Prostaglandins (PGs) are oxygenated derivatives of arachidonic acid, synthesized through sequential catalysis involving cyclooxygenase (COX) and PG terminal synthases. Of the two COX enzymes, COX-2 is induced by inflammatory and pro-carcinogenic stimuli and it not only promotes inflammatory reactions but it also plays a role in the development of various tumors. Nonsteroidal anti-inflammatory drugs (NSAIDs), which suppress inflammatory responses by inhibiting COX, have also been reported to suppress carcinogenesis in the colon. However, long-term use of NSAIDs for the prevention of cancer causes several side-effects; therefore, an alternative COX target is required. In this review, the role of PG synthases that are produced downstream of COX in carcinogenesis will be explained and novel drug targets to inhibit carcinogenesis will be discussed. Microsomal PGE synthase (mPGES)-1 and prostacyclin synthase (PGIS), which are coupled with COX-2 to generate PGE₂ and PGI₂, respectively, promote inflammation. In mPGES-1 knock-out mice, carcinogenesis in the colon, skin, and bladder were suppressed. As mPGES-1 deficiency does not result in abnormalities, mPGES-1 inhibitors are expected to be promising alternatives to NSAIDs for the suppression of cancer. On the other hand, it has been reported that PGIS suppresses colon cancer, suggesting that it has an opposite role to mPGES-1 in carcinogenesis in the colon. However, PGIS not affect carcinogenesis in the skin. These results suggest that PGIS has differential effects on carcinogenesis in different tissues.

Fibromyalgia (FM) is a chronic disorder characterized by widespread pain and various accompanying symptoms, with complex mechanisms involving both peripheral and central nervous systems that remain unclear. Herein, we introduce a study employing a reserpine-induced rat model of FM, investigating the spinal dorsal horn in particular. In reserpine-induced FM model rats, we observed pronounced mechanical hypersensitivity of cutaneous and muscular C-fiber nociceptors. Moreover, increased expression of the ASIC3 (one of acid-sensing ion channel) in dorsal root ganglia implicated its role in peripheral sensitization. Within the spinal dorsal horn, enhanced microglial activation was evident; pharmacological inhibition with minocycline significantly attenuated mechanical hyperalgesia, indicating the critical involvement of microglial activity in central pain processing. Furthermore, patch-clamp recordings revealed altered synaptic transmission characterized by enhanced spontaneous excitatory postsynaptic currents (EPSCs) and reduced inhibitory postsynaptic currents (IPSCs), contributing to heightened pain signaling in the FM model. These findings suggest that an imbalance of intensified excitatory and diminished inhibitory neurotransmission in the spinal dorsal horn leads to impaired sensory gating and augmented nociceptive transmission to higher centers, a pivotal mechanism in the pathophysiology of FM.

Synaptic plasticity is a key mechanism underlying long-term memory and learning, with proposed associations with altered actin cytoskeleton and gene expression in neurons. Myocardin-related transcription factor (MRTF) family members, abundantly expressed in the brain, have actin-binding motifs at the N-terminus and act as cofactors of serum response factor (SRF). Rho signaling may promote MRTF’s release from G-actin and subsequent translocation into the nucleus, and increases SRF-dependent gene expression. MRTF is therefore thought to act as a link between morphological change and gene expression in neurons. In this review, we focus on the neurotrophin, brain-derived neurotrophic factor (BDNF). BDNF plays crucial roles in neuronal survival, gene expression, and dendritic growth, which are essential for neuronal plasticity. As previous studies suggest that BDNF triggers the activation of MRTF/SRF-mediated signal transduction, we have studied how this supposed regulatory ligand is involved in the functional MRTF changes in neurons. We review the BDNF-mediated roles of MRTF in neuronal morphology and gene expression and briefly discuss the possible involvement of MRTF in neurodevelopmental disorders, such as autism spectrum disorder and intellectual disability.

Emerging and reemerging viral infections, such as the dengue virus (DENV), continue to cause public health concerns, affecting millions of people worldwide annually. The recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak resulted in significant morbidity and mortality worldwide, seriously impacting human health and the global economy. Given the lack of effective and specific therapeutics against most emerging or reemerging viruses, the development of effective therapeutic measures against such viruses is urgently needed. Most RNA viruses have RNA-dependent RNA polymerase (RdRp), which is indispensable for the replication and transcription of viral genomes. Moreover, the core structural features of viral RdRps are functionally essential and conserved across a wide range of viruses. Thus, viral RdRp serves as a promising target for broad-spectrum antivirals. In this study, we screened nucleoside analogues from a compound library of Hokkaido University, identifying 2-thiouridine (s2U) as a broad-spectrum antiviral ribonucleoside analogue. In particular, s2U exhibited potent antiviral activity against several positive-strand RNA [ssRNA(+)] viruses, including orthoflaviviruses such as DENV and coronaviruses such as SARS-CoV-2. s2U inhibited RNA synthesis catalyzed by viral RdRp, thereby reducing viral RNA replication and improving the survival rate of mice challenged with lethal DENV2 or SARS-CoV-2 in our animal models. In addition to the potent antiviral activities in vitro and in vivo, s2U exhibited no significant toxicity, suggesting its potential as a broad-spectrum antiviral agent against ssRNA(+) viruses, including orthoflaviviruses and coronaviruses.

The cytokine interleukin 6 (IL-6) has redundant biological activities in regulating the proliferation, differentiation, and function of various cell types. IL-6 regulates inflammation, immune responses, and hematopoiesis, as well as homeostasis of the nervous, renal, hormonal, and bone systems. IL-6 is also involved in tumorigenesis, including myeloma cell growth. The janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is one of the key IL-6 signals both in normal and pathological conditions. In particular, STAT3 plays essential roles in mediating IL-6 signals, and its dysregulation can induce cancer and/or autoimmune diseases. In addition to biological and molecular mechanisms of IL-6-mediated signals, we have identified STAT3-interacting proteins, which regulate STAT3-mediated signals at various steps and mediate crosstalk between STAT3 and other intracellular signaling pathways. This review focuses on tyrosine kinase 2 (TYK2) and signal-transducing adapter protein-2 (STAP-2), followed by their potential as therapeutic targets in the development of novel treatments.

Thymic stromal lymphopoietin (TSLP) is a key cytokine produced primarily by epithelial cells that induces a Th2-type immune response. We have studied the regulation of TSLP production by low-molecular-weight compounds and proposed their use as immunoregulators. Several compounds, including xylene, nonanoic acid, and valeric acid, induce TSLP production. Painting mouse skin with xylene enhanced ovalbumin-specific immunoglobulin E (IgE) production, indicating that environmental pollutants that induce TSLP production may enhance the evocation of allergic responses. By contrast, retinoic acid, which strongly induces TSLP production, can enhance immunoglobulin G (IgG) production against influenza HA antigen in mice, indicating that TSLP inducers can serve as chemical adjuvants. During our analyses of the regulation of TSLP expression, we found that TSLP production was reduced under hypoxic conditions in response to increased hypoxia inducible factor (HIF)-1 levels. We also found that HIF proline hydroxylase inhibitors, which stabilize HIF-1, can inhibit TSLP production, and identified a novel TSLP production inhibitor in a chemical library screen. This compound inhibits TSLP production in vitro and in vivo. The target of this inhibitors a bromodomain and extraterminal (BET) family protein. BET family proteins are thus potential therapeutic targets for allergic diseases. In conclusion, TSLP is a unique cytokine produced by epithelial cells that is regulated with low-molecular-weight compounds. Regulators of TSLP production by epithelial cells may serve as novel antiallergic drugs and/or chemical adjuvants.

Lansoprazole is a proton pump inhibitor (PPI), frequently used for the treatment of gastroesophageal reflux disease. It may also be used in pregnant women; however, the safety of lansoprazole exposure during pregnancy remains unclear. In this study, we assessed the risk of major malformation and the effects on other pregnancy and birth outcomes resulting from lansoprazole exposure during the first trimester based on data from two Japanese facilities that provided counseling on drug use during pregnancy between 1988 and 2017. The study included 106 cases of lansoprazole exposure and 1788 control individuals. The risk of major malformation following exposure to lansoprazole after the first trimester was compared with that of the control group administered non-teratogenic drugs during the first trimester. The incidence of major malformation in singleton liveborn infants was 1.0% (1/96) in the lansoprazole group and 1.9% (31/1670) in the control group. Adjusted multivariable logistic regression analysis revealed no significant difference in the incidence between the control and lansoprazole groups [adjusted OR: 0.51 (95% confidence interval: 0.07–3.79), p=0.507]. Furthermore, no differences were observed between the two groups in the incidence of stillbirth, miscarriage, and birth weight. The results indicate that lansoprazole exposure during the first trimester is not associated with an increased risk of major malformations. Overall, our findings provide valuable insight for selecting gastroesophageal reflux disease medications for use in pregnant women.

The angiotensin system participates in regulation of neuronal activity in the central and peripheral nervous systems, in addition to its role in the control of cardiovascular functions and fluid balance. A fundamental study employing laboratory animals and retrospective analysis of hospitals’ medical records have recently suggested that treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II AT₁ receptor blockers (ARBs) reduces the development of diabetic peripheral neuropathy (DPN) accompanying type 2 diabetes. To validate this novel notion, we conducted a retrospective cohort study, using pharmacy claims data obtained from 148 branches of a chain pharmacy. Of 8188 older people with type 2 diabetes, 6093 underwent antihypertensive pharmacotherapy. The proportion of individuals receiving anti-DPN agents or antiplatelet agents was significantly greater in the antihypertensive agent-treated group than the untreated group. After some confounding factors were balanced between the anti-DPN agent-treated and untreated patients by a propensity score matching, multivariate logistic analyses indicated significant negative association of prescription of ACEIs and ARBs (adjusted odds ratios were 0.54 [95% confidence interval, 0.33–0.89] and 0.75 [0.59–0.96], respectively), but not the other antihypertensive agents, with intake of anti-DPN agents. On the other hand, prescription of most antihypertensive agents including ACEIs and ARBs was positively associated with intake of antiplatelet agents, when analyzed in the same manner. These data suggest that the angiotensin system inhibition reduces DPN development in older diabetic patients, while the onset of hypertension, as indicated by prescription of antihypertensive agents, promotes arterial circulatory disturbance, as indicated by prescription of antiplatelet agents.

The General Tests 〈2.66〉 Elemental Impurities section was newly included in the 18th edition of the Japanese Pharmacopoeia to support the transition from the conventional simultaneous control of elements in drug products via colorimetric methods to the individual control of elemental impurities via instrumental analyses. This shift enables a more appropriate form of control that considers the toxicological risks of each element. Although the control method outlined in 〈2.66〉 does not apply to crude drugs, we herein investigated its applicability to crude drugs and Kampo Extracts to understand the risks of elemental impurities further. Based on the principles in 〈2.66〉, the quantities of seven elements [cadmium (Cd), lead (Pb), arsenic (As), mercury (Hg), cobalt (Co), vanadium (V), and nickel (Ni)]—classified as Class 1 and 2A elemental impurities that require a thorough risk assessment—were measured. Ten crude drugs, whose medicinal parts are roots and rhizomes (which are more likely than other parts to accumulate elements from the soil), and twelve Kampo Extracts containing these crude drugs were tested via validation of the analytical methods. We consider that the procedures of Elemental Impurities described in 〈2.66〉 can be applied to the herbal medicines and Kampo Extracts examined in this study. However, considering the administration route of crude drugs and their products, controlling the elemental concentrations as per the permitted concentrations is challenging; instead, the elements should be controlled individually in Official Monographs considering actual measured contents.