Emerging molecules, tools, technology, and future of surgical knife in gastroenterology.

The 21st century has started with several innovations in the medical sciences, with wide applications in health care management. This development has taken in the field of medicines (newer drugs/molecules), various tools and technology which has completely changed the patient management including abdominal surgery. Surgery for abdominal diseases has moved from maximally invasive to minimally invasive (laparoscopic and robotic) surgery. Some of the newer medicines have its impact on need for surgical intervention. This article focuses on the development of these emerging molecules, tools, and technology and their impact on present surgical form and its future effects on the surgical intervention in gastroenterological diseases.

Synthesis and in silico inhibitory action studies of azo-anchored imidazo[4,5-b]indole scaffolds against the COVID-19 main protease (Mpro).

The present work elicits a novel approach to combating COVID-19 by synthesizing a series of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives. The envisaged methodology involves the L-proline-catalyzed condensation of para-amino-functionalized azo benzene, indoline-2,3-dione, and ammonium acetate precursors with pertinent aryl aldehyde derivatives under ultrasonic conditions. The structures of synthesized compounds were corroborated through FT-IR, 1H NMR, 13C NMR, and mass analysis data. Molecular docking studies assessed the inhibitory potential of these compounds against the main protease (Mpro) of SARS-CoV-2. Remarkably, in silico investigations revealed significant inhibitory action surpassing standard drugs such as Remdesivir, Paxlovid, Molnupiravir, Chloroquine, Hydroxychloroquine (HCQ), and (N3), an irreversible Michael acceptor inhibitor. Furthermore, the highly active compound was also screened for cytotoxicity activity against HEK-293 cells and exhibited minimal toxicity across a range of concentrations, affirming its favorable safety profile and potential suitability. The pharmacokinetic properties (ADME) of the synthesized compounds have also been deliberated. This study paves the way for in vitro and in vivo testing of these scaffolds in the ongoing battle against SARS-CoV-2.

Heavy metal association with chronic kidney disease of unknown cause in central India-results from a case-control study.

BACKGROUND: Chronic Kidney Disease of unknown cause (CKDu) a disease of exclusion, and remains unexplained in various parts of the world, including India. Previous studies have reported mixed findings about the role of heavy metals or agrochemicals in CKDu. These studies compared CKDu with healthy controls but lacked subjects with CKD as controls. The purpose of this study was to test the hypothesis whether heavy metals, i.e. Arsenic (As), Cadmium (Cd), Lead (Pb), and Chromium (Cr) are associated with CKDu, in central India. METHODS: The study was conducted in a case-control manner at a tertiary care hospital. CKDu cases (n = 60) were compared with CKD (n = 62) and healthy subjects (n = 54). Blood and urine levels of As, Cd, Pb, and Cr were measured by Inductively Coupled Plasma- Optical Emission Spectrometry. Pesticide use, painkillers, smoking, and alcohol addiction were also evaluated. The median blood and urine metal levels were compared among the groups by the Kruskal-Wallis rank sum test. RESULTS: CKDu had significantly higher pesticide and surface water usage as a source of drinking water. Blood As levels (median, IQR) were significantly higher in CKDu 91.97 (1.3-132.7) µg/L compared to CKD 4.5 (0.0-58.8) µg/L and healthy subjects 39.01 (4.8-67.4) µg/L (p < 0.001) On multinominal regression age and sex adjusted blood As was independently associated with CKDu[ OR 1.013 (95%CI 1.003-1.024) P < .05].Blood and urinary Cd, Pb, and Cr were higher in CKD compared to CKDu (p > .05). Urinary Cd, Pb and Cr were undetectable in healthy subjects and were significantly higher in CKDu and CKD compared to healthy subjects (P = < 0.001). There was a significant correlation of Cd, Pb and Cr in blood and urine with each other in CKDu and CKD subjects as compared to healthy subjects. Surface water use also associated with CKDu [OR 3.178 (95%CI 1.029-9.818) p < .05). CONCLUSION: The study showed an independent association of age and sex adjusted blood As with CKDu in this Indian cohort. Subjects with renal dysfunction (CKDu and CKD) were found to have significantly higher metal burden of Pb, Cd, As, and Cr as compared to healthy controls. CKDu subjects had significantly higher pesticide and surface water usage, which may be the source of differential As exposure in these subjects.

Comparison of propofol and desflurane for postoperative neurocognitive function in patients with aneurysmal subarachnoid hemorrhage: A prospective randomized trial.

Background: Following aneurysmal subarachnoid hemorrhage, 40-50% of survivors experience cognitive dysfunction, which affects their quality of life. Anesthetic agents play a pivotal role in aneurysm surgeries. However, substantial evidence regarding their effects on neurocognitive function is lacking. This study evaluated the effects of propofol and desflurane on postoperative neurocognitive function and serum S-100B levels. Methods: One hundred patients were equally randomized to receive either propofol (Group P) or desflurane (Group D). Cognitive function was assessed using the Montreal Cognitive Assessment scale at three different time points: Preoperatively, at the time of discharge, and one month after surgery. Perioperative serum levels of S-100B were also measured. Results: The preoperative mean cognitive score in Group P was 21.64 + 4.46 and in Group D was 21.66 + 4.07 (P = 0.79). At discharge, a significant decrease in cognitive scores was observed compared to preoperative scores (Group P- 20.91 + 3.94, P = 0.03 and Group D-19.28 + 4.22, P = 0.00); however, scores were comparable between the two groups (P = 0.09). One month following surgery, mean cognitive scores were 22.63 + 3.57 in Group P and 20.74 + 3.89 in Group D, and the difference was significant (P = 0.04). Higher memory and orientation scores were observed in Group P than in Group D at one month (P < 0.05) in the subgroup analysis. Both groups had similar serum S-100B levels. Conclusion: The mean cognitive scores one month after surgery improved significantly with propofol compared with desflurane, but without clinical significance. Individual domain analysis demonstrated that orientation and memory scores were better preserved with propofol.

Caudal duplication syndrome: A rare entity.

The rare caudal duplication syn drome is a spectrum of anomalie s primarily involving par tial or compl ete dupl ication of organ s comp risin g the gastro intest ina l, genitourinary and distal neu ral tube system s. These findings are considered to be a result of aberrant embryogenesis. We hereby report a case of an adult female with comple te duplicat ion o f the genital and ur inary systems (ureth ra and bladder), hindgut a nd lower end of vertebral col umn with no functional impairment. She presented in her first pregnancy at 36 weeks gestation, in labo ur. To the author's knowle dge this is the first case of caudal duplication syn drom e with pregnanc y fro m Pakistan.

A Multistep In Silico Approach Identifies Potential Glioblastoma Drug Candidates via Inclusive Molecular Targeting of Glioblastoma Stem Cells.

Glioblastoma (GBM) is the highest grade of glioma for which no effective therapy is currently available. Despite extensive research in diagnosis and therapy, there has been no significant improvement in GBM outcomes, with a median overall survival continuing at a dismal 15-18 months. In recent times, glioblastoma stem cells (GSCs) have been identified as crucial drivers of treatment resistance and tumor recurrence, and GBM therapies targeting GSCs are expected to improve patient outcomes. We used a multistep in silico screening strategy to identify repurposed candidate drugs against selected therapeutic molecular targets in GBM with potential to concomitantly target GSCs. Common differentially expressed genes (DEGs) were identified through analysis of multiple GBM and GSC datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). For identification of target genes, we selected the genes with most significant effect on overall patient survival. The relative mRNA and protein expression of the selected genes in TCGA control versus GBM samples was also validated and their cancer dependency scores were assessed. Drugs targeting these genes and their corresponding proteins were identified from LINCS database using Connectivity Map (CMap) portal and by in silico molecular docking against each individual target using FDA-approved drug library from the DrugBank database, respectively. The molecules thus obtained were further evaluated for their ability to cross blood brain barrier (BBB) and their likelihood of resulting in drug resistance by acting as p-glycoprotein (p-Gp) substrates. The growth inhibitory effect of these final shortlisted compounds was examined on a panel of GBM cell lines and compared with temozolomide through the drug sensitivity EC50 values and AUC from the PRISM Repurposing Secondary Screen, and the IC50 values were obtained from GDSC portal. We identified RPA3, PSMA2, PSMC2, BLVRA, and HUS1 as molecular targets in GBM including GSCs with significant impact on patient survival. Our results show GSK-2126458/omipalisib, linifanib, drospirenone, eltrombopag, nilotinib, and PD198306 as candidate drugs which can be further evaluated for their anti-tumor potential against GBM. Through this work, we identified repurposed candidate therapeutics against GBM utilizing a GSC inclusive targeting approach, which demonstrated high in vitro efficacy and can prospectively evade drug resistance. These drugs have the potential to be developed as individual or combination therapy to improve GBM outcomes.

Psychometric evaluation of the Chinese version of the burnout syndrome assessment scale in nurses.

Objective: This study aimed to translate the Burnout Syndrome Assessment Scale (BOSAS) into Chinese and validate its reliability and validity among Chinese emergency department and ICU nurses. Methods: The scale was translated into Chinese using Brislin's translation principle. A total of 626 nurses from Jiangxi, Zhejiang, and Fujian provinces in China participated in an online questionnaire survey. The survey included the general information questionnaire for nurses developed by the research team and the Chinese version of the Burnout Syndrome Assessment Scale. Reliability and validity of the Chinese version of the scale were analyzed using SPSS.25 and AMOS.24 software. Results: The Chinese version of the Burnout Syndrome Assessment Scale consists of a total of 20 items, encompassing two dimensions: personal burnout and job burnout. This structure is consistent with the original English version of the scale. The Chinese version of BOSAS demonstrated high internal consistency, with a Cronbach's α coefficient of 0.941. Additionally, the scale exhibited good split-half reliability (0.765) and test-retest reliability (0.871). The content validity index (S-CVI) was 0.971, indicating strong content validity. Exploratory factor analysis confirmed the same 2-factor structure as the original scale, and confirmatory factor analysis further validated this structure, with all fit indices indicating appropriateness. Conclusion: The Burnout Syndrome Assessment Scale has been successfully introduced and its reliability and validity have been verified in Chinese emergency department and ICU nurses.

Unconventional Activation of IRE1 Enhances TH17 Responses and Promotes Airway Neutrophilia.

Heightened unfolded protein responses (UPRs) are associated with the risk for asthma, including severe asthma. Treatment-refractory severe asthma manifests a neutrophilic phenotype with TH17 responses. However, how UPRs participate in the deregulation of TH17 cells leading to neutrophilic asthma remains elusive. This study found that the UPR sensor IRE1 is induced in the murine lung with fungal asthma and is highly expressed in TH17 cells relative to naïve CD4+ T cells. Cytokine (e.g. IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by both human and mouse TH17 cells. Ern1 (encoding IRE1)-deficiency decreases the expression of ER stress factors and impairs the differentiation and cytokine secretion of TH17 cells. Genetic ablation of Ern1 leads to alleviated TH17 responses and airway neutrophilia in a fungal airway inflammation model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances TH17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPR-mediated secretory function of TH17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in TH17-biased TH2-low asthma.

Lipophilic bioactive compounds from thermophilic cyanobacterium Leptolyngbya sp. HNBGU-004: Implications for countering VRSA resistance.

Extremophiles thrive in extreme conditions, showcasing rich and unexplored diversity. This resilience hints at the existence of novel biochemical pathways and unique bioactive compounds. In contrast, the issue of drug resistance and excessive misuse of antibiotics in various settings, such as healthcare, agriculture, and veterinary medicine, has contributed to the emergence and spread of drug-resistant microorganisms. In the present research, Leptolyngbya sp. HNBGU-004, was obtained from an extreme location, a hot water spring in the Garhwal Himalayan region of India. The lipophilic fraction derived from Leptolyngbya sp. HNBGU-004 exhibited significant inhibitory effects against vancomycin-resistant Staphylococcus aureus (VRSA), displaying a bactericidal concentration of 0.5 mg mL-1. Furthermore, gas chromatography-mass spectrometry (GC-MS) analysis of the lipophilic extract unveiled the major constituents. Leptolyngbya sp. HNBGU-004 holds significant promise as a primary source of potent anti-vancomycin-resistant S. aureus components. These findings emphasize the importance of Leptolyngbya sp. HNBGU-004 as a foundational source for use as both a synergistic and alternative agent against VRSA.

Catalytic synergy of WS2-anchored PdSe2 for highly sensitive hydrogen gas sensor.

Hydrogen (H2) is widely used in industrial processes and is one of the well-known choices for storage of renewable energy. H2 detection has become crucial for safety in manufacturing, storage, and transportation due to its strong explosivity. To overcome the issue of explosion, there is a need for highly selective and sensitive H2 sensors that can function at low temperatures. In this research, we have adequately fabricated an unreported van der Waals (vdWs) PdSe2/WS2 heterostructure, which exhibits exceptional properties as a H2 sensor. The formation of these heterostructure devices involves the direct selenization process using chemical vapor deposition (CVD) of Pd films that have been deposited on the substrate of SiO2/Si by DC sputtering, followed by drop casting of WS2 nanoparticles prepared by a hydrothermal method onto device substrates including pre-patterned electrodes. The confirmation of the heterostructure has been done through the utilization of powder X-ray diffraction (XRD), depth-dependent X-ray photoelectron spectroscopy (XPS) and field-emission scanning electron microscopy (FE-SEM) techniques. Also, the average roughness of thin films is decided by Atomic Force Microscopy (AFM). The comprehensive research shows that the PdSe2/WS2 heterostructure-based sensor produces a response that is equivalent to 67.4% towards 50 ppm H2 at 100 °C. The response could be a result of the heterostructure effect and the superior selectivity for H2 gas in contrast to other gases, including NO2, CH4, CO and CO2, suggesting tremendous potential for H2 detection. Significantly, the sensor exhibits fast response and a recovery time of 31.5 s and 136.6 s, respectively. Moreover, the explanation of the improvement in gas sensitivity was suggested by exploiting the energy band positioning of the PdSe2/WS2 heterostructure, along with a detailed study of variations in the surface potential. This study has the potential to provide a road map for the advancement of gas sensors utilizing two-dimensional (2D) vdWs heterostructures, which exhibit superior performance at low temperatures.

Specific connectivity optimizes learning in thalamocortical loops.

Thalamocortical loops have a central role in cognition and motor control, but precisely how they contribute to these processes is unclear. Recent studies showing evidence of plasticity in thalamocortical synapses indicate a role for the thalamus in shaping cortical dynamics through learning. Since signals undergo a compression from the cortex to the thalamus, we hypothesized that the computational role of the thalamus depends critically on the structure of corticothalamic connectivity. To test this, we identified the optimal corticothalamic structure that promotes biologically plausible learning in thalamocortical synapses. We found that corticothalamic projections specialized to communicate an efference copy of the cortical output benefit motor control, while communicating the modes of highest variance is optimal for working memory tasks. We analyzed neural recordings from mice performing grasping and delayed discrimination tasks and found corticothalamic communication consistent with these predictions. These results suggest that the thalamus orchestrates cortical dynamics in a functionally precise manner through structured connectivity.

Isolation, Characterization, and Expression Analysis of NAC Transcription Factor from Andrographis paniculata (Burm. f.) Nees and Their Role in Andrographolide Production.

Andrographis paniculata (Burm. f.) Nees is an important medicinal plant known for its bioactive compound andrographolide. NAC transcription factors (NAM, ATAF1/2, and CUC2) play a crucial role in secondary metabolite production, stress responses, and plant development through hormonal signaling. In this study, a putative partial transcript of three NAC family genes (ApNAC83, ApNAC21 22 and ApNAC02) was used to isolate full length genes using RACE. Bioinformatics analyses such as protein structure prediction, cis-acting regulatory elements, and gene ontology analysis were performed. Based on in silico predictions, the diterpenoid profiling of the plant's leaves (five-week-old) and the real-time PCR-based expression analysis of isolated NAC genes under abscisic acid (ABA) treatment were performed. Additionally, the expression analysis of isolated NAC genes under MeJA treatment and transient expression in Nicotiana tabacum was performed. Full-length sequences of three members of the NAC transcription factor family, ApNAC83 (1102 bp), ApNAC21 22 (996 bp), and ApNAC02 (1011 bp), were isolated and subjected to the promoter and gene ontology analysis, which indicated their role in transcriptional regulation, DNA binding, ABA-activated signaling, and stress management. It was observed that ABA treatment leads to a higher accumulation of andrographolide and 14-deoxyandrographolide content, along with the upregulation of ApNAC02 (9.6-fold) and the downregulation of ApNAC83 and ApNAC21 22 in the leaves. With methyl jasmonate treatment, ApNAC21 22 expression decreased, while ApNAC02 increased (1.9-fold), with no significant change being observed in ApNAC83. The transient expression of the isolated NAC genes in a heterologous system (Nicotiana benthamiana) demonstrated their functional transcriptional activity, leading to the upregulation of the NtHMGR gene, which is related to the terpene pathway in tobacco. The expression analysis and heterologous expression of ApNAC21 22 and ApNAC02 indicated their role in andrographolide biosynthesis.

Xanthan gum-capped Chromia Nanoparticles (XG-CrNPs): A promising nanoprobe for the detection of heavy metal ions.

The present study reports on the selective and sensitive detection of metals using xanthan gum-capped chromia nanoparticles (XG-CrNPs). The nanoparticles were synthesized by the chemical reduction method using sodium borohydride and xanthan gum as the reducing and capping agents, respectively. The synthesis of XG-CrNPs was confirmed by the appearance of the two absorption peaks at 272 nm and 371 nm in the UV-visible region. The nanoparticles have been extensively characterized by FTIR, TEM-EDX, XRD, and TGA analyses. The well-dispersed XG-CrNPs exhibited a quasi-spherical structure with an average particle size of 3 nm. A significantly low amount (2 µg/L) of XG-CrNPs was used for selective and sensitive detection of heavy metal ions. It showed excellent metal detecting properties by quenching its band gap signal which was extraordinarily conspicuous for Co(II), Hg(II), and Cd(II) in comparison to other metal ions like Ag(I), Ba(II), Mg(II), Mn(II), Ni(II), and Zn(II). The limit of detection of Co(II), Cd(II), and Hg(II) with this nanoprobe was found to be 2.167 µM, 1.065 µM, and 0.601 µM respectively. The nanoparticles manifested higher shelf-life and can be reused up to three consecutive cycles where most of its activity was conserved even after being used. Thus, it may find use in metal sensor devices for the detection of hazardous metals.

Proteomic and metabolomic insights into seed germination of Ferula assa-foetida.

Cold stratification is known to affect the speed of seed germination; however, its regulation at the molecular level in Ferula assa-foetida remains ambiguous. Here, we used cold stratification (4 °C in the dark) to induce germination in F. assa-foetida and adopted a proteomic and metabolomic approach to understand the molecular mechanism of germination. Compared to the control, we identified 209 non-redundant proteins and 96 metabolites in germinated F. assa-foetida seed. Results highlight the common and unique regulatory mechanisms like signaling cascade, reactivation of energy metabolism, activation of ROS scavenging system, DNA repair, gene expression cascade, cytoskeleton, and cell wall modulation in F. assa-foetida germination. A protein-protein interaction network identifies 18 hub protein species central to the interactome and could be a key player in F. assa-foetida germination. Further, the predominant metabolic pathways like glucosinolate biosynthesis, arginine and proline metabolism, cysteine and methionine metabolism, aminoacyl-tRNA biosynthesis, and carotenoid biosynthesis in germinating seed may indicate the regulation of carbon and nitrogen metabolism is prime essential to maintain the physiology of germinating seedlings. The findings of this study provide a better understanding of cold stratification-induced seed germination, which might be utilized for genetic modification and traditional breeding of Ferula assa-foetida. SIGNIFICANCE: Seed germination is the fundamental checkpoint for plant growth and development, which has ecological significance. Ferula assa-foetida L., commonly known as "asafoetida," is a medicinal and food crop with huge therapeutic potential. To date, our understanding of F. assa-foetida seed germination is rudimentary. Therefore, studying the molecular mechanism that governs dormancy decay and the onset of germination in F. assa-foetida is essential for understanding the basic principle of seed germination, which could offer to improve genetic modification and traditional breeding.

Post Cholecystectomy Bile Duct Injury in an Acute Setting: Categorization, Triaging, and Management Algorithm.

Background Postcholecystectomy bile duct injury (BDI) is a management challenge with significant morbidity, mortality, and effects on long-term quality of life. Early referral to a specialized hepatobiliary center and appropriate early management are crucial to improving outcomes and overall quality of life. In this retrospective analysis, we examined patients who were managed at our center over the past 10 years and proposed a triage and management algorithm for BDI in acute settings. Methods Patients referred to our center with BDI from January 2011 to December 2020 were reviewed retrospectively. The primary objective of initial management is to control sepsis and minimize BDI-related morbidity and mortality. All the patients were resuscitated with intravenous fluid, antibiotics (preferably culture-based), correction of electrolyte deficiencies, and organ support if required. A triage module and management algorithm were framed based on our experience. All the patients were triaged based on the presence or absence of bile leaks. Each group was further subdivided into red, yellow, and green zones (depending on the presence of sepsis, organ failure, and associated injuries), and the results were analyzed as per the proposed algorithm. Results One hundred twenty-eight patients with acute BDI were referred to us during the study period, and 116 patients had BDI with a bile leak and 12 patients were without a bile leak. Out of bile leak patients, 106 patients (91.38%) had sepsis with or without organ failure (red and yellow zone) and required invasive intervention in the form of PCD insertion (n=99, 85.34%) and/or laparotomy, lavage, and drainage (n=7, 6.03%). Another 10 patients (8.62%) had controlled external biliary fistula (green zone), of which four were managed with antibiotics, four underwent endoscopic retrograde cholangiopancreatography stenting, and only two (1.7%) patients could undergo Roux-en-Y hepaticojejunostomy upfront due to late referral. Among patients with BDI without bile leaks, nine (75%) had cholangitis (red and yellow zones). Out of these, five required PTBD along with antibiotics and four were managed with antibiotics alone. Only three (25%) patients in this group could undergo definitive repair without any restriction on the timing of referral and were sepsis-free at presentation (green zone). A total of nine patients had a vascular injury, and four of them required digital subtraction angiography and coil embolization. There were three (2.34%) mortalities; all were in the red zone of rest and had successful initial management. In total, five patients were managed with early repair in the acute setting, and the rest underwent definitive intervention at subsequent admissions after being converted to green zone patients with initial management. Conclusion The presented categorization, triaging, and management algorithm provides optimum insight to understand the severity, simplify these complex scenarios, expedite the decision-making process, and thus enhance patient outcomes in early acute settings following BDI.

A Crosstalk between the Receptor Tyrosine Kinase-Like Orphan Receptors ROR1/2 and S1P Signaling Pathways in Lung Cancer.

OBJECTIVE: Availability of multimodal treatment strategies, including targeted therapies and immunotherapies, have improved the survival of non-small cell lung carcinoma (NSCLC). However, some patients still progress or respond poorly due to inherent resistance, acquired resistance, or lack of druggable driver mutations. Sphingosine-1-phosphate (S1P) and receptor tyrosine kinase-like orphan receptor (ROR1/2) signaling pathways are activated during lung carcinogenesis. METHODS: In this study, we have evaluated the crosstalk of S1P and ROR1/2 signaling pathways in lung cancer cells. RESULTS: S1P treatment of lung cancer cells decreases ROR1 and ROR2 transcript levels. While treatment with PF-543, a pharmacological SphK1 inhibitor or genetic knockdown of SPHK1 by shRNA, raises ROR1 and ROR2. Furthermore, simultaneous inhibition of SphK1 along with ROR1 reduced the migration of lung cancer cells. CONCLUSION: These findings demonstrate the reciprocal regulation of both pathways, suggesting that both pathways have an inverse relation i.e, in the absence of one pathway, another pathway may take charge of the other pathway. Therefore, simultaneously targeting both pathways could serve as a potential therapeutic target for lung cancer treatment.

ER stress and ERO1: Potential therapeutic targets for inherited myopathies.

Selenoprotein N-related myopathy (SEPN1-RM) is a genetic disease that causes muscle weakness and respiratory failure. Germani et al.1 demonstrate that diaphragm weakness in SEPN1-RM is prevented by the inhibition of ER stress or ERO1 oxidoreductase regulated by transcription factor CHOP.

Regulation of metastatic potential by drug repurposing and mitochondrial targeting in colorectal cancer cells.

BACKGROUND: Increased mitochondrial activities contributing to cancer cell proliferation, invasion, and metastasis have been reported in different cancers; however, studies on the therapeutic targeting of mitochondria in regulating cell proliferation and invasiveness are limited. Because mitochondria are believed to have evolved through bacterial invasion in mammalian cells, antibiotics could provide an alternative approach to target mitochondria, especially in cancers with increased mitochondrial activities. In this study, we investigated the therapeutic potential of bacteriostatic antibiotics in regulating the growth potential of colorectal cancer (CRC) cells, which differ in their metastatic potential and mitochondrial functions. METHODS: A combination of viability, cell migration, and spheroid formation assays was used to measure the effect on metastatic potential. The effect on mitochondrial mechanisms was investigated by measuring mitochondrial DNA copy number by qPCR, biogenesis (by qPCR and immunoblotting), and functions by measuring reactive oxygen species, membrane potential, and ATP using standard methods. In addition, the effect on assembly and activities of respiratory chain (RC) complexes was determined using blue native gel electrophoresis and in-gel assays, respectively). Changes in metastatic and cell death signaling were measured by immunoblotting with specific marker proteins and compared between CRC cells. RESULTS: Both tigecycline and tetracycline effectively reduced the viability, migration, and spheroid-forming capacity of highly metastatic CRC cells. This increased sensitivity was attributed to reduced mtDNA content, mitochondrial biogenesis, ATP content, membrane potential, and increased oxidative stress. Specifically, complex I assembly and activity were significantly inhibited by these antibiotics in high-metastatic cells. Significant down-regulation in the expression of mitochondrial-mediated survival pathways, such as phospho-AKT, cMYC, phospho-SRC, and phospho-FAK, and upregulation in cell death (apoptosis and autophagy) were observed, which contributed to the enhanced sensitivity of highly metastatic CRC cells toward these antibiotics. In addition, the combined treatment of the CRC chemotherapeutic agent oxaliplatin with tigecycline/tetracycline at physiological concentrations effectively sensitized these cells at early time points. CONCLUSION: Altogether, our study reports that bacterial antibiotics, such as tigecycline and tetracycline, target mitochondrial functions specifically mitochondrial complex I architecture and activity and would be useful in combination with cancer chemotherapeutics for high metastatic conditions.

Promises of Protein Kinase Inhibitors in Recalcitrant Small-Cell Lung Cancer: Recent Scenario and Future Possibilities.

SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is a significant need to understand the roles of kinases in regulating therapeutic responses, acknowledge the existing knowledge gaps, and discuss future directions for improved therapeutics for recalcitrant SCLC. Here, we extensively review the effect of dysregulated kinases in SCLC. We further discuss the pharmacological inhibitors of kinases used in targeted therapies for recalcitrant SCLC. We also describe the role of kinases in the ICI-mediated activation of antitumor immune responses. Finally, we summarize the clinical trials evaluating the potential of kinase inhibitors and ICIs. This review overviews dysregulated kinases in SCLC and summarizes their potential as targeted therapeutic agents. We also discuss their clinical efficacy in enhancing anticancer responses mediated by ICIs.