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Background: Respiratory Syncytial Virus (RSV) presents a significant health threat, especially to young children. In-depth understanding of RSV entry mechanisms is essential for effective antiviral development. This study introduces an innovative RSV variant, featuring the fusion of the beta-lactamase (BlaM) enzyme with the RSV-P phosphoprotein, providing a versatile tool for dissecting viral entry dynamics. Methods: Using the AlphaFold2 algorithm, we modeled the tertiary structure of the P-BlaM chimera, revealing structural similarities with both RSV-P and BlaM. Functional assessments, utilizing flow cytometry, quantified beta-lactamase activity and GFP expression in infected bronchial epithelial cells. Western blot analysis confirmed the integrity of P-BlaM within virions. Results: The modeled P-BlaM chimera exhibited structural parallels with RSV-P and BlaM. Functional assays demonstrated robust beta-lactamase activity in recombinant virions, confirming successful P-BlaM incorporation as a structural protein. Quercetin, known for its antiviral properties, impeded viral entry by affecting virion fusion. Additionally, Ulixertinib, an ERK-1/2 inhibitor, significantly curtailed viral entry, implicating ERK-1/2 pathway signaling. Conclusions: Our engineered RSV-P-BlaM chimera emerges as a valuable tool, illuminating RSV entry mechanisms. Structural and functional analyses unveil potential therapeutic targets. Quercetin and Ulixertinib, identified as distinct stage inhibitors, show promise for targeted antiviral strategies. Time-of-addition assays pinpoint quercetin's specific interference stage, advancing our comprehension of RSV entry and guiding future antiviral developments.

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Sepsis, a life-threatening condition arising from infection, often results in multi-organ failure, including cardiac dysfunction. This study investigated Xanthohumol, a natural compound, and its potential mechanism of action to enhance heart function following sepsis. A total of twenty-four adult male Swiss albino mice were allocated randomly to one of four equal groups (n=6): sham, CLP, vehicle Xanthohumol the same amount of DMSO injected IP 10 minutes before the CLP, and Xanthohumol group (0.4 mg/kg of Xanthohumol administered IP before the CLP process). Toll-like receptor 4, pro-inflammatory mediators, anti-inflammatory markers, oxidative stress indicators, apoptosis markers, and serum cardiac damage biomarkers were measured in the cardiac tissue using ELISA. Data with normal distribution were analyzed using t-test and ANOVA tests (p<0.05). In comparison to the sham group, the sepsis group had significantly higher levels of TLR-4, IL-6, TNF-α, MIF, F2-isoprostane, caspase-3, cTn-I, and CK-MB, while the pre-treated group with Xanthohumol had significantly lower levels (p<0.05) of these markers than the sepsis group. Bcl-2 showed no significant difference in Xanthohumol pre-treated group relative to the sepsis group, while IL-10 was significantly elevated. Xanthohumol dramatically reduced cardiac tissue injury (p<0.05) relative to the CLP group. By blocking the downstream signal transduction pathways of TLR-4 and NF-kB, Xanthohumol was shown to lessen cardiac damage in male mice during CLP-induced polymicrobial sepsis.

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As sepsis is associated with a 50% increase in mortality, sepsis-induced cardiomyopathy has become a critical topic. A multidisciplinary approach is required for the diagnosis and treatment of septic cardiomyopathy. This study looked at Sulforaphane, a natural product that aims to evaluate cardiac function after sepsis, and its likely mechanism of action. Twenty-four adult male Swiss albino mice were randomly divided into 4 equal groups (n=6): sham, CLP, vehicle Sulforaphane (the same amount of DMSO injected IP one hour before the CLP), and Sulforaphane group (one hour before the CLP, a 5mg/kg dose of Sulforaphane was injected). Cardiac tissue levels of toll-like receptor 4 (TLR-4), pro-inflammatory mediators, anti-inflammatory markers, oxidative stress markers, apoptosis markers, and serum cardiac damage biomarkers were assessed using ELISA. Statistical analyses, including t-tests and ANOVA tests, were performed with a significance level of 0.05 for normally distributed data. Compared to the sham group, the sepsis group had significantly elevated levels of TLR-4, IL-6, TNF-α, MIF, F2-isoprostane, caspase-3, cTn-I, and CK-MB (p<0.05). In contrast, the Sulforaphane pre-treated group demonstrated significantly lower levels of these markers (p<0.05). Additionally, Bcl-2 levels were significantly reduced (p<0.05) in the Sulforaphane group. Sulforaphane administration also significantly attenuated cardiac tissue injury (p<0.05). The findings suggest that Sulforaphane can decrease heart damage in male mice during CLP-induced polymicrobial sepsis by suppressing TLR-4/NF-kB downstream signal transduction pathways.

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Sphingosine 1-phosphate (S1P) is one of the lipid mediators involved in diverse physiological functions. S1P circulates in blood and lymph bound to carrier proteins. Three S1P carrier proteins have been reported, albumin, apolipoprotein M (ApoM) and apolipoprotein A4 (ApoA4). The carrier-bound S1P exerts its functions via specific S1P receptors (S1PR1-5) on target cells. Previous studies showed several differences in physiological functions between albumin-bound S1P and ApoM-bound S1P. However, molecular mechanisms underlying the carrier-dependent differences have not been clarified. In addition, ApoA4 is a recently identified S1P carrier protein, and its functional differences from albumin and ApoM have not been addressed. Here, we compared the three carrier proteins in the processes of S1P degradation, release from S1P-producing cells and receptor activation. ApoM retained S1P more stable than albumin and ApoA4 in the cell culture medium when compared in the equimolar amounts. ApoM facilitated theS1P release from endothelial cells most efficiently. Furthermore, ApoM-bound S1P showed a tendency to induce prolonged activation of Akt via S1PR1 and S1PR3. These results suggest that the carrier-dependent functional differences of S1P are partly ascribed to the differences in the S1P stability, S1P-releasing efficiency and signaling duration.

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Mechanistic target of rapamycin complex 1 (mTORC1) is a serine-threonine kinase that is activated by extracellular signals, such as nutrients and growth factors. It plays a key role in the control of various biological processes, such as protein synthesis and energy metabolism by mediating or regulating the phosphorylation of multiple target molecules, some of which remain to be identified. We have here reanalysed a large-scale phosphoproteomics data set for mTORC1 target molecules and identified pre-B cell leukemia transcription factor 2 (PBX2) as such a novel target that is dephosphorylated downstream of mTORC1. We confirmed that PBX2, but not other members of the PBX family, is dephosphorylated in an mTORC1 activity-dependent manner. Furthermore, pharmacological and gene knockdown experiments revealed that glycogen synthase kinase 3 (GSK3) and protein phosphatase 1 (PP1) are responsible for the phosphorylation and dephosphorylation of PBX2, respectively. Our results thus suggest that the balance between the antagonistic actions of GSK3 and PP1 determines the phosphorylation status of PBX2 and its regulation by mTORC1.

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The Nudt family has been identified as enzymes performing Coenzyme A to 3'5'-ADP + 4'-phospho pantetheine catalysis. The members of this family have been shown to be particularly involved in lipid metabolism, while their involvement in gene regulation through regulating transcription or mRNA metabolism has also been suggested. Here, we focused on peroxisomal NUDT7, possessing enzymatic activity similar to that of its paralog, peroxisomal NUDT19, which is involved in mRNA degradation. No reports have been published about the Nudt family in zebrafish. Our transcriptomic data showed that the Nudt family members are highly expressed around zygotic gene activation (ZGA) in developing zebrafish embryos. Therefore, we confirmed the computational prediction that the products of the nudt7 gene in zebrafish were localized in the peroxisome and highly expressed in early embryogenesis. The depletion of nudt7 genes by the CRISPR/Cas9 system did not affect development; however, it decreased the rate of transcription in ZGA. In addition, H3K27ac ChIP-seq analysis demonstrated that this decrease in transcription was correlated with the genome-wide decrease of H3K27ac level. This study suggests that peroxisomal Nudt7 functions in regulating transcription in ZGA via formation of the H3K27ac domain in active chromatin.

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The active hormonal form of vitamin D, 1α,25-dihydroxyvitamin D3, is reported to have 1000s of biological targets. The growth-suppressive properties of 1α,25-dihydroxyvitamin D3 and its synthetic analogs have attracted interest for the development of treatment and/or prevention of cancer. We examined effects of 1α,25-dihydroxyvitamin D3 and the vitamin D analog tacalcitol on signaling pathways and anchorage-independent growth in T98G and U251 glioblastoma cells. Assay of signaling proteins important for cellular growth indicated suppression of p70-S6 kinase levels by 1α,25-dihydroxyvitamin D3 and tacalcitol in T98G cells, whereas the levels of PLCγ, a target for phospholipid signaling, was slightly increased. Activation of STAT3, an important regulator of malignancy, was suppressed by 1α,25-dihydroxyvitamin D3 and tacalcitol in T98G and U251 cells. However, despite the close structural similarity of these compounds, suppression was stronger by tacalcitol (1α,24-dihydroxyvitamin D3), indicating that even minor modifications of a vitamin D analog can impact its effects on signaling. Experiments using soft agar colony formation assay in T98G and U251 cells revealed significant suppression by 1α,25-dihydroxyvitamin D3 and tacalcitol on anchorage-independent growth, a property for cancer invasion and metastasis known to correlate with tumorigenicity. These findings indicate that vitamin D and its analogs may be able to counteract the oncogenic transformation, invasion and metastatic potential of glioblastoma and prompt further study of these compounds in the development of improved therapy for brain cancer.

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Transient receptor potential (TRP) channels are one primary type of calcium (Ca2+) permeable channels, and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems. Nowadays, however, accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression, inducing tumor invasion and metastasis. However, the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive. Therefore, in this review, we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance (MDR), metastasis, apoptosis, proliferation, immune surveillance evasion, and the alterations of relevant tumor micro-environment. Moreover, we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors' efficacy. The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented. Furthermore, it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.

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Cardiometabolic disease (CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids (BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor (FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.

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BACKGROUND: Uncontrolled inflammation causes health problems. Extracellular signal-regulated kinase (ERK) phosphorylates signal transducer and activator of transcription 3 (STAT3) at Ser727, resulting in inflammation. The leaf of Vernonia amygdalina (VA) is a medicinal herb for managing inflammation-associated diseases. Oral administration or topical application of VA leaf extract exerts anti-inflammatory effects in rat models. However, the anti-inflammatory mechanisms of the herb are not fully understood. PURPOSE: In this study, we aimed to investigate the involvement of ERK/STAT3 (Ser727) signaling in the anti-inflammatory effects of an ethanolic extract of VA leaves. STUDY DESIGN AND METHODS: Extracts of VA leaves were prepared with different concentrations of ethanol. A LPS-stimulated RAW264.7 cell model was used for in vitro assays, and a TPA (12-O-tetradecanoylphorbol-13-acetate)-induced ear edema mouse model was employed for in vivo assays. The 95% ethanol extract of VA leaves (VAE) exerted the strongest inhibitory effect on nitric oxide (NO) production in LPS-stimulated macrophages; thus it was selected for use in this study. Hematoxylin and eosin (H&E) staining was used to examine pathological conditions of mouse ear tissues. Griess reagent was employed to examine NO generation in cell cultures. Immunoblotting and ELISA were used to examine protein levels, and RT-qPCR was employed to examine mRNA levels. RESULTS: Topical application of VAE ameliorated mouse ear edema induced by TPA. VAE suppressed the phosphorylation of ERK (Thr202/Tyr204) and STAT3 (Ser727); and decreased protein levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-6, IL-1ß and tumor necrosis factor-α (TNF-α) in the mouse ear tissues and in LPS-stimulated RAW 264.7 cells. VAE also inhibited NO production, and lowered mRNA levels of IL-6, IL-1ß and TNF-α in the macrophages. CONCLUSIONS: VAE ameliorates TPA-induced mouse ear edema. Suppression of ERK/STAT3 (Ser727) signaling is involved in VAE's anti-inflammatory effects. These novel data provide further pharmacological justifications for the medicinal use of VA in treating inflammation-associated diseases, and lay the groundwork for developing VAE into a new anti-inflammatory agent.

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Rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors have revolutionized melanoma treatment. Approximately half of patients with melanoma harbor a BRAF gene mutation with subsequent dysregulation of the RAF-MEK-ERK signaling pathway. Targeting this pathway with BRAF and MEK blockade results in control of cell proliferation and, in most cases, disease control. These pathways also have cardioprotective effects and are necessary for normal vascular and cardiac physiology. BRAF and MEK inhibitors are associated with adverse cardiovascular effects including hypertension, left ventricular dysfunction, venous thromboembolism, atrial arrhythmia, and electrocardiographic QT interval prolongation. These effects may be underestimated in clinical trials. Baseline cardiovascular assessment and follow-up, including serial imaging and blood pressure assessment, are essential to balance optimal anti-cancer therapy while minimizing cardiovascular side effects. In this review, an overview of BRAF/MEK inhibitor-induced cardiovascular toxicity, the mechanisms underlying these, and strategies for surveillance, prevention, and treatment of these effects are provided.

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A water-soluble heteropolysaccharide (SGP2-1) was purified from Suillus granulatus fruiting bodies by anion-exchange chromatography and gel permeation chromatography. The structural characteristics were analyzed by high-performance gel permeation chromatography, high-performance liquid chromatography, Fourier transform infrared spectroscopy, gas chromatography-mass spectrometry, and nuclear magnetic resonance spectroscopy. The immunostimulatory activity was investigated using RAW 264.7 macrophages. Results showed that SGP2-1 with weight average molecular weight of 150.75 kDa was composed of mannose, glucose, and xylose. The backbone of SGP2-1 was mainly composed of â†’ 4)-α-Glcp-(1→, and the terminal group α-d-Glcp â†’ was linked to the main chain by O-6 position. SGP2-1 could significantly enhance pinocytic capacity, reactive oxygen species production, and cytokines secretion. SGP2-1 exerted immunomodulatory effects through interacting with toll-like receptor 2, and activating mitogen-activated protein kinase, phosphatidylinositol-3-kinase/protein kinase B, and nuclear factor-kappa B signaling pathways. These findings indicated that SGP2-1 could be explored as a potential immunomodulatory agent for application in functional foods.

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Cutaneous squamous cell carcinoma is a common skin cancer that is responsible for 1,000,000 cases and up to 9,000 deaths annually in the United States. Metastases occur in 2-5% of patients and are responsible for significant morbidity and mortality. The objective of this study is to perform targeted next-generation sequencing on a cohort of squamous cell carcinoma primary tumors and patient-matched lymph node metastases. An oncology 76-gene panel was run from formalin-fixed paraffin-embedded samples of patient-matched primary squamous cell carcinomas (10) and resultant metastases (10). ALK was discovered to be a driver mutation in metastases using two different algorithms, oncoCLUSTand dNdScv. Mutational concordance between primary tumors and metastases was notably lower in immunosuppressed patients, especially among pathogenic mutations (41.7% vs. 83.3%, P = 0.01). Sequencing of matched squamous cell carcinoma primary tumors and lymph node metastases identified genes and pathways that may have clinical importance, most notably ALK as a potential driver mutation of metastasis. Sequencing of both primary tumors and metastases may improve the efficacy of targeted therapies.

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Hepatocellular carcinoma (HCC) is an aggressive human cancer with increasing incidence worldwide. Multiple efforts have been made to explore pharmaceutical therapies to treat HCC, such as targeted tyrosine kinase inhibitors, immune based therapies and combination of chemotherapy. However, limitations exist in current strategies including chemoresistance for instance. Tumor initiation and progression is driven by reprogramming of metabolism, in particular during HCC development. Recently, metabolic associated fatty liver disease (MAFLD), a reappraisal of new nomenclature for non-alcoholic fatty liver disease (NAFLD), indicates growing appreciation of metabolism in the pathogenesis of liver disease, including HCC, thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment. In this review, we introduce directions by highlighting the metabolic targets in glucose, fatty acid, amino acid and glutamine metabolism, which are suitable for HCC pharmaceutical intervention. We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment. Furthermore, opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

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Introduction: Activation of T cell receptor (TCR) signaling is critical for clonal expansion of CD8+ T cells. However, the effects of augmenting TCR signaling during chronic antigen exposure is less understood. Here, we investigated the role of diacylglycerol (DAG)-mediated signaling downstream of the TCR during chronic lymphocytic choriomeningitis virus clone 13 (LCMV CL13) infection by blocking DAG kinase zeta (DGKζ), a negative regulator of DAG. Methods: We examined the activation, survival, expansion, and phenotype of virus-specific T cell in the acute and chronic phases of LCMV CL13-infected in mice after DGKζ blockade or selective activation of ERK. Results: Upon LCMV CL13 infection, DGKζ deficiency promoted early short-lived effector cell (SLEC) differentiation of LCMV-specific CD8+ T cells, but this was followed by abrupt cell death. Short-term inhibition of DGKζ with ASP1570, a DGKζ-selective pharmacological inhibitor, augmented CD8+ T cell activation without causing cell death, which reduced virus titers both in the acute and chronic phases of LCMV CL13 infection. Unexpectedly, the selective enhancement of ERK, one key signaling pathway downstream of DAG, lowered viral titers and promoted expansion, survival, and a memory phenotype of LCMV-specific CD8+ T cells in the acute phase with fewer exhausted T cells in the chronic phase. The difference seen between DGKζ deficiency and selective ERK enhancement could be potentially explained by the activation of the AKT/mTOR pathway by DGKζ deficiency, since the mTOR inhibitor rapamycin rescued the abrupt cell death seen in virus-specific DGKζ KO CD8+ T cells. Discussion: Thus, while ERK is downstream of DAG signaling, the two pathways lead to distinct outcomes in the context of chronic CD8+ T cell activation, whereby DAG promotes SLEC differentiation and ERK promotes a memory phenotype.

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There is no doubt that cell signaling manipulation is a key strategy for anticancer therapy. Furthermore, cell state determines drug response. Thus, establishing the relationship between cell state and therapeutic sensitivity is essential for the development of cancer therapies. In the era of personalized medicine, the use of patient-derived ex vivo cell models is a promising approach in the translation of key research findings into clinics. Here, we were focused on the non-oncogene dependencies of cell resistance to anticancer treatments. Signaling-related mechanisms of response to inhibitors of MEK/ERK and PI3K/AKT pathways (regulators of key cellular functions) were investigated using a panel of patients' lung tumor-derived cell lines with various stemness- and EMT-related markers, varying degrees of ERK1/2 and AKT phosphorylation, and response to anticancer treatment. The study of interactions between kinases was the goal of our research. Although MEK/ERK and PI3K/AKT interactions are thought to be cell line-specific, where oncogenic mutations have a decisive role, we demonstrated negative feedback loops between MEK/ERK and PI3K/AKT signaling pathways in all cell lines studied, regardless of genotype and phenotype differences. Our work showed that various and distinct inhibitors of ERK signaling - selumetinib, trametinib, and SCH772984 - increased AKT phosphorylation, and conversely, inhibitors of AKT - capivasertib, idelalisib, and AKT inhibitor VIII - increased ERK phosphorylation in both control and cisplatin-treated cells. Interaction between kinases, however, was dependent on cellular state. The feedback between ERK and AKT was attenuated by the focal adhesion kinase inhibitor PF573228, and in cells grown in suspension, showing the possible role of extracellular contacts in the regulation of crosstalk between kinases. Moreover, studies have shown that the interplay between MEK/ERK and PI3K/AKT signaling pathways may be dependent on the strength of the chemotherapeutic stimulus. The study highlights the importance of spatial location of the cells and the strength of the treatment during anticancer therapy.

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Neuroinflammation causes various neurological disorders, including depression and neurodegenerative diseases. Therefore, regulation of neuroinflammation is a promising therapeutic strategy for inflammation-related neurological disorders. This study aimed to investigate whether yomogin, isolated from Artemisia iwayomogi, has anti-neuroinflammatory effects. First, we evaluated the effects of yomogin by assessing pro-inflammatory mediators and cytokines in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The results showed that yomogin inhibited the increase in neuroinflammatory factors, including nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6, and tumor necrosis factor-α, and suppressed phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase and p38, which participate in the mitogen-activated protein kinase (MAPK) pathway. To confirm these effects in vivo, we measured the activation of astrocyte and microglia in LPS-injected mouse brains. Results showed that yomogin treatment decreased astrocyte and microglia activations. Collectively, these results suggest that yomogin suppresses neuroinflammation by regulating the MAPK pathway and it could be a potential candidate for inflammation-mediated neurological diseases.

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Peroxisome proliferator-activated receptor (PPAR) α is widely expressed in the vasculature and has pleiotropic and lipid-lowering independent effects, but its role in the growth and function of vascular smooth muscle cells (VSMCs) during vascular pathophysiology is still unclear. Herein, VSMC-specific PPARα-deficient mice (Ppara ΔSMC) were generated by Cre-LoxP site-specific recombinase technology and VSMCs were isolated from mice aorta. PPARα deficiency attenuated VSMC apoptosis induced by angiotensin (Ang) II and hydrogen peroxide, and increased the migration of Ang II-challenged cells.

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The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) patients has been claimed as associated with the risk of COVID-19 infection and its subsequent morbidities and mortalities. These claims were resulting from the possibility of upregulating the expression of angiotensin-converting enzyme 2 (ACE2), facilitation of SARS-CoV-2 entry, and increasing the susceptibility of infection in such treated cardiovascular patients. ACE2 and renin-angiotensin-aldosterone system (RAAS) products have a critical function in controlling the severity of lung injury, fibrosis, and failure following the initiation of the disease. This review is to clarify the mechanisms beyond the possible deleterious effects of angiotensin II (Ang II), and the potential protective role of angiotensin 1-7 (Ang 1-7) against pulmonary fibrosis, with a subsequent discussion of the latest updates on ACEIs/ARBs use and COVID-19 susceptibility in the light of these mechanisms and biochemical explanation.

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All physiological events in living organisms originated as specific chemical/biochemical signals on the cell surface and transmitted into the cytoplasm. This signal is translated within milliseconds-hours to a specific and unique order required to maintain optimum performance and homeostasis of living organisms. Examples of daily biological functions include neuronal communication and neurotransmission in the process of learning and memory, secretion (hormones, sweat, and saliva), muscle contraction, cellular growth, differentiation and migration during wound healing, and immunity to fight infections. Among the different transducers for such life-dependent signals is the large family of G protein-coupled receptors (GPCRs). GPCRs constitute roughly 800 genes, corresponding to 2% of the human genome. While GPCRs control a plethora of pathophysiological disorders, only approximately one-third of GPCR families have been deorphanized and characterized. Recent drug data show that around 40% of the recommended drugs available in the market target mainly GPCRs. In this review, we presented how such system signals, either through G protein or via other players, independent of G protein, function within the biological system. We also discussed drugs in the market or clinical trials targeting mainly GPCRs in various diseases, including cancer.