Molecular Targets of Valeric Acid: A Bioactive Natural Product for Endocrine, Metabolic, and Immunological Disorders.

BACKGROUNDS: Postbiotics produced by gut microbiota have exhibited diverse pharmacological activities. Valeric acid, a postbiotic material produced by gut microbiota and some plant species like valerian, has been explored to have diverse pharmacological activities. METHODS: This narrative review aims to summarise the beneficial role of valeric acid for different health conditions along with its underlying mechanism. In order to get ample scientific evidence, various databases like Science Direct, PubMed, Scopus, Google Scholar and Google were exhaustively explored to collect relevant information. Collected data were arranged and analyzed to reach meaningful a conclusion regarding the bioactivity profiling of valeric acid, its mechanism, and future prospects. RESULTS: Valeric acid belongs to short-chain fatty acids (SCFAs) compounds like acetate, propionate, butyrate, pentanoic (valeric) acid, and hexanoic (caproic) acid. Valeric acid has been identified as one of the potent histone deacetylase (HDAC) inhibitors. In different preclinical in -vitro and in-vivo studies, valeric acid has been found to have anti-cancer, anti-diabetic, antihypertensive, anti-inflammatory, and immunomodulatory activity and affects molecular pathways of different diseases like Alzheimer's, Parkinson's, and epilepsy. CONCLUSION: These findings highlight the role of valeric acid as a potential novel therapeutic agent for endocrine, metabolic and immunity-related health conditions, and it must be tested under clinical conditions to develop as a promising drug.

Design, synthesis, molecular docking and pharmacological evaluation of some thiadiazole based nipecotic acid derivatives as a potential anticonvulsant and antidepressant agents.

In our continuous effort to develop novel antiepileptic drug, a new series of nipecotic acid derivatives having1,3,4-thiadiazole nucleus were designed and synthesized. This study aims to improve the lipophilicity of nipecotic acid by attaching some lipophilic anchors like thiadiazole and substituted aryl acid derivatives. In our previous study, we noticed that the N-substituted oxadiazole derivative of nipecotic acid exhibited significant antiepileptic activity in the rodent model. The synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, Mass, and elemental analysis. The anticonvulsant activity was evaluated by using the maximal electroshock-induced seizure model in rats (MES) and the subcutaneous pentylenetetrazol (scPTZ) test in mice. None of the compounds were found to be active in the MES model whereas compounds (TN2, TN9, TN12, TN13, and TN15) produced significant protection against the scPTZ-induced seizures model. The compounds showing antiepileptic activity were additionally evaluated for antidepressant activity by using the forced swim test, 5-hydroxytryptophan (5-HTP)-induced head twitch test, and learned helplessness test. All the molecules that showed anticonvulsant activity (TN2, TN9, TN12, TN13, and TN15), also exerted significant antidepressant effects in the animal models. The selected compounds were subjected to different toxicity studies. Compounds were found to have no neurotoxicity in the rota-rod test and devoid of hepatic and renal toxicity in 30 days repeated oral toxicity test. Further, a homology model was developed to perform the in-silico molecular docking and dynamics studies which revealed the similar binding of compound TN9 within the active binding pocket and were found to be the most potent anti-epileptic agent. The market expectation for newly developed antiepileptic thiadiazole-based nipecotic acid derivatives is significant, driven by their potential to offer improved therapeutic outcomes and reduced side effects, addressing a critical need in epilepsy treatment. These innovative compounds hold promise for meeting the demand for more effective and safer antiepileptic medications. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03897-1.

Efficacy of Different Volumes of 0.2% Ropivacaine in Suprainguinal Fascia Iliaca Compartment Block for Multimodal Analgesia in Lower Limb Surgery.

Background Ultrasound-guided (USG) suprainguinal fascia iliaca (SIFI) block is being used widely for post-operative analgesia in patients undergoing hip and femur surgeries. However, the optimal volume of local anesthetic required for SIFI block is not well defined. Thus, we compared different volumes of 0.2% ropivacaine in SIFI for post-operative pain relief in lower limb surgeries. Material and methods A total of 90 patients undergoing hip and femur surgeries were randomly allocated into three groups: A, B, and C, who received USG SIFI block with 20 mL, 30 mL, and 40 mL of 0.2% ropivacaine, respectively. Intravenous tramadol was used as rescue analgesia when the numeric rating scale (NRS) score exceeded 3. Time to first request of rescue analgesic was the primary outcome. NRS scores in the first 24 hours post-operatively, total amount of tramadol consumption in 24 hours, and patient satisfaction with pain management were secondary outcomes. Results The time to first request to rescue analgesic was significantly longer in group B and group C as compared to group A. NRS scores were significantly reduced in group B and group C than group A in the 24-hour post-operative period. Median 24-hour tramadol consumption was significantly less in group C as compared to group A and group B. Patient satisfaction with pain management was better with group B and group C as compared to group A. Conclusion In comparison to 20 mL of 0.2% ropivacaine, 30 mL and 40 mL of 0.2% ropivacaine in SIFI compartment block are more efficacious in reducing post-operative pain after hip and lower limb surgeries.

Computational systems biology approach for permanent tumor elimination and normal tissue protection using negative biasing: Experimental validation in malignant melanoma as case study.

Complete spontaneous tumor regression (without treatment) is well documented to occur in animals and humans as epidemiological analysis show, whereby the malignancy is permanently eliminated. We have developed a novel computational systems biology model for this unique phenomenon to furnish insight into the possibility of therapeutically replicating such regression processes on tumors clinically, without toxic side effects. We have formulated oncological informatics approach using cell-kinetics coupled differential equations while protecting normal tissue. We investigated three main tumor-lysis components: (ⅰ) DNA blockade factors, (ⅱ) Interleukin-2 (IL-2), and (ⅲ) Cytotoxic T-cells (CD8+ T). We studied the temporal variations of these factors, utilizing preclinical experimental investigations on malignant tumors, using mammalian melanoma microarray and histiocytoma immunochemical assessment. We found that permanent tumor regression can occur by: 1) Negative-Bias shift in population trajectory of tumor cells, eradicating them under first-order asymptotic kinetics, and 2) Temporal alteration in the three antitumor components (DNA replication-blockade, Antitumor T-lymphocyte, IL-2), which are respectively characterized by the following patterns: (a) Unimodal Inverted-U function, (b) Bimodal M-function, (c) Stationary-step function. These provide a time-wise orchestrated tri-phasic cytotoxic profile. We have also elucidated gene-expression levels corresponding to the above three components: (ⅰ) DNA-damage G2/M checkpoint regulation [genes: CDC2-CHEK], (ⅱ) Chemokine signaling: IL-2/15 [genes: IL2RG-IKT3], (ⅲ) T-lymphocyte signaling (genes: TRGV5-CD28). All three components quantitatively followed the same activation profiles predicted by our computational model (Smirnov-Kolmogorov statistical test satisfied, α = 5%). We have shown that the genes CASP7-GZMB are signatures of Negative-bias dynamics, enabling eradication of the residual tumor. Using the negative-biasing principle, we have furnished the dose-time profile of equivalent therapeutic agents (DNA-alkylator, IL-2, T-cell input) so that melanoma tumor may therapeutically undergo permanent extinction by replicating the spontaneous tumor regression dynamics.

A mechanistic analysis of spontaneous cancer remission phenomenon: identification of genomic basis and effector biomolecules for therapeutic applicability.

Based on the well-documented studies, numerous tumors episodically regress permanently without treatment. Knowing the host tissue-initiated causative factors would offer considerable translational applicability, as a permanent regression process may be therapeutically replicated on patients. For this, we developed a systems biological formulation of the regression process with experimental verification and identified the relevant candidate biomolecules for therapeutic utility. We devised a cellular kinetics-based quantitative model of tumor extinction in terms of the temporal behavior of three main tumor-lysis entities: DNA blockade factor, cytotoxic T-lymphocyte and interleukin-2. As a case study, we analyzed the time-wise biopsy and microarrays of spontaneously regressing melanoma and fibrosarcoma tumors in mammalian/human hosts. We analyzed the differentially expressed genes (DEGs), signaling pathways, and bioinformatics framework of regression. Additionally, prospective biomolecules that could cause complete tumor regression were investigated. The tumor regression process follows a first-order cellular dynamics with a small negative bias, as verified by experimental fibrosarcoma regression; the bias is necessary to eliminate the residual tumor. We identified 176 upregulated and 116 downregulated DEGs, and enrichment analysis showed that the most significant were downregulated cell-division genes: TOP2A-KIF20A-KIF23-CDK1-CCNB1. Moreover, Topoisomerase-IIA inhibition might actuate spontaneous regression, with collateral confirmation provided from survival and genomic analysis of melanoma patients. Candidate molecules such as Dexrazoxane/Mitoxantrone, with interleukin-2 and antitumor lymphocytes, may potentially replicate permanent tumor regression process of melanoma. To conclude, episodic permanent tumor regression is a unique biological reversal process of malignant progression, and signaling pathway understanding, with candidate biomolecules, may plausibly therapeutically replicate the regression process on tumors clinically. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03515-0.

A low-cost, wearable sEMG sensor for upper limb prosthetic application.

This paper proposes a low-cost and sensitive surface electromyography (sEMG) sensor for the myoelectric prosthesis. The sensor consists of a skin interface, signal conditioning circuitry and power supply unit all encased in a single package. The tuned RC parameters based envelope detection scheme employed in the sensor enables faster as well as reliable recognition of EMG signal patterns regardless of its strength and subject variability. The output performance of the developed sensor was compared with a commercial EMG sensor regarding signal-to-noise ratio (SNR), amplitude sensitivity and response time. EMG signals with both the devices were acquired for 10 subjects (three amputees and seven healthy subjects), to perform this comparative analysis. The results showed 4× greater SNR values and 50% higher sensitivity of the developed sensor than the commercial EMG sensor. Also, the proposed sensor was 57% faster than the commercial sensor in producing the output response. The sensor was successfully tested on amputees for controlling a 3D printed hand prototype utilising a proportional control strategy. The enhanced output parameters of the sensor were responsible for smooth, faster and intuitive actuation of the prosthetic hand fingers.