reactive oxygen species (ROS) levels and HIF-1α expression, which started the downstream molecular cascade and activated JNK/caspase-3 signaling pathway. Flow cytometry data revealed the arrest of the cell cycle in the S-phase, which has led to apoptosis of PCa cells. Furthermore, the results of ALP (Alkaline phosphatase) and TRAP (tartrate-resistant acid phosphatase) staining signifies that α-LA supplementation diminished the PCa-mediated differentiation of osteoblasts and osteoclasts, respectively, in the MC3T3-E1 and bone marrow macrophages (BMMs) cells. In summary, α-LA supplementation enhanced cellular apoptosis via increased ROS levels, HIF-1α expression, and JNK/caspase-3 signaling pathway in advanced human PCa cell lines. Also, the treatment of α-LA improved bone health by reducing PCa-mediated bone cell modulation.

Risk-adjusted analysis of patients undergoing emergency laparotomy using POSSUM and P-POSSUM score: a prospective study

Background: Comparison of operative morbidity rates after emergency laparotomy between units may be misleading because it does not take into account the physiological variables of patients' conditions. Surgical risk scores have been created, and the most commonly used is the Physiological and Operative Severity Score for the enumeration of Mortality (POSSUM) or one of its modifications, the Portsmouth-POSSUM (P-POSSUM), usually requires intraoperative information. Objective: The objective of this study is to evaluate the POSSUM and P-POSSUM scores in predicting postoperative morbidity and mortality in patients undergoing emergency laparotomy. Methodology: This is a prospective, cross-sectional, and hospital-based study that was conducted at J.L.N. Medical College and Hospital, Ajmer, Rajasthan, India, from April 2017 to December 2017. Adult patients who presented at the causality and underwent emergency laparotomy were included in the study. Observed and predicted mortality and morbidity were calculated using POSSUM and P-POSSUM equations, and statistical significance was calculated using Chi-square test. Results: A total of 100 patients were included in this study, with a mean age of 42.83 ± 18.21 years. The observed (O) mortality was 12 (12.0%), while POSSUM predicted 40 (40%) and P-POSSUM 27 (27%). The O/E ratio for POSSUM was 0.29 and for P-POSSUM was 0.44, and this means that they both overestimate mortality. When the results were tested by Chi-square test, the P value was found to be 0.55 and 0.85 for POSSUM and P-POSSUM, respectively, which showed no significant correlation for observed and expected mortality. The observed morbidity was 69 (69%), while POSSUM expected morbidity was 79 (79%), O/E ratio is 0.87, and this again overestimates the morbidity. POSSUM is overpredicting the rate of morbidity, and test of correlation showed no significance with P = 0.75. Conclusion: POSSUM and P-POSSUM were found to overestimate mortality and morbidity in our patient's population